Federal Practitioner

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further clinical data continue to show benefit from preoperative treatment with the immune checkpoint inhibitor nivolumab (Opdivo) with chemotherapy.

The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.

Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.

“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.

The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.

Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”

“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”

Importance of Neoadjuvant Immunotherapy

New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.

Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).

In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).

Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.

“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
 

Neoadjuvant slow to catch on

About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.

Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.

The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.

In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.

In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.

“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”

Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.

“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
 

Fears of delaying surgery

In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.

“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”

In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
 

CheckMate 816 details

In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.

After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.

At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.

Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.

In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.

The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.

The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.

Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.

CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

A version of this article first appeared on Medscape.com.

Extraverts and individuals who are disciplined are less likely to experience cognitive decline later in life, whereas those with neuroticism have an increased risk for cognitive dysfunction, new research shows.

Investigators analyzed data from almost 2,000 individuals enrolled in the Rush Memory and Aging Project (MAP) – a longitudinal study of older adults living in the greater Chicago metropolitan region and northeastern Illinois – with recruitment that began in 1997 and continues through today. Participants received a personality assessment as well as annual assessments of their cognitive abilities.

Those with high scores on measures of conscientiousness were significantly less likely to progress from normal cognition to mild cognitive impairment (MCI) during the study. In fact, scoring an extra 1 standard deviation on the conscientiousness scale was associated with a 22% lower risk of transitioning from no cognitive impairment (NCI) to MCI. On the other hand, scoring an additional 1 SD on a neuroticism scale was associated with a 12% increased risk of transitioning to MCI.

Participants who scored high on extraversion, as well as those who scored high on conscientiousness or low on neuroticism, tended to maintain normal cognitive functioning longer than other participants.

“Personality traits reflect relatively enduring patterns of thinking and behaving, which may cumulatively affect engagement in healthy and unhealthy behaviors and thought patterns across the lifespan,” lead author Tomiko Yoneda, PhD, a postdoctoral researcher in the department of medical social sciences, Northwestern University, Chicago, said in an interview.

“The accumulation of lifelong experiences may then contribute to susceptibility of particular diseases or disorders, such as mild cognitive impairment, or contribute to individual differences in the ability to withstand age-related neurological changes,” she added.

The study was published online in the Journal of Personality and Social Psychology.
 

Competing risk factors

Personality traits “reflect an individual’s persistent patterns of thinking, feeling, and behaving,” Dr. Yoneda said.

“For example, conscientiousness is characterized by competence, dutifulness, and self-discipline, while neuroticism is characterized by anxiety, depressive symptoms, and emotional instability. Likewise, individuals high in extraversion tend to be enthusiastic, gregarious, talkative, and assertive,” she added.

Previous research “suggests that low conscientiousness and high neuroticism are associated with an increased risk of cognitive impairment,” she continued. However, “there is also an increased risk of death in older adulthood – in other words, these outcomes are ‘competing risk factors.’”

Dr. Yoneda said her team wanted to “examine the impact of personality traits on the simultaneous risk of transitioning to mild cognitive impairment, dementia, and death.”  

For the study, the researchers analyzed data from 1,954 participants in MAP (mean age at baseline 80 years, 73.7% female, 86.8% White), who received a personality assessment and annual assessments of their cognitive abilities.

To assess personality traits – in particular, conscientiousness, neuroticism, and extraversion – the researchers used the NEO Five Factor Inventory (NEO-FFI). They also used multistate survival modeling to examine the potential association between these traits and transitions from one cognitive status category to another (NCI, MCI, and dementia) and to death.
 

Cognitive healthspan

By the end of the study, over half of the sample (54%) had died.

Most transitions showed “relative stability in cognitive status across measurement occasions.”

• NCI to NCI (n = 7,368)
• MCI to MCI (n = 1,244)
• Dementia to dementia (n = 876)

There were 725 “backward transitions” from MCI to NCI, “which may reflect improvement or within-person variability in cognitive functioning, or learning effects,” the authors note.

There were only 114 “backward transitions” from dementia to MCI and only 12 from dementia to NCI, “suggesting that improvement in cognitive status was relatively rare, particularly once an individual progresses to dementia.”

After adjusting for demographics, depressive symptoms, and apolipoprotein (APOE) ε4 allele, the researchers found that personality traits were the most important factors in the transition from NCI to MCI.

Higher conscientiousness was associated with a decreased risk of transitioning from NCI to MCI (hazard ratio, 0.78; 95% confidence interval, 0.72-0.85). Conversely, higher neuroticism was associated with an increased risk of transitioning from NCI to MCI (HR, 1.12; 95% CI, 1.04-1.21) and a significantly decreased likelihood of transition back from MCI to NCI (HR, 0.90; 95% CI, 0.81-1.00).

Scoring ~6 points on a conscientiousness scale ranging from 0-48 (that is, 1 SD on the scale) was significantly associated with ~22% lower risk of transitioning forward from NCI to MCI, while scoring ~7 more points on a neuroticism scale (1 SD) was significantly associated with ~12% higher risk of transitioning from NCI to MCI.

Higher extraversion was associated with an increased likelihood of transitioning from MCI back to NCI (HR, 1.12; 95% CI, 1.03-1.22), and although extraversion was not associated with a longer total lifespan, participants who scored high on extraversion, as well as those who scored low on conscientiousness or low on neuroticism, maintained normal cognitive function longer than other participants.

“Our results suggest that high conscientiousness and low neuroticism may protect individuals against mild cognitive impairment,” said Dr. Yoneda.

Importantly, individuals who were either higher in conscientiousness, higher in extraversion, or lower in neuroticism had more years of “cognitive healthspan,” meaning more years without cognitive impairment,” she added.

In addition, “individuals lower in neuroticism and higher in extraversion were more likely to recover after receiving an MCI diagnosis, suggesting that these traits may be protective even after an individual starts to progress to dementia,” she said.

The authors note that the study focused on only three of the Big Five personality traits, while the other 2 – openness to experience and agreeableness – may also be associated with cognitive aging processes and mortality.

Nevertheless, given the current results, alongside extensive research in the personality field, aiming to increase conscientiousness through persistent behavioral change is one potential strategy for promoting healthy cognitive aging, Dr. Yoneda said.
 

‘Invaluable window’

In a comment, Brent Roberts, PhD, professor of psychology, University of Illinois Urbana-Champaign, said the study provides an “invaluable window into how personality affects the process of decline and either accelerates it, as in the role of neuroticism, or decelerates it, as in the role of conscientiousness.”

“I think the most fascinating finding was the fact that extraversion was related to transitioning from MCI back to NCI. These types of transitions have simply not been part of prior research, and it provides utterly unique insights and opportunities for interventions that may actually help people recover from a decline,” said Dr. Roberts, who was not involved in the research.

Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, called the paper “novel” because it investigated the transitions between normal cognition and mild impairment and between mild impairment and dementia.

Dr. Sexton, who was associated with this research team, cautioned that is it observational, “so it can illuminate associations or correlations, but not causes. As a result, we can’t say for sure what the mechanisms are behind these potential connections between personality and cognition, and more research is needed.”

The research was supported by the Alzheimer Society Research Program, Social Sciences and Humanities Research Council, and the National Institute on Aging of the National Institutes of Health. Dr. Yoneda and co-authors, Dr. Roberts, and Dr. Sexton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extraverts and individuals who are disciplined are less likely to experience cognitive decline later in life, whereas those with neuroticism have an increased risk for cognitive dysfunction, new research shows.

Investigators analyzed data from almost 2,000 individuals enrolled in the Rush Memory and Aging Project (MAP) – a longitudinal study of older adults living in the greater Chicago metropolitan region and northeastern Illinois – with recruitment that began in 1997 and continues through today. Participants received a personality assessment as well as annual assessments of their cognitive abilities.

Those with high scores on measures of conscientiousness were significantly less likely to progress from normal cognition to mild cognitive impairment (MCI) during the study. In fact, scoring an extra 1 standard deviation on the conscientiousness scale was associated with a 22% lower risk of transitioning from no cognitive impairment (NCI) to MCI. On the other hand, scoring an additional 1 SD on a neuroticism scale was associated with a 12% increased risk of transitioning to MCI.

Participants who scored high on extraversion, as well as those who scored high on conscientiousness or low on neuroticism, tended to maintain normal cognitive functioning longer than other participants.

“Personality traits reflect relatively enduring patterns of thinking and behaving, which may cumulatively affect engagement in healthy and unhealthy behaviors and thought patterns across the lifespan,” lead author Tomiko Yoneda, PhD, a postdoctoral researcher in the department of medical social sciences, Northwestern University, Chicago, said in an interview.

“The accumulation of lifelong experiences may then contribute to susceptibility of particular diseases or disorders, such as mild cognitive impairment, or contribute to individual differences in the ability to withstand age-related neurological changes,” she added.

The study was published online in the Journal of Personality and Social Psychology.
 

Competing risk factors

Personality traits “reflect an individual’s persistent patterns of thinking, feeling, and behaving,” Dr. Yoneda said.

“For example, conscientiousness is characterized by competence, dutifulness, and self-discipline, while neuroticism is characterized by anxiety, depressive symptoms, and emotional instability. Likewise, individuals high in extraversion tend to be enthusiastic, gregarious, talkative, and assertive,” she added.

Previous research “suggests that low conscientiousness and high neuroticism are associated with an increased risk of cognitive impairment,” she continued. However, “there is also an increased risk of death in older adulthood – in other words, these outcomes are ‘competing risk factors.’”

Dr. Yoneda said her team wanted to “examine the impact of personality traits on the simultaneous risk of transitioning to mild cognitive impairment, dementia, and death.”  

For the study, the researchers analyzed data from 1,954 participants in MAP (mean age at baseline 80 years, 73.7% female, 86.8% White), who received a personality assessment and annual assessments of their cognitive abilities.

To assess personality traits – in particular, conscientiousness, neuroticism, and extraversion – the researchers used the NEO Five Factor Inventory (NEO-FFI). They also used multistate survival modeling to examine the potential association between these traits and transitions from one cognitive status category to another (NCI, MCI, and dementia) and to death.
 

Cognitive healthspan

By the end of the study, over half of the sample (54%) had died.

Most transitions showed “relative stability in cognitive status across measurement occasions.”

• NCI to NCI (n = 7,368)
• MCI to MCI (n = 1,244)
• Dementia to dementia (n = 876)

There were 725 “backward transitions” from MCI to NCI, “which may reflect improvement or within-person variability in cognitive functioning, or learning effects,” the authors note.

There were only 114 “backward transitions” from dementia to MCI and only 12 from dementia to NCI, “suggesting that improvement in cognitive status was relatively rare, particularly once an individual progresses to dementia.”

After adjusting for demographics, depressive symptoms, and apolipoprotein (APOE) ε4 allele, the researchers found that personality traits were the most important factors in the transition from NCI to MCI.

Higher conscientiousness was associated with a decreased risk of transitioning from NCI to MCI (hazard ratio, 0.78; 95% confidence interval, 0.72-0.85). Conversely, higher neuroticism was associated with an increased risk of transitioning from NCI to MCI (HR, 1.12; 95% CI, 1.04-1.21) and a significantly decreased likelihood of transition back from MCI to NCI (HR, 0.90; 95% CI, 0.81-1.00).

Scoring ~6 points on a conscientiousness scale ranging from 0-48 (that is, 1 SD on the scale) was significantly associated with ~22% lower risk of transitioning forward from NCI to MCI, while scoring ~7 more points on a neuroticism scale (1 SD) was significantly associated with ~12% higher risk of transitioning from NCI to MCI.

Higher extraversion was associated with an increased likelihood of transitioning from MCI back to NCI (HR, 1.12; 95% CI, 1.03-1.22), and although extraversion was not associated with a longer total lifespan, participants who scored high on extraversion, as well as those who scored low on conscientiousness or low on neuroticism, maintained normal cognitive function longer than other participants.

“Our results suggest that high conscientiousness and low neuroticism may protect individuals against mild cognitive impairment,” said Dr. Yoneda.

Importantly, individuals who were either higher in conscientiousness, higher in extraversion, or lower in neuroticism had more years of “cognitive healthspan,” meaning more years without cognitive impairment,” she added.

In addition, “individuals lower in neuroticism and higher in extraversion were more likely to recover after receiving an MCI diagnosis, suggesting that these traits may be protective even after an individual starts to progress to dementia,” she said.

The authors note that the study focused on only three of the Big Five personality traits, while the other 2 – openness to experience and agreeableness – may also be associated with cognitive aging processes and mortality.

Nevertheless, given the current results, alongside extensive research in the personality field, aiming to increase conscientiousness through persistent behavioral change is one potential strategy for promoting healthy cognitive aging, Dr. Yoneda said.
 

‘Invaluable window’

In a comment, Brent Roberts, PhD, professor of psychology, University of Illinois Urbana-Champaign, said the study provides an “invaluable window into how personality affects the process of decline and either accelerates it, as in the role of neuroticism, or decelerates it, as in the role of conscientiousness.”

“I think the most fascinating finding was the fact that extraversion was related to transitioning from MCI back to NCI. These types of transitions have simply not been part of prior research, and it provides utterly unique insights and opportunities for interventions that may actually help people recover from a decline,” said Dr. Roberts, who was not involved in the research.

Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, called the paper “novel” because it investigated the transitions between normal cognition and mild impairment and between mild impairment and dementia.

Dr. Sexton, who was associated with this research team, cautioned that is it observational, “so it can illuminate associations or correlations, but not causes. As a result, we can’t say for sure what the mechanisms are behind these potential connections between personality and cognition, and more research is needed.”

The research was supported by the Alzheimer Society Research Program, Social Sciences and Humanities Research Council, and the National Institute on Aging of the National Institutes of Health. Dr. Yoneda and co-authors, Dr. Roberts, and Dr. Sexton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Extraverts and individuals who are disciplined are less likely to experience cognitive decline later in life, whereas those with neuroticism have an increased risk for cognitive dysfunction, new research shows.

Investigators analyzed data from almost 2,000 individuals enrolled in the Rush Memory and Aging Project (MAP) – a longitudinal study of older adults living in the greater Chicago metropolitan region and northeastern Illinois – with recruitment that began in 1997 and continues through today. Participants received a personality assessment as well as annual assessments of their cognitive abilities.

Those with high scores on measures of conscientiousness were significantly less likely to progress from normal cognition to mild cognitive impairment (MCI) during the study. In fact, scoring an extra 1 standard deviation on the conscientiousness scale was associated with a 22% lower risk of transitioning from no cognitive impairment (NCI) to MCI. On the other hand, scoring an additional 1 SD on a neuroticism scale was associated with a 12% increased risk of transitioning to MCI.

Participants who scored high on extraversion, as well as those who scored high on conscientiousness or low on neuroticism, tended to maintain normal cognitive functioning longer than other participants.

“Personality traits reflect relatively enduring patterns of thinking and behaving, which may cumulatively affect engagement in healthy and unhealthy behaviors and thought patterns across the lifespan,” lead author Tomiko Yoneda, PhD, a postdoctoral researcher in the department of medical social sciences, Northwestern University, Chicago, said in an interview.

“The accumulation of lifelong experiences may then contribute to susceptibility of particular diseases or disorders, such as mild cognitive impairment, or contribute to individual differences in the ability to withstand age-related neurological changes,” she added.

The study was published online in the Journal of Personality and Social Psychology.
 

Competing risk factors

Personality traits “reflect an individual’s persistent patterns of thinking, feeling, and behaving,” Dr. Yoneda said.

“For example, conscientiousness is characterized by competence, dutifulness, and self-discipline, while neuroticism is characterized by anxiety, depressive symptoms, and emotional instability. Likewise, individuals high in extraversion tend to be enthusiastic, gregarious, talkative, and assertive,” she added.

Previous research “suggests that low conscientiousness and high neuroticism are associated with an increased risk of cognitive impairment,” she continued. However, “there is also an increased risk of death in older adulthood – in other words, these outcomes are ‘competing risk factors.’”

Dr. Yoneda said her team wanted to “examine the impact of personality traits on the simultaneous risk of transitioning to mild cognitive impairment, dementia, and death.”  

For the study, the researchers analyzed data from 1,954 participants in MAP (mean age at baseline 80 years, 73.7% female, 86.8% White), who received a personality assessment and annual assessments of their cognitive abilities.

To assess personality traits – in particular, conscientiousness, neuroticism, and extraversion – the researchers used the NEO Five Factor Inventory (NEO-FFI). They also used multistate survival modeling to examine the potential association between these traits and transitions from one cognitive status category to another (NCI, MCI, and dementia) and to death.
 

Cognitive healthspan

By the end of the study, over half of the sample (54%) had died.

Most transitions showed “relative stability in cognitive status across measurement occasions.”

• NCI to NCI (n = 7,368)
• MCI to MCI (n = 1,244)
• Dementia to dementia (n = 876)

There were 725 “backward transitions” from MCI to NCI, “which may reflect improvement or within-person variability in cognitive functioning, or learning effects,” the authors note.

There were only 114 “backward transitions” from dementia to MCI and only 12 from dementia to NCI, “suggesting that improvement in cognitive status was relatively rare, particularly once an individual progresses to dementia.”

After adjusting for demographics, depressive symptoms, and apolipoprotein (APOE) ε4 allele, the researchers found that personality traits were the most important factors in the transition from NCI to MCI.

Higher conscientiousness was associated with a decreased risk of transitioning from NCI to MCI (hazard ratio, 0.78; 95% confidence interval, 0.72-0.85). Conversely, higher neuroticism was associated with an increased risk of transitioning from NCI to MCI (HR, 1.12; 95% CI, 1.04-1.21) and a significantly decreased likelihood of transition back from MCI to NCI (HR, 0.90; 95% CI, 0.81-1.00).

Scoring ~6 points on a conscientiousness scale ranging from 0-48 (that is, 1 SD on the scale) was significantly associated with ~22% lower risk of transitioning forward from NCI to MCI, while scoring ~7 more points on a neuroticism scale (1 SD) was significantly associated with ~12% higher risk of transitioning from NCI to MCI.

Higher extraversion was associated with an increased likelihood of transitioning from MCI back to NCI (HR, 1.12; 95% CI, 1.03-1.22), and although extraversion was not associated with a longer total lifespan, participants who scored high on extraversion, as well as those who scored low on conscientiousness or low on neuroticism, maintained normal cognitive function longer than other participants.

“Our results suggest that high conscientiousness and low neuroticism may protect individuals against mild cognitive impairment,” said Dr. Yoneda.

Importantly, individuals who were either higher in conscientiousness, higher in extraversion, or lower in neuroticism had more years of “cognitive healthspan,” meaning more years without cognitive impairment,” she added.

In addition, “individuals lower in neuroticism and higher in extraversion were more likely to recover after receiving an MCI diagnosis, suggesting that these traits may be protective even after an individual starts to progress to dementia,” she said.

The authors note that the study focused on only three of the Big Five personality traits, while the other 2 – openness to experience and agreeableness – may also be associated with cognitive aging processes and mortality.

Nevertheless, given the current results, alongside extensive research in the personality field, aiming to increase conscientiousness through persistent behavioral change is one potential strategy for promoting healthy cognitive aging, Dr. Yoneda said.
 

‘Invaluable window’

In a comment, Brent Roberts, PhD, professor of psychology, University of Illinois Urbana-Champaign, said the study provides an “invaluable window into how personality affects the process of decline and either accelerates it, as in the role of neuroticism, or decelerates it, as in the role of conscientiousness.”

“I think the most fascinating finding was the fact that extraversion was related to transitioning from MCI back to NCI. These types of transitions have simply not been part of prior research, and it provides utterly unique insights and opportunities for interventions that may actually help people recover from a decline,” said Dr. Roberts, who was not involved in the research.

Claire Sexton, DPhil, Alzheimer’s Association director of scientific programs and outreach, called the paper “novel” because it investigated the transitions between normal cognition and mild impairment and between mild impairment and dementia.

Dr. Sexton, who was associated with this research team, cautioned that is it observational, “so it can illuminate associations or correlations, but not causes. As a result, we can’t say for sure what the mechanisms are behind these potential connections between personality and cognition, and more research is needed.”

The research was supported by the Alzheimer Society Research Program, Social Sciences and Humanities Research Council, and the National Institute on Aging of the National Institutes of Health. Dr. Yoneda and co-authors, Dr. Roberts, and Dr. Sexton have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

A version of this article first appeared on Medscape.com.

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

A version of this article first appeared on Medscape.com.

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

A version of this article first appeared on Medscape.com.

In an unprecedented murder case about end-of-life care, a physician accused of killing 14 critically ill patients with opioid overdoses in a Columbus, Ohio, hospital ICU over a period of 4 years was found not guilty by a jury April 20.

The jury, after a 7-week trial featuring more than 50 witnesses in the Franklin County Court of Common Pleas, declared William Husel, DO, not guilty on 14 counts of murder and attempted murder.

In a news conference after the verdict was announced, lead defense attorney Jose Baez said Dr. Husel, whom he called a “great doctor,” hopes to practice medicine again in the future. The verdict, he argued, offers an encouraging sign that physicians and other providers won’t face prosecution for providing “comfort care” to patients suffering pain. “They don’t need to be looking over their shoulders worrying about whether they’ll get charged with crimes,” he said.

The prosecutors in the case declined to comment, other than to say they “accept” the verdict.

Legal experts said it’s highly unlikely that Ohio or any other state would restore Dr. Husel’s suspended medical license. “I doubt he could ever work in medicine again,” said Mark Schumacher, a Columbus medical malpractice defense attorney who retired in 2020 after practicing for 39 years. Mr. Schumacher followed the trial closely.

The trial raised the specific issue of what constitutes a medically justifiable dose of opioid painkillers during the end-of-life procedure known as palliative extubation, in which critically ill patients are withdrawn from the ventilator when they are expected to die. Under medicine’s so-called double-effect principle, physicians must weigh the benefits and risks of ordering potentially lethal doses of painkillers and sedatives to provide comfort care for critically ill patients.

To many observers, however, the case really centered on the largely hidden debate over whether it’s acceptable to hasten the deaths of dying patients who haven’t chosen that path. That’s called euthanasia, which is illegal in the United States. In contrast, 10 states plus the District of Columbia allow physicians to prescribe lethal drugs to terminally ill, mentally competent adults who can self-administer them. That’s called medical aid in dying, or physician-assisted dying or suicide.

“Maybe this is a wake-up call that people believe this is the right thing to do,” said Lewis Nelson, MD, chair of emergency medicine at New Jersey Medical School in Newark. “The medical community has a sense that we often prolong life unnecessarily. But a physician cannot unilaterally decide it’s time for someone to die. It sounds like [Dr. Husel] took that decision into his own hands.”

The case also exposed major gaps in the patient safety culture at Mount Carmel West Hospital in Columbus, which is owned by the Catholic chain Trinity Health. Experts say failures by hospital staff to question physicians’ orders and raise patient safety concerns, as happened at Mount Carmel, occur at many hospitals around the country. Experts say the Husel case offers vital lessons for health care professionals about improving safety procedures.

“This is an extreme example, that everyone should learn from, about what not to do,” said Michael Cohen, RPh, founder and president emeritus of the Institute for Safe Medication Practices. “Husel was giving massive overdoses of drugs, people knew it was problematic, and someone didn’t put their foot down. You’ve got to have a process in place to address these situations where there is disagreement over the safety of a medication order.”

Dr. Husel was charged with killing the 14 patients from 2015 through 2018 by ordering single large doses of the painkiller fentanyl – from 500 to 2,000 micrograms – often in combination with other opioids and sedatives, while working as the solo physician on the overnight shift in the ICU at Mount Carmel West Hospital and at Mount Carmel St. Ann’s Hospital in Westerville, Ohio.

Dr. Husel ordered administration of the drugs while his patients were having an endotracheal tube removed as part of palliative extubation. There was conflicting testimony during the trial about whether the patients were showing signs of pain or were even capable of feeling pain.

Prosecutors argued that Dr. Husel, who did a residency and fellowship in critical care medicine at Cleveland Clinic and started working at Mount Carmel in 2013 in his first job as a full-fledged physician, intended to kill the patients or hasten their deaths. They contended that the inexperienced nurses in the ICU went along with his large drug doses because they were “in thrall” to him because of his prestigious background at the Cleveland Clinic and his willingness to take the time to teach them.

“With his training in anesthesiology, he knew what those drugs do,” assistant prosecutor David Zeyen said in closing arguments. “This isn’t negligence. This is on purpose ... Euthanizing animals with the intent to kill is fine in veterinary medicine. It’s not fine in the ICU at Mount Carmel or anywhere.”

The defense team argued that Dr. Husel was a caring and compassionate physician who ordered the drugs to relieve the patients’ pain and discomfort during the extubation process. He did not testify.

“Common sense says Dr Husel had no motive to harm patients,” defense attorney Baez said in his closing. “He dedicated his life to taking care of patients and saving lives, not taking them. ... Why would this man risk his family, career, and 17 years of trying to be a doctor to hasten someone’s death or kill them?”

There were 35 Mount Carmel patients who died in the ICU under Dr. Husel’s care after receiving large fentanyl doses during palliative extubation. The state originally charged him with murder in 25 of those cases, then reduced that to 14.

Many of Dr. Husel’s drug orders were given verbally instead of through the regular process of being entered into the electronic health record. He and the nurses on duty also skipped the standard nonemergency process of getting approval from the pharmacist on duty, instead using the override function on Mount Carmel’s automated Pyxis drug dispensing system.

Dr. Husel’s unusual dosing patterns were first reported to Mount Carmel officials by pharmacists in October 2018, spurring an investigation. The hospital system let him go in December 2018, after concluding that the opioid dosages he used were “significantly excessive and potentially fatal” and “went beyond providing comfort.”

Nearly two dozen RNs and two pharmacists involved in these cases have faced state disciplinary action, mostly license suspension. Federal and state agencies have cited the Mount Carmel system for faults in its patient safety processes and culture that were exposed by the Husel cases.

The Mount Carmel CEO; the chief clinical officer; other physician, nursing, and pharmacy leaders; and dozens of nurses and pharmacists were forced out following the Husel investigation.

In 2019, the Centers for Medicare & Medicaid  Services, after threatening to cut off federal reimbursements to Mount Carmel, accepted the hospital system’s correction plan restricting the use of verbal drug orders and prohibiting Pyxis system overrides for opioids except in life-threatening emergencies. The Ohio Board of Pharmacy hit Mount Carmel with $477,000 in fines and costs for pharmacy rules violations.

Mount Carmel and Trinity have settled a number of civil wrongful death lawsuits filed by the families of Dr. Husel’s patients for nearly $20 million, with many more suits pending. Gerry Leeseberg, a Columbus medical malpractice plaintiff attorney who is representing 17 of the families, said a number of the cases are set for trial starting in June.

During the trial, family members of many of the 14 patients whom Dr. Husel allegedly murdered testified that Dr. Husel told them their loved ones were dying. Some said they felt rushed into making a decision to extubate the person.

Before performing a palliative extubation, physicians commonly administer opioids and/or sedatives to ease pain and discomfort, and spare family members from witnessing their loved ones gasping for breath. But most medical experts – including the state’s two physician expert witnesses – say the fentanyl doses Dr. Husel ordered were 5-20 times larger than doses normally used in palliative extubation. Such doses, they say, will quickly kill most patients – except those with high opioid tolerance – by stopping their breathing.

Physicians say they typically give much smaller doses of fentanyl or morphine, then administer more as needed if they observe the patient experiencing pain or distress. Mount Carmel’s 2016 guidelines for IV administration of fentanyl specified a dosage range of 50-100 micrograms for relieving pain, and its 2018 guidelines reduced that to 25-50 micrograms.

The doses Dr. Husel ordered are lethal, even for most patients with some tolerance to opioids, said Rutgers EM chair Dr. Nelson, who practices medical toxicology and addiction medicine. “Those are doses to provide euthanasia, not to relieve pain.”

At trial, the prosecutors had to overcome two big challenges to win murder convictions against Dr. Husel: They had to prove beyond a reasonable doubt that the drugs Dr. Husel ordered are what directly caused these critically ill patients to die, and that he intended to kill them.

Late in the trial, at the state’s request, the judge ruled to allow the jury to also consider attempted murder charges, which require proof of intent but not that the defendant’s actions directly caused the deaths.

Another challenge was that physicians have certain legal protections for administering drugs to patients for the purpose of relieving pain and suffering, even if the drugs hasten the patients’ deaths – as long the intent was not to cause death and the drugs were properly used. This is known as the double-effect principle. In contrast, intentional killing to relieve pain and suffering is called euthanasia. That’s what prosecutors accused Dr. Husel of doing.

“If you hasten a person’s death, even if their death is as sure as the sun is going to rise in the morning ... you have caused their death in the eyes of the law,” assistant prosecutor Mr. Zeyen said in his closing. “You don’t get a pass for killing a dying man ...”

Mr. Leeseberg said it was always going to be extremely hard to convince a jury to convict a physician of murder, with the potential of life in prison, in a case where the physician’s acts occurred openly over 4 years in a hospital setting where no one did anything to stop him. It would have been much easier to convince a jury to convict him of reckless homicide, a lesser offense with a shorter prison term. That would have required proving that he acted in reckless disregard for his patients’ health and safety.

In post-verdict comments to the news media, Judge Michael Holbrook said jurors told him that the procedures for the dispensing of fentanyl and other drugs at Mount Carmel weren’t properly explained to them during the trial, and that they were confused by the large number of prosecution witnesses. He also said they were confused that no one had stated a maximum dosage for fentanyl.

Mr. Schumacher, the retired malpractice defense lawyer who followed the trial, disagreed with defense attorney Baez’s takeaway about the impact of the case on pain-relief practices. In his view, the case likely will heighten rather than reduce the anxiety of physicians and nurses about administering opioids, even when the dosages are clearly needed and appropriate. He doesn’t think Dr. Husel’s dosages can be justified, however. 

“Physicians have a naive overreaction to any legal development, and overgeneralize from a particular case to everyday practice,” he said.

There is only one known prior case that’s somewhat comparable of a physician tried for murder or attempted murder for giving a critically ill patient opioids for pain relief. In 1996, a Kansas jury convicted Lloyd Stanley Naramore, DO, of attempted murder in the death of a patient to whom he gave an opioid, and of second-degree murder for removing a patient from a ventilator. After Dr. Naramore served 6 months in prison, an appellate court reversed the convictions for lack of evidence.

In March, RaDonda Vaught, a nurse who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted of criminal neglect and negligent homicide for mistakenly administering a fatal dose of the paralyzing drug vecuronium, instead of the prescribed drug Versed (midazolam), to a patient. Providers around the country were alarmed by her criminal prosecution for what was clearly an unintentional error.

But legal and medical experts said Dr. Husel’s case was sharply different from Vaught’s and Dr. Naramore’s because he deliberately and repeatedly ordered large doses of fentanyl and other drugs that he knew or should have known were potentially lethal. “You don’t need 2,000 micrograms of fentanyl plus other drugs for comfort care, and repeat that again and again for patient after patient,” said Mr. Cohen, of the Institute for Safe Medication Practices. “No one gives that to patients. You’ll knock them off.”

During the trial, prosecutors said repeatedly that no one except Dr. Husel knows what he was thinking when he ordered those huge drug dosages for his ICU patients. Judge Holbrook told the jury the state did not have to prove motive, only intent. But many observers still have wondered what his motives were.

Dr. Husel’s own view of his care in these cases soon will become public. Immediately after the April 20 verdict, Mr. Leeseberg filed a notice requesting a May 9 deposition of Dr. Husel, who will no longer be able to claim the Fifth Amendment right against self-incrimination. He predicted the deposition will last about a week, and then the transcript will be publicly available.

A version of this article first appeared on Medscape.com.

In an unprecedented murder case about end-of-life care, a physician accused of killing 14 critically ill patients with opioid overdoses in a Columbus, Ohio, hospital ICU over a period of 4 years was found not guilty by a jury April 20.

The jury, after a 7-week trial featuring more than 50 witnesses in the Franklin County Court of Common Pleas, declared William Husel, DO, not guilty on 14 counts of murder and attempted murder.

In a news conference after the verdict was announced, lead defense attorney Jose Baez said Dr. Husel, whom he called a “great doctor,” hopes to practice medicine again in the future. The verdict, he argued, offers an encouraging sign that physicians and other providers won’t face prosecution for providing “comfort care” to patients suffering pain. “They don’t need to be looking over their shoulders worrying about whether they’ll get charged with crimes,” he said.

The prosecutors in the case declined to comment, other than to say they “accept” the verdict.

Legal experts said it’s highly unlikely that Ohio or any other state would restore Dr. Husel’s suspended medical license. “I doubt he could ever work in medicine again,” said Mark Schumacher, a Columbus medical malpractice defense attorney who retired in 2020 after practicing for 39 years. Mr. Schumacher followed the trial closely.

The trial raised the specific issue of what constitutes a medically justifiable dose of opioid painkillers during the end-of-life procedure known as palliative extubation, in which critically ill patients are withdrawn from the ventilator when they are expected to die. Under medicine’s so-called double-effect principle, physicians must weigh the benefits and risks of ordering potentially lethal doses of painkillers and sedatives to provide comfort care for critically ill patients.

To many observers, however, the case really centered on the largely hidden debate over whether it’s acceptable to hasten the deaths of dying patients who haven’t chosen that path. That’s called euthanasia, which is illegal in the United States. In contrast, 10 states plus the District of Columbia allow physicians to prescribe lethal drugs to terminally ill, mentally competent adults who can self-administer them. That’s called medical aid in dying, or physician-assisted dying or suicide.

“Maybe this is a wake-up call that people believe this is the right thing to do,” said Lewis Nelson, MD, chair of emergency medicine at New Jersey Medical School in Newark. “The medical community has a sense that we often prolong life unnecessarily. But a physician cannot unilaterally decide it’s time for someone to die. It sounds like [Dr. Husel] took that decision into his own hands.”

The case also exposed major gaps in the patient safety culture at Mount Carmel West Hospital in Columbus, which is owned by the Catholic chain Trinity Health. Experts say failures by hospital staff to question physicians’ orders and raise patient safety concerns, as happened at Mount Carmel, occur at many hospitals around the country. Experts say the Husel case offers vital lessons for health care professionals about improving safety procedures.

“This is an extreme example, that everyone should learn from, about what not to do,” said Michael Cohen, RPh, founder and president emeritus of the Institute for Safe Medication Practices. “Husel was giving massive overdoses of drugs, people knew it was problematic, and someone didn’t put their foot down. You’ve got to have a process in place to address these situations where there is disagreement over the safety of a medication order.”

Dr. Husel was charged with killing the 14 patients from 2015 through 2018 by ordering single large doses of the painkiller fentanyl – from 500 to 2,000 micrograms – often in combination with other opioids and sedatives, while working as the solo physician on the overnight shift in the ICU at Mount Carmel West Hospital and at Mount Carmel St. Ann’s Hospital in Westerville, Ohio.

Dr. Husel ordered administration of the drugs while his patients were having an endotracheal tube removed as part of palliative extubation. There was conflicting testimony during the trial about whether the patients were showing signs of pain or were even capable of feeling pain.

Prosecutors argued that Dr. Husel, who did a residency and fellowship in critical care medicine at Cleveland Clinic and started working at Mount Carmel in 2013 in his first job as a full-fledged physician, intended to kill the patients or hasten their deaths. They contended that the inexperienced nurses in the ICU went along with his large drug doses because they were “in thrall” to him because of his prestigious background at the Cleveland Clinic and his willingness to take the time to teach them.

“With his training in anesthesiology, he knew what those drugs do,” assistant prosecutor David Zeyen said in closing arguments. “This isn’t negligence. This is on purpose ... Euthanizing animals with the intent to kill is fine in veterinary medicine. It’s not fine in the ICU at Mount Carmel or anywhere.”

The defense team argued that Dr. Husel was a caring and compassionate physician who ordered the drugs to relieve the patients’ pain and discomfort during the extubation process. He did not testify.

“Common sense says Dr Husel had no motive to harm patients,” defense attorney Baez said in his closing. “He dedicated his life to taking care of patients and saving lives, not taking them. ... Why would this man risk his family, career, and 17 years of trying to be a doctor to hasten someone’s death or kill them?”

There were 35 Mount Carmel patients who died in the ICU under Dr. Husel’s care after receiving large fentanyl doses during palliative extubation. The state originally charged him with murder in 25 of those cases, then reduced that to 14.

Many of Dr. Husel’s drug orders were given verbally instead of through the regular process of being entered into the electronic health record. He and the nurses on duty also skipped the standard nonemergency process of getting approval from the pharmacist on duty, instead using the override function on Mount Carmel’s automated Pyxis drug dispensing system.

Dr. Husel’s unusual dosing patterns were first reported to Mount Carmel officials by pharmacists in October 2018, spurring an investigation. The hospital system let him go in December 2018, after concluding that the opioid dosages he used were “significantly excessive and potentially fatal” and “went beyond providing comfort.”

Nearly two dozen RNs and two pharmacists involved in these cases have faced state disciplinary action, mostly license suspension. Federal and state agencies have cited the Mount Carmel system for faults in its patient safety processes and culture that were exposed by the Husel cases.

The Mount Carmel CEO; the chief clinical officer; other physician, nursing, and pharmacy leaders; and dozens of nurses and pharmacists were forced out following the Husel investigation.

In 2019, the Centers for Medicare & Medicaid  Services, after threatening to cut off federal reimbursements to Mount Carmel, accepted the hospital system’s correction plan restricting the use of verbal drug orders and prohibiting Pyxis system overrides for opioids except in life-threatening emergencies. The Ohio Board of Pharmacy hit Mount Carmel with $477,000 in fines and costs for pharmacy rules violations.

Mount Carmel and Trinity have settled a number of civil wrongful death lawsuits filed by the families of Dr. Husel’s patients for nearly $20 million, with many more suits pending. Gerry Leeseberg, a Columbus medical malpractice plaintiff attorney who is representing 17 of the families, said a number of the cases are set for trial starting in June.

During the trial, family members of many of the 14 patients whom Dr. Husel allegedly murdered testified that Dr. Husel told them their loved ones were dying. Some said they felt rushed into making a decision to extubate the person.

Before performing a palliative extubation, physicians commonly administer opioids and/or sedatives to ease pain and discomfort, and spare family members from witnessing their loved ones gasping for breath. But most medical experts – including the state’s two physician expert witnesses – say the fentanyl doses Dr. Husel ordered were 5-20 times larger than doses normally used in palliative extubation. Such doses, they say, will quickly kill most patients – except those with high opioid tolerance – by stopping their breathing.

Physicians say they typically give much smaller doses of fentanyl or morphine, then administer more as needed if they observe the patient experiencing pain or distress. Mount Carmel’s 2016 guidelines for IV administration of fentanyl specified a dosage range of 50-100 micrograms for relieving pain, and its 2018 guidelines reduced that to 25-50 micrograms.

The doses Dr. Husel ordered are lethal, even for most patients with some tolerance to opioids, said Rutgers EM chair Dr. Nelson, who practices medical toxicology and addiction medicine. “Those are doses to provide euthanasia, not to relieve pain.”

At trial, the prosecutors had to overcome two big challenges to win murder convictions against Dr. Husel: They had to prove beyond a reasonable doubt that the drugs Dr. Husel ordered are what directly caused these critically ill patients to die, and that he intended to kill them.

Late in the trial, at the state’s request, the judge ruled to allow the jury to also consider attempted murder charges, which require proof of intent but not that the defendant’s actions directly caused the deaths.

Another challenge was that physicians have certain legal protections for administering drugs to patients for the purpose of relieving pain and suffering, even if the drugs hasten the patients’ deaths – as long the intent was not to cause death and the drugs were properly used. This is known as the double-effect principle. In contrast, intentional killing to relieve pain and suffering is called euthanasia. That’s what prosecutors accused Dr. Husel of doing.

“If you hasten a person’s death, even if their death is as sure as the sun is going to rise in the morning ... you have caused their death in the eyes of the law,” assistant prosecutor Mr. Zeyen said in his closing. “You don’t get a pass for killing a dying man ...”

Mr. Leeseberg said it was always going to be extremely hard to convince a jury to convict a physician of murder, with the potential of life in prison, in a case where the physician’s acts occurred openly over 4 years in a hospital setting where no one did anything to stop him. It would have been much easier to convince a jury to convict him of reckless homicide, a lesser offense with a shorter prison term. That would have required proving that he acted in reckless disregard for his patients’ health and safety.

In post-verdict comments to the news media, Judge Michael Holbrook said jurors told him that the procedures for the dispensing of fentanyl and other drugs at Mount Carmel weren’t properly explained to them during the trial, and that they were confused by the large number of prosecution witnesses. He also said they were confused that no one had stated a maximum dosage for fentanyl.

Mr. Schumacher, the retired malpractice defense lawyer who followed the trial, disagreed with defense attorney Baez’s takeaway about the impact of the case on pain-relief practices. In his view, the case likely will heighten rather than reduce the anxiety of physicians and nurses about administering opioids, even when the dosages are clearly needed and appropriate. He doesn’t think Dr. Husel’s dosages can be justified, however. 

“Physicians have a naive overreaction to any legal development, and overgeneralize from a particular case to everyday practice,” he said.

There is only one known prior case that’s somewhat comparable of a physician tried for murder or attempted murder for giving a critically ill patient opioids for pain relief. In 1996, a Kansas jury convicted Lloyd Stanley Naramore, DO, of attempted murder in the death of a patient to whom he gave an opioid, and of second-degree murder for removing a patient from a ventilator. After Dr. Naramore served 6 months in prison, an appellate court reversed the convictions for lack of evidence.

In March, RaDonda Vaught, a nurse who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted of criminal neglect and negligent homicide for mistakenly administering a fatal dose of the paralyzing drug vecuronium, instead of the prescribed drug Versed (midazolam), to a patient. Providers around the country were alarmed by her criminal prosecution for what was clearly an unintentional error.

But legal and medical experts said Dr. Husel’s case was sharply different from Vaught’s and Dr. Naramore’s because he deliberately and repeatedly ordered large doses of fentanyl and other drugs that he knew or should have known were potentially lethal. “You don’t need 2,000 micrograms of fentanyl plus other drugs for comfort care, and repeat that again and again for patient after patient,” said Mr. Cohen, of the Institute for Safe Medication Practices. “No one gives that to patients. You’ll knock them off.”

During the trial, prosecutors said repeatedly that no one except Dr. Husel knows what he was thinking when he ordered those huge drug dosages for his ICU patients. Judge Holbrook told the jury the state did not have to prove motive, only intent. But many observers still have wondered what his motives were.

Dr. Husel’s own view of his care in these cases soon will become public. Immediately after the April 20 verdict, Mr. Leeseberg filed a notice requesting a May 9 deposition of Dr. Husel, who will no longer be able to claim the Fifth Amendment right against self-incrimination. He predicted the deposition will last about a week, and then the transcript will be publicly available.

A version of this article first appeared on Medscape.com.

In an unprecedented murder case about end-of-life care, a physician accused of killing 14 critically ill patients with opioid overdoses in a Columbus, Ohio, hospital ICU over a period of 4 years was found not guilty by a jury April 20.

The jury, after a 7-week trial featuring more than 50 witnesses in the Franklin County Court of Common Pleas, declared William Husel, DO, not guilty on 14 counts of murder and attempted murder.

In a news conference after the verdict was announced, lead defense attorney Jose Baez said Dr. Husel, whom he called a “great doctor,” hopes to practice medicine again in the future. The verdict, he argued, offers an encouraging sign that physicians and other providers won’t face prosecution for providing “comfort care” to patients suffering pain. “They don’t need to be looking over their shoulders worrying about whether they’ll get charged with crimes,” he said.

The prosecutors in the case declined to comment, other than to say they “accept” the verdict.

Legal experts said it’s highly unlikely that Ohio or any other state would restore Dr. Husel’s suspended medical license. “I doubt he could ever work in medicine again,” said Mark Schumacher, a Columbus medical malpractice defense attorney who retired in 2020 after practicing for 39 years. Mr. Schumacher followed the trial closely.

The trial raised the specific issue of what constitutes a medically justifiable dose of opioid painkillers during the end-of-life procedure known as palliative extubation, in which critically ill patients are withdrawn from the ventilator when they are expected to die. Under medicine’s so-called double-effect principle, physicians must weigh the benefits and risks of ordering potentially lethal doses of painkillers and sedatives to provide comfort care for critically ill patients.

To many observers, however, the case really centered on the largely hidden debate over whether it’s acceptable to hasten the deaths of dying patients who haven’t chosen that path. That’s called euthanasia, which is illegal in the United States. In contrast, 10 states plus the District of Columbia allow physicians to prescribe lethal drugs to terminally ill, mentally competent adults who can self-administer them. That’s called medical aid in dying, or physician-assisted dying or suicide.

“Maybe this is a wake-up call that people believe this is the right thing to do,” said Lewis Nelson, MD, chair of emergency medicine at New Jersey Medical School in Newark. “The medical community has a sense that we often prolong life unnecessarily. But a physician cannot unilaterally decide it’s time for someone to die. It sounds like [Dr. Husel] took that decision into his own hands.”

The case also exposed major gaps in the patient safety culture at Mount Carmel West Hospital in Columbus, which is owned by the Catholic chain Trinity Health. Experts say failures by hospital staff to question physicians’ orders and raise patient safety concerns, as happened at Mount Carmel, occur at many hospitals around the country. Experts say the Husel case offers vital lessons for health care professionals about improving safety procedures.

“This is an extreme example, that everyone should learn from, about what not to do,” said Michael Cohen, RPh, founder and president emeritus of the Institute for Safe Medication Practices. “Husel was giving massive overdoses of drugs, people knew it was problematic, and someone didn’t put their foot down. You’ve got to have a process in place to address these situations where there is disagreement over the safety of a medication order.”

Dr. Husel was charged with killing the 14 patients from 2015 through 2018 by ordering single large doses of the painkiller fentanyl – from 500 to 2,000 micrograms – often in combination with other opioids and sedatives, while working as the solo physician on the overnight shift in the ICU at Mount Carmel West Hospital and at Mount Carmel St. Ann’s Hospital in Westerville, Ohio.

Dr. Husel ordered administration of the drugs while his patients were having an endotracheal tube removed as part of palliative extubation. There was conflicting testimony during the trial about whether the patients were showing signs of pain or were even capable of feeling pain.

Prosecutors argued that Dr. Husel, who did a residency and fellowship in critical care medicine at Cleveland Clinic and started working at Mount Carmel in 2013 in his first job as a full-fledged physician, intended to kill the patients or hasten their deaths. They contended that the inexperienced nurses in the ICU went along with his large drug doses because they were “in thrall” to him because of his prestigious background at the Cleveland Clinic and his willingness to take the time to teach them.

“With his training in anesthesiology, he knew what those drugs do,” assistant prosecutor David Zeyen said in closing arguments. “This isn’t negligence. This is on purpose ... Euthanizing animals with the intent to kill is fine in veterinary medicine. It’s not fine in the ICU at Mount Carmel or anywhere.”

The defense team argued that Dr. Husel was a caring and compassionate physician who ordered the drugs to relieve the patients’ pain and discomfort during the extubation process. He did not testify.

“Common sense says Dr Husel had no motive to harm patients,” defense attorney Baez said in his closing. “He dedicated his life to taking care of patients and saving lives, not taking them. ... Why would this man risk his family, career, and 17 years of trying to be a doctor to hasten someone’s death or kill them?”

There were 35 Mount Carmel patients who died in the ICU under Dr. Husel’s care after receiving large fentanyl doses during palliative extubation. The state originally charged him with murder in 25 of those cases, then reduced that to 14.

Many of Dr. Husel’s drug orders were given verbally instead of through the regular process of being entered into the electronic health record. He and the nurses on duty also skipped the standard nonemergency process of getting approval from the pharmacist on duty, instead using the override function on Mount Carmel’s automated Pyxis drug dispensing system.

Dr. Husel’s unusual dosing patterns were first reported to Mount Carmel officials by pharmacists in October 2018, spurring an investigation. The hospital system let him go in December 2018, after concluding that the opioid dosages he used were “significantly excessive and potentially fatal” and “went beyond providing comfort.”

Nearly two dozen RNs and two pharmacists involved in these cases have faced state disciplinary action, mostly license suspension. Federal and state agencies have cited the Mount Carmel system for faults in its patient safety processes and culture that were exposed by the Husel cases.

The Mount Carmel CEO; the chief clinical officer; other physician, nursing, and pharmacy leaders; and dozens of nurses and pharmacists were forced out following the Husel investigation.

In 2019, the Centers for Medicare & Medicaid  Services, after threatening to cut off federal reimbursements to Mount Carmel, accepted the hospital system’s correction plan restricting the use of verbal drug orders and prohibiting Pyxis system overrides for opioids except in life-threatening emergencies. The Ohio Board of Pharmacy hit Mount Carmel with $477,000 in fines and costs for pharmacy rules violations.

Mount Carmel and Trinity have settled a number of civil wrongful death lawsuits filed by the families of Dr. Husel’s patients for nearly $20 million, with many more suits pending. Gerry Leeseberg, a Columbus medical malpractice plaintiff attorney who is representing 17 of the families, said a number of the cases are set for trial starting in June.

During the trial, family members of many of the 14 patients whom Dr. Husel allegedly murdered testified that Dr. Husel told them their loved ones were dying. Some said they felt rushed into making a decision to extubate the person.

Before performing a palliative extubation, physicians commonly administer opioids and/or sedatives to ease pain and discomfort, and spare family members from witnessing their loved ones gasping for breath. But most medical experts – including the state’s two physician expert witnesses – say the fentanyl doses Dr. Husel ordered were 5-20 times larger than doses normally used in palliative extubation. Such doses, they say, will quickly kill most patients – except those with high opioid tolerance – by stopping their breathing.

Physicians say they typically give much smaller doses of fentanyl or morphine, then administer more as needed if they observe the patient experiencing pain or distress. Mount Carmel’s 2016 guidelines for IV administration of fentanyl specified a dosage range of 50-100 micrograms for relieving pain, and its 2018 guidelines reduced that to 25-50 micrograms.

The doses Dr. Husel ordered are lethal, even for most patients with some tolerance to opioids, said Rutgers EM chair Dr. Nelson, who practices medical toxicology and addiction medicine. “Those are doses to provide euthanasia, not to relieve pain.”

At trial, the prosecutors had to overcome two big challenges to win murder convictions against Dr. Husel: They had to prove beyond a reasonable doubt that the drugs Dr. Husel ordered are what directly caused these critically ill patients to die, and that he intended to kill them.

Late in the trial, at the state’s request, the judge ruled to allow the jury to also consider attempted murder charges, which require proof of intent but not that the defendant’s actions directly caused the deaths.

Another challenge was that physicians have certain legal protections for administering drugs to patients for the purpose of relieving pain and suffering, even if the drugs hasten the patients’ deaths – as long the intent was not to cause death and the drugs were properly used. This is known as the double-effect principle. In contrast, intentional killing to relieve pain and suffering is called euthanasia. That’s what prosecutors accused Dr. Husel of doing.

“If you hasten a person’s death, even if their death is as sure as the sun is going to rise in the morning ... you have caused their death in the eyes of the law,” assistant prosecutor Mr. Zeyen said in his closing. “You don’t get a pass for killing a dying man ...”

Mr. Leeseberg said it was always going to be extremely hard to convince a jury to convict a physician of murder, with the potential of life in prison, in a case where the physician’s acts occurred openly over 4 years in a hospital setting where no one did anything to stop him. It would have been much easier to convince a jury to convict him of reckless homicide, a lesser offense with a shorter prison term. That would have required proving that he acted in reckless disregard for his patients’ health and safety.

In post-verdict comments to the news media, Judge Michael Holbrook said jurors told him that the procedures for the dispensing of fentanyl and other drugs at Mount Carmel weren’t properly explained to them during the trial, and that they were confused by the large number of prosecution witnesses. He also said they were confused that no one had stated a maximum dosage for fentanyl.

Mr. Schumacher, the retired malpractice defense lawyer who followed the trial, disagreed with defense attorney Baez’s takeaway about the impact of the case on pain-relief practices. In his view, the case likely will heighten rather than reduce the anxiety of physicians and nurses about administering opioids, even when the dosages are clearly needed and appropriate. He doesn’t think Dr. Husel’s dosages can be justified, however. 

“Physicians have a naive overreaction to any legal development, and overgeneralize from a particular case to everyday practice,” he said.

There is only one known prior case that’s somewhat comparable of a physician tried for murder or attempted murder for giving a critically ill patient opioids for pain relief. In 1996, a Kansas jury convicted Lloyd Stanley Naramore, DO, of attempted murder in the death of a patient to whom he gave an opioid, and of second-degree murder for removing a patient from a ventilator. After Dr. Naramore served 6 months in prison, an appellate court reversed the convictions for lack of evidence.

In March, RaDonda Vaught, a nurse who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted of criminal neglect and negligent homicide for mistakenly administering a fatal dose of the paralyzing drug vecuronium, instead of the prescribed drug Versed (midazolam), to a patient. Providers around the country were alarmed by her criminal prosecution for what was clearly an unintentional error.

But legal and medical experts said Dr. Husel’s case was sharply different from Vaught’s and Dr. Naramore’s because he deliberately and repeatedly ordered large doses of fentanyl and other drugs that he knew or should have known were potentially lethal. “You don’t need 2,000 micrograms of fentanyl plus other drugs for comfort care, and repeat that again and again for patient after patient,” said Mr. Cohen, of the Institute for Safe Medication Practices. “No one gives that to patients. You’ll knock them off.”

During the trial, prosecutors said repeatedly that no one except Dr. Husel knows what he was thinking when he ordered those huge drug dosages for his ICU patients. Judge Holbrook told the jury the state did not have to prove motive, only intent. But many observers still have wondered what his motives were.

Dr. Husel’s own view of his care in these cases soon will become public. Immediately after the April 20 verdict, Mr. Leeseberg filed a notice requesting a May 9 deposition of Dr. Husel, who will no longer be able to claim the Fifth Amendment right against self-incrimination. He predicted the deposition will last about a week, and then the transcript will be publicly available.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.

Women diagnosed with early breast cancer facing surgery often have a choice of having all of their breast or only a part of the breast removed.

A new study shows that a patient’s satisfaction with their breasts at 10 years after surgery is similar for both groups of women.

However, superior psychosocial and sexual well-being at 10 years after surgery was reported by women who underwent breast-conserving surgery and adjuvant radiation therapy (RT), compared with those who underwent mastectomy and reconstruction.

“These findings may inform preference-sensitive decision-making for women with early-stage breast cancer,” write the authors, led by Benjamin D. Smith, MD, department of radiation oncology, University of Texas MD Anderson Cancer Center, Houston.

The study was published online in JAMA Surgery.

These findings have important implications for patient decision-making, given that more women eligible for breast-conserving surgery are opting for a mastectomy, say Sudheer Vemuru, MD, from the University of Colorado at Denver, Aurora, and colleagues, writing in an accompanying editorial.

“Overall, the preponderance of evidence suggests superior short-term and long-term patient-reported outcomes in patients with early-stage breast cancer undergoing breast conserving surgery compared with mastectomy,” they comment.
 

Study details

For their study, Dr. Smith and colleagues conducted a comparative effectiveness research study using data from the Texas Cancer Registry and identified women diagnosed with stage 0-II breast cancer and treated with breast-conserving surgery or mastectomy and reconstruction between 2006 and 2008.

A total of 647 patients were included in their analysis (40%; 356 had undergone breast-conserving surgery; 291 had undergone mastectomy and reconstruction), 551 (85.2%) confirmed treatment with breast-conserving surgery with RT (n = 315) or mastectomy and reconstruction without RT (n = 236).

The median age of the cohort was 53 years and the median time from diagnosis to survey was 10.3 years. Mastectomy and reconstruction were more common among women who were White, younger, node positive, had larger tumors, had bilateral breast cancer, received chemotherapy, and had higher income.

The primary outcome was patient satisfaction with their breasts, as measured with the BREAST-Q patient-reported outcome measure. Secondary outcomes included physical well-being, psychosocial well-being, and sexual well-being. The EuroQol Health-Related Quality of Life 5-Dimension, 3-Level gaged health utility, and local therapy decisional regret was measured via the Decisional Regret Scale.

Using breast-conserving surgery plus RT as the referent, the authors did not find any significant differences in breast satisfaction, physical well-being, health utility, or decisional regret among the study cohorts: breast satisfaction: effect size, 2.71 (P = .30); physical well-being: effect size, –1.80 (P = .36); health utility: effect size, –0.003 (P = .83); and decisional regret: effect size, 1.32 (P = .61).

However, psychosocial well-being (effect size, –8.61; P < .001) and sexual well-being (effect size, –10.68; P < .001) were significantly worse among women who had undergone mastectomy and reconstruction without RT.

They noted that interactions of race and ethnicity and age by treatment group were not significant for reported satisfaction with breast outcomes. But the findings “indicated that the burden of poor long-term QOL outcomes was greater among younger individuals, those with lower educational attainment and income, and certain racial and ethnic minority populations,” they write. “These findings suggest that opportunities exist to enhance equity in the long-term QOL of individuals with breast cancer.”

The editorialists note that previous studies have also found diminished quality of life following mastectomy compared with breast-conserving surgery. However, most of these prior studies included patients undergoing breast-conserving surgery without RT, patients undergoing mastectomy without reconstruction, and patients undergoing mastectomy with RT.

In contrast, this latest study “directly compared breast-conserving surgery with RT vs. mastectomy and reconstruction without RT to avoid those potential confounders,” they point out.

The study was supported by grants from the National Cancer Institute and other bodies. Several of the study authors disclosed relationships with industry and/or with nonprofit organizations. The full list can be found with the original article. Editorialist Clara Lee, MD, reported receiving grants from the Agency for Healthcare Research and Quality during the conduct of the study.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

Psychiatric disorders are tied to an increased risk of COVID-19 breakthrough infection, particularly among older adults, new research shows.

“Psychiatric disorders remained significantly associated with incident breakthrough infections above and beyond sociodemographic and medical factors, suggesting that mental health is important to consider in conjunction with other risk factors,” wrote the investigators, led by Aoife O’Donovan, PhD, University of California, San Francisco.

Individuals with psychiatric disorders “should be prioritized for booster vaccinations and other critical preventive efforts, including increased SARS-CoV-2 screening, public health campaigns, or COVID-19 discussions during clinical care,” they added.

The study was published online in JAMA Network Open.
 

Elderly most vulnerable

The researchers reviewed the records of 263,697 veterans who were fully vaccinated against COVID-19.

Just over a half (51.4%) had one or more psychiatric diagnoses within the last 5 years and 14.8% developed breakthrough COVID-19 infections, confirmed by a positive SARS-CoV-2 test.

Psychiatric diagnoses among the veterans included depression, posttraumatic stress, anxiety, adjustment disorder, substance use disorder, bipolar disorder, psychosis, ADHD, dissociation, and eating disorders.

In the overall sample, a history of any psychiatric disorder was associated with a 7% higher incidence of breakthrough COVID-19 infection in models adjusted for potential confounders (adjusted relative risk, 1.07; 95% confidence interval, 1.05-1.09) and a 3% higher incidence in models additionally adjusted for underlying medical comorbidities and smoking (aRR, 1.03; 95% CI, 1.01-1.05).

Most psychiatric disorders were associated with a higher incidence of breakthrough infection, with the highest relative risk observed for substance use disorders (aRR, 1.16; 95% CI, 1.12 -1.21) and adjustment disorder (aRR, 1.13; 95% CI, 1.10-1.16) in fully adjusted models.

Older vaccinated veterans with psychiatric illnesses appear to be most vulnerable to COVID-19 reinfection.

In veterans aged 65 and older, all psychiatric disorders were associated with an increased incidence of breakthrough infection, with increases in the incidence rate ranging from 3% to 24% in fully adjusted models.

In the younger veterans, in contrast, only anxiety, adjustment, and substance use disorders were associated with an increased incidence of breakthrough infection in fully adjusted models.

Psychotic disorders were associated with a 10% lower incidence of breakthrough infection among younger veterans, perhaps because of greater social isolation, the researchers said.
 

Risky behavior or impaired immunity?

“Although some of the larger observed effect sizes are compelling at an individual level, even the relatively modest effect sizes may have a large effect at the population level when considering the high prevalence of psychiatric disorders and the global reach and scale of the pandemic,” Dr. O’Donovan and colleagues wrote.

They noted that psychiatric disorders, including depression, schizophrenia, and bipolar disorders, have been associated with impaired cellular immunity and blunted response to vaccines. Therefore, it’s possible that those with psychiatric disorders have poorer responses to COVID-19 vaccination.

It’s also possible that immunity following vaccination wanes more quickly or more strongly in people with psychiatric disorders and they could have less protection against new variants, they added.

Patients with psychiatric disorders could be more apt to engage in risky behaviors for contracting COVID-19, which could also increase the risk for breakthrough infection, they said.

The study was supported by a UCSF Department of Psychiatry Rapid Award and UCSF Faculty Resource Fund Award. Dr. O’Donovan reported no relevant disclosures.

A version of this article first appeared on Medscape.com.

The International Cancer Benchmarking Partnership, a collaboration of physicians, clinicians, researchers, policy makers, and data experts, has reached a consensus on key actions designed to standardize and homogenize lung cancer care that includes early diagnosis and access to care for all patients.

This consensus, reported at the 2022 European Lung Cancer Congress, is an effort to address disparities in care recognized by the group’s in-house research team. The team identified significantly different survival rates in early stage lung cancer patients from a group of countries with similar health care metrics, such as health care expenditure and universal access to health care.

“This group of countries is very comparable, but we saw a 20% difference in survival in localized, stage I and II cancers. When you consider that lung cancer is a bigger killer than any other cancer –more than breast, prostate, and colon cancer combined – that’s thousands of people,” said the project’s lead clinician, Christian Finley, MD, a thoracic surgeon with St. Joseph’s Healthcare Hamilton (Ont.).

Founded in 2009, the ICBP includes about 500 experts in its core countries of Sweden, Norway, Denmark, Australia, the United Kingdom, and Canada; New Zealand and Ireland have also participated. The goal of the partnership is to benchmark survival and other outcomes in cancer and to research why disparities between countries exist.

“That’s why we keep the membership fairly small, so that we can actually make more meaningful research projects to get into depth in factors beyond benchmarking survival and mortality,” said study author Charlotte Lynch, MSc, a senior researcher with Cancer Research UK in London.

To help narrow the disparity gap, Ms. Lynch, Dr. Finley and colleagues brought together nine key informants from ICBP countries to discuss local clinical insights and best practices, and ultimately came up a list of five recommendations considered most crucial: implementing cost-effective, equitable, and effective screening; ensuring diagnoses of lung cancer within 30 days of referral; developing thoracic centers of excellence; launching an international audit of lung cancer care; and prioritizing the recognition of improvements in lung cancer care and outcomes.

They identified 13 best practice points to support the development and implementation of the calls to action.

“For example, points supporting the screening call to action focus on timely access to cross-sectional imaging and availability and development of patient and health care practitioner lung cancer awareness materials,” Ms. Lynch said.

Another example would be the point that describes the need for a minimum data set to evaluate lung cancer patients’ diagnosis, treatment, and aftercare.

“I think we all work in a very disrupted system right now. Screening programs really took a hit during the pandemic, and I think people coming out of those disruptions are trying to imagine a more effective system using tools like information technologies, mobile clinics and having a better understanding of equity,” Dr. Finley said.

Ms. Lynch said the ICBP intends to use the consensus to generate concrete actions. “We’re thinking about how we can get everyone in the room to share lessons learned and best practices to push things forward rather than saying, ‘this is what should be done,’ making sure we do the next steps, collaborative thinking, and moving forward.”

In a press release, Antonio Passaro, MD, a lung cancer expert from the European Institute of Oncology in Milan, said there is a need to prioritize primary and secondary prevention of lung cancer.

“Although a much-debated topic in recent years, a strong body of research has now shown that lung cancer screening through annual computed tomography scans in individuals with a history of smoking can improve detection rates. Targeting the right populations with these interventions will be crucial to implementing screening approaches that are both efficacious and cost effective,” he stated.

The authors declared no conflicts of interest and this study was not funded.

The International Cancer Benchmarking Partnership, a collaboration of physicians, clinicians, researchers, policy makers, and data experts, has reached a consensus on key actions designed to standardize and homogenize lung cancer care that includes early diagnosis and access to care for all patients.

This consensus, reported at the 2022 European Lung Cancer Congress, is an effort to address disparities in care recognized by the group’s in-house research team. The team identified significantly different survival rates in early stage lung cancer patients from a group of countries with similar health care metrics, such as health care expenditure and universal access to health care.

“This group of countries is very comparable, but we saw a 20% difference in survival in localized, stage I and II cancers. When you consider that lung cancer is a bigger killer than any other cancer –more than breast, prostate, and colon cancer combined – that’s thousands of people,” said the project’s lead clinician, Christian Finley, MD, a thoracic surgeon with St. Joseph’s Healthcare Hamilton (Ont.).

Founded in 2009, the ICBP includes about 500 experts in its core countries of Sweden, Norway, Denmark, Australia, the United Kingdom, and Canada; New Zealand and Ireland have also participated. The goal of the partnership is to benchmark survival and other outcomes in cancer and to research why disparities between countries exist.

“That’s why we keep the membership fairly small, so that we can actually make more meaningful research projects to get into depth in factors beyond benchmarking survival and mortality,” said study author Charlotte Lynch, MSc, a senior researcher with Cancer Research UK in London.

To help narrow the disparity gap, Ms. Lynch, Dr. Finley and colleagues brought together nine key informants from ICBP countries to discuss local clinical insights and best practices, and ultimately came up a list of five recommendations considered most crucial: implementing cost-effective, equitable, and effective screening; ensuring diagnoses of lung cancer within 30 days of referral; developing thoracic centers of excellence; launching an international audit of lung cancer care; and prioritizing the recognition of improvements in lung cancer care and outcomes.

They identified 13 best practice points to support the development and implementation of the calls to action.

“For example, points supporting the screening call to action focus on timely access to cross-sectional imaging and availability and development of patient and health care practitioner lung cancer awareness materials,” Ms. Lynch said.

Another example would be the point that describes the need for a minimum data set to evaluate lung cancer patients’ diagnosis, treatment, and aftercare.

“I think we all work in a very disrupted system right now. Screening programs really took a hit during the pandemic, and I think people coming out of those disruptions are trying to imagine a more effective system using tools like information technologies, mobile clinics and having a better understanding of equity,” Dr. Finley said.

Ms. Lynch said the ICBP intends to use the consensus to generate concrete actions. “We’re thinking about how we can get everyone in the room to share lessons learned and best practices to push things forward rather than saying, ‘this is what should be done,’ making sure we do the next steps, collaborative thinking, and moving forward.”

In a press release, Antonio Passaro, MD, a lung cancer expert from the European Institute of Oncology in Milan, said there is a need to prioritize primary and secondary prevention of lung cancer.

“Although a much-debated topic in recent years, a strong body of research has now shown that lung cancer screening through annual computed tomography scans in individuals with a history of smoking can improve detection rates. Targeting the right populations with these interventions will be crucial to implementing screening approaches that are both efficacious and cost effective,” he stated.

The authors declared no conflicts of interest and this study was not funded.