Lung Cancer

The combination of nivolumab, ipilimumab, and two cycles of platinum doublet chemotherapy appears to be an important new option for patients with advanced non–small cell lung cancer (NSCLC).

Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.

Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).

A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).

In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
 

Details of CheckMate 9LA

CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.

The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.

If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.

Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.

The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
 

Results prompt FDA approval

Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).

With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).

Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.

One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.

Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.

Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.

Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.


 

Challenges to overcome

In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.

Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.

With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).

Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
 

Better by design

In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.

Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.

Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.

Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.

Longer follow-up needed

In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.

As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.

It would be ideal to know whether the tail of the OS curve will flatten out.
 

Do the best you can

Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.

In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.

Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Reck M et al. ASCO 2020, Abstract 9501.

The combination of nivolumab, ipilimumab, and two cycles of platinum doublet chemotherapy appears to be an important new option for patients with advanced non–small cell lung cancer (NSCLC).

Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.

Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).

A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).

In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
 

Details of CheckMate 9LA

CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.

The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.

If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.

Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.

The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
 

Results prompt FDA approval

Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).

With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).

Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.

One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.

Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.

Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.

Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.


 

Challenges to overcome

In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.

Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.

With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).

Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
 

Better by design

In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.

Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.

Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.

Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.

Longer follow-up needed

In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.

As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.

It would be ideal to know whether the tail of the OS curve will flatten out.
 

Do the best you can

Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.

In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.

Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Reck M et al. ASCO 2020, Abstract 9501.

The combination of nivolumab, ipilimumab, and two cycles of platinum doublet chemotherapy appears to be an important new option for patients with advanced non–small cell lung cancer (NSCLC).

Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.

Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).

A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).

In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
 

Details of CheckMate 9LA

CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.

The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.

If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.

Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.

The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
 

Results prompt FDA approval

Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).

With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).

Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.

One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.

Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.

Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.

Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.


 

Challenges to overcome

In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.

Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.

With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).

Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
 

Better by design

In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.

Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.

Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.

Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.

Longer follow-up needed

In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.

As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.

It would be ideal to know whether the tail of the OS curve will flatten out.
 

Do the best you can

Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.

In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.

Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Reck M et al. ASCO 2020, Abstract 9501.

Patients with metastatic small-cell lung cancer (SCLC) whose disease has progressed after or during treatment with platinum-based chemotherapy now have a new option to try — lurbinectedin (Zepzelca, Jazz Pharma/PharmaMar).

The drug was granted accelerated approval by the US Food and Drug Administration (FDA) based on response data. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the FDA notes.

“Small-cell lung cancer is a disease with limited treatment options,” said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals. “While patients may initially respond to traditional chemotherapy, they often experience an aggressive recurrence that is historically resistant to treatment.”

“Seeing first-hand the aggressive nature of SCLC and knowing that the large majority of those diagnosed will experience relapse, I am excited to see an effective new treatment demonstrating durable responses,” Jeff Petty, MD, oncology specialist, Wake Forest Baptist Health, Winston-Salem, North Carolina, commented in the company press release. This new drug “is an important and much-needed addition to the treatment landscape for relapsing SCLC,” he added.
 

Approval based on monotherapy trial

The approval is based on a monotherapy clinical trial in 105 patients, which was published in May in Lancet Oncology, with first author José Trigo, MD, from the Hospital Universitario Virgen de la Victoria in Malaga, Spain.  

These were adult patients with both platinum-sensitive and platinum-resistant SCLC who had disease progression after treatment with platinum-based chemotherapy. They were treated at 26 hospitals across six European countries and the US. All patients received lurbinectedin at 3.2 mg/m² by intravenous infusion over 1 hour. Median follow-up was 17.1 months.

Overall response by investigator assessment was seen in 37 (35.2%) of the 105 patients. The response was greater (at 45%) among the patients with platinum-sensitive disease and smaller (22.2%) among those with platinum-resistant disease.

Lurbinectedin demonstrated a median duration of response of 5.3 months as measured by investigator assessment.

In a post-hoc analysis, among the 37 patients who had an initial objective response, the median overall survival was just over 1 year (12.6 months). It was even longer among patients who had platinum-sensitive disease (15.8 months), although it was shorter in patients with resistant disease (10.9 months).

These data are “particularly encouraging,” comment the authors of an accompanying editorial, led by Oscar Arrieta, MD, from the Thoracic Oncology Unit at the Instituto Nacional de Cancerología in Mexico City, Mexico. These response rates “outperform all previous results achieved with topotecan and other less established treatment schemes including cyclophosphamide, doxorubicin, and vincristine, or platinum re-challenge, in this setting.”

“Lurbinectedin represents an innovative approach to conventional anti-cancer drugs, with an elegant mechanism of action based on the inhibition of transcription-dependent replication stress and genome instability of tumor cells,” the editorialists comment. “The drug binds to specific DNA triplets commonly found in transcription sites and triggers cellular apoptosis.”

“At present, the only evidence-based second-line treatment approved for SCLC is topotecan, a topoisomerase 1 inhibitor with moderate activity in patients with sensitive disease, although its effect is much less evident in patients with resistant SCLC,” they continue.

“Overall, the study by Trigo and colleagues presents novel data for a very challenging disease for which few treatment options exist, and the data on response and survival do seem to outperform data from historical controls,” Arrieta and colleagues write.

The editorialists also note that, in this trial, a few patients had received immunotherapy as part of their first-line treatment, and some of these patients (5 of 8 patients, 68%) had “an outstanding rate of durable response to lurbinectedin.” This raises the possibility of a synergistic effect between immunotherapy and lurbinectedin, as the combination seems to enhance immune memory and impair subsequent tumor growth, they add. Further trials will need to explore sequencing of therapy, they suggest.

A large phase 3 study known as ATLANTIS is currently underway.  

The most common grade 3-4 adverse events in the present trial were hematologic abnormalities: anemia (9% of patients), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). Serious treatment-related adverse events occurred in 10% of patients, of which neutropenia and febrile neutropenia were the most common (5% each). No treatment-related deaths were reported.

The study was funded by PharmaMar. Trigo and coauthors, and Arrieta and fellow editorialists, all report relationships with pharmaceutical companies, as detailed in the published articles.

This article first appeared on Medscape.com.

Patients with metastatic small-cell lung cancer (SCLC) whose disease has progressed after or during treatment with platinum-based chemotherapy now have a new option to try — lurbinectedin (Zepzelca, Jazz Pharma/PharmaMar).

The drug was granted accelerated approval by the US Food and Drug Administration (FDA) based on response data. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the FDA notes.

“Small-cell lung cancer is a disease with limited treatment options,” said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals. “While patients may initially respond to traditional chemotherapy, they often experience an aggressive recurrence that is historically resistant to treatment.”

“Seeing first-hand the aggressive nature of SCLC and knowing that the large majority of those diagnosed will experience relapse, I am excited to see an effective new treatment demonstrating durable responses,” Jeff Petty, MD, oncology specialist, Wake Forest Baptist Health, Winston-Salem, North Carolina, commented in the company press release. This new drug “is an important and much-needed addition to the treatment landscape for relapsing SCLC,” he added.
 

Approval based on monotherapy trial

The approval is based on a monotherapy clinical trial in 105 patients, which was published in May in Lancet Oncology, with first author José Trigo, MD, from the Hospital Universitario Virgen de la Victoria in Malaga, Spain.  

These were adult patients with both platinum-sensitive and platinum-resistant SCLC who had disease progression after treatment with platinum-based chemotherapy. They were treated at 26 hospitals across six European countries and the US. All patients received lurbinectedin at 3.2 mg/m² by intravenous infusion over 1 hour. Median follow-up was 17.1 months.

Overall response by investigator assessment was seen in 37 (35.2%) of the 105 patients. The response was greater (at 45%) among the patients with platinum-sensitive disease and smaller (22.2%) among those with platinum-resistant disease.

Lurbinectedin demonstrated a median duration of response of 5.3 months as measured by investigator assessment.

In a post-hoc analysis, among the 37 patients who had an initial objective response, the median overall survival was just over 1 year (12.6 months). It was even longer among patients who had platinum-sensitive disease (15.8 months), although it was shorter in patients with resistant disease (10.9 months).

These data are “particularly encouraging,” comment the authors of an accompanying editorial, led by Oscar Arrieta, MD, from the Thoracic Oncology Unit at the Instituto Nacional de Cancerología in Mexico City, Mexico. These response rates “outperform all previous results achieved with topotecan and other less established treatment schemes including cyclophosphamide, doxorubicin, and vincristine, or platinum re-challenge, in this setting.”

“Lurbinectedin represents an innovative approach to conventional anti-cancer drugs, with an elegant mechanism of action based on the inhibition of transcription-dependent replication stress and genome instability of tumor cells,” the editorialists comment. “The drug binds to specific DNA triplets commonly found in transcription sites and triggers cellular apoptosis.”

“At present, the only evidence-based second-line treatment approved for SCLC is topotecan, a topoisomerase 1 inhibitor with moderate activity in patients with sensitive disease, although its effect is much less evident in patients with resistant SCLC,” they continue.

“Overall, the study by Trigo and colleagues presents novel data for a very challenging disease for which few treatment options exist, and the data on response and survival do seem to outperform data from historical controls,” Arrieta and colleagues write.

The editorialists also note that, in this trial, a few patients had received immunotherapy as part of their first-line treatment, and some of these patients (5 of 8 patients, 68%) had “an outstanding rate of durable response to lurbinectedin.” This raises the possibility of a synergistic effect between immunotherapy and lurbinectedin, as the combination seems to enhance immune memory and impair subsequent tumor growth, they add. Further trials will need to explore sequencing of therapy, they suggest.

A large phase 3 study known as ATLANTIS is currently underway.  

The most common grade 3-4 adverse events in the present trial were hematologic abnormalities: anemia (9% of patients), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). Serious treatment-related adverse events occurred in 10% of patients, of which neutropenia and febrile neutropenia were the most common (5% each). No treatment-related deaths were reported.

The study was funded by PharmaMar. Trigo and coauthors, and Arrieta and fellow editorialists, all report relationships with pharmaceutical companies, as detailed in the published articles.

This article first appeared on Medscape.com.

Patients with metastatic small-cell lung cancer (SCLC) whose disease has progressed after or during treatment with platinum-based chemotherapy now have a new option to try — lurbinectedin (Zepzelca, Jazz Pharma/PharmaMar).

The drug was granted accelerated approval by the US Food and Drug Administration (FDA) based on response data. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, the FDA notes.

“Small-cell lung cancer is a disease with limited treatment options,” said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals. “While patients may initially respond to traditional chemotherapy, they often experience an aggressive recurrence that is historically resistant to treatment.”

“Seeing first-hand the aggressive nature of SCLC and knowing that the large majority of those diagnosed will experience relapse, I am excited to see an effective new treatment demonstrating durable responses,” Jeff Petty, MD, oncology specialist, Wake Forest Baptist Health, Winston-Salem, North Carolina, commented in the company press release. This new drug “is an important and much-needed addition to the treatment landscape for relapsing SCLC,” he added.
 

Approval based on monotherapy trial

The approval is based on a monotherapy clinical trial in 105 patients, which was published in May in Lancet Oncology, with first author José Trigo, MD, from the Hospital Universitario Virgen de la Victoria in Malaga, Spain.  

These were adult patients with both platinum-sensitive and platinum-resistant SCLC who had disease progression after treatment with platinum-based chemotherapy. They were treated at 26 hospitals across six European countries and the US. All patients received lurbinectedin at 3.2 mg/m² by intravenous infusion over 1 hour. Median follow-up was 17.1 months.

Overall response by investigator assessment was seen in 37 (35.2%) of the 105 patients. The response was greater (at 45%) among the patients with platinum-sensitive disease and smaller (22.2%) among those with platinum-resistant disease.

Lurbinectedin demonstrated a median duration of response of 5.3 months as measured by investigator assessment.

In a post-hoc analysis, among the 37 patients who had an initial objective response, the median overall survival was just over 1 year (12.6 months). It was even longer among patients who had platinum-sensitive disease (15.8 months), although it was shorter in patients with resistant disease (10.9 months).

These data are “particularly encouraging,” comment the authors of an accompanying editorial, led by Oscar Arrieta, MD, from the Thoracic Oncology Unit at the Instituto Nacional de Cancerología in Mexico City, Mexico. These response rates “outperform all previous results achieved with topotecan and other less established treatment schemes including cyclophosphamide, doxorubicin, and vincristine, or platinum re-challenge, in this setting.”

“Lurbinectedin represents an innovative approach to conventional anti-cancer drugs, with an elegant mechanism of action based on the inhibition of transcription-dependent replication stress and genome instability of tumor cells,” the editorialists comment. “The drug binds to specific DNA triplets commonly found in transcription sites and triggers cellular apoptosis.”

“At present, the only evidence-based second-line treatment approved for SCLC is topotecan, a topoisomerase 1 inhibitor with moderate activity in patients with sensitive disease, although its effect is much less evident in patients with resistant SCLC,” they continue.

“Overall, the study by Trigo and colleagues presents novel data for a very challenging disease for which few treatment options exist, and the data on response and survival do seem to outperform data from historical controls,” Arrieta and colleagues write.

The editorialists also note that, in this trial, a few patients had received immunotherapy as part of their first-line treatment, and some of these patients (5 of 8 patients, 68%) had “an outstanding rate of durable response to lurbinectedin.” This raises the possibility of a synergistic effect between immunotherapy and lurbinectedin, as the combination seems to enhance immune memory and impair subsequent tumor growth, they add. Further trials will need to explore sequencing of therapy, they suggest.

A large phase 3 study known as ATLANTIS is currently underway.  

The most common grade 3-4 adverse events in the present trial were hematologic abnormalities: anemia (9% of patients), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). Serious treatment-related adverse events occurred in 10% of patients, of which neutropenia and febrile neutropenia were the most common (5% each). No treatment-related deaths were reported.

The study was funded by PharmaMar. Trigo and coauthors, and Arrieta and fellow editorialists, all report relationships with pharmaceutical companies, as detailed in the published articles.

This article first appeared on Medscape.com.

Visits to the emergency department (ED) and hospitalizations are often frequent occurrences for cancer patients, but what if the “hospital” could be brought into the home instead?

A new American cohort study provides evidence that this can be a workable option for cancer patients. The authors report improved patient outcomes, with 56% lower odds of unplanned hospitalizations (P = .001), 45% lower odds of ED visits (P = .037), and 50% lower cumulative charges (P = .001), as compared with patients who received usual care.

“The oncology hospital-at-home model of care that extends acute-level care to the patient at home offers promise in addressing a long-term gap in cancer care service delivery,” said lead author Kathi Mooney, PhD, RN, interim senior director of population sciences at the Huntsman Cancer Institute and distinguished professor of nursing at the University of Utah, Salt Lake City. “In light of the current global pandemic, we are compelled to consider new ways to provide cancer care, and the oncology hospital-at-home model is on point to address critical elements of an improved cancer care delivery system.”

Mooney presented the findings during the virtual scientific program of the American Society of Clinical Oncology 2020 annual meeting (abstract 7000).

The hospital-at-home model of care provides hospital-level care in the comfort of the patient’s home and is a component of many healthcare systems worldwide. Although it was introduced in the United States more than 2 decades ago, it has not been widely adopted or studied specifically in oncology.

Most cancer treatment is provided on an outpatient basis, which means that patients experience significant adverse events, toxicities, and disease progression while they are at home. Thus, Mooney noted, patients tend to rely heavily on the ED and sometimes experience unplanned hospitalizations and 30-day readmissions.

“These care patterns are distressing to the patients and their families and tax healthcare resources,” she said. “They are even more concerning and salient as we endeavor to protect cancer patients and provide cancer care during a pandemic.”

Currently, strategies to evaluate and support cancer patients and caregivers at home are limited. In 2018, the Huntsman Cancer Institute implemented Huntsman at Home, a demonstration project to evaluate the utility of an oncology hospital-at-home model.
 

Significantly Fewer Unplanned Hospitalizations

Huntsman at Home is run by nurse practitioner and registered nurse teams who deliver acute-level care at home. Physicians provide backup support for both medical oncology and palliative care. Nurse practitioners also work directly with the patient’s oncology team to coordinate care needs, including services such as social work and physical therapy.

To evaluate the hospital-at-home model, Mooney and colleagues compared patients who were enrolled in the program with those who received usual care. The usual-care comparison group was drawn from patients who lived in the Salt Lake City area. These patients would have qualified for enrollment in the Huntsman at Home program, but they lived outside the 20-mile service area.

The cohort included 367 patients (169 Huntsman at Home patients and 198 usual-care patients). Of those patients, 77% had stage IV cancer. A range of cancer types was represented; the most common were colon, gynecologic, prostate, and lung cancers. As compared to the usual-care group, those in the home model were more likely to be women (61% vs 43%).

During the first 30 days after admission, Huntsman at Home patients had significantly fewer unplanned hospitalizations (19.5% vs 35.4%) and a shorter length of stay (1.4 vs 2.6 days). Their care was also less expensive. The estimated charges for the hospital-at-home patients was $10,238, compared with $21,363 for the usual-care patients. There was no real difference in stays in the intensive care unit between the two groups.

Mooney noted that since there have been few studies of the hospital-at-home model for oncology patients, the investigators’ initial focus was on patients at hospital discharge who needed continued acute-level care and those who had acute problems identified through their oncology care clinic. Therefore, patients were not admitted to the program directly from emergency services, and chemotherapy infusions were not provided, although these are “other areas to consider in an oncology hospital-at-home model.”

Other limitations of the study were that it was not a randomized trial, and the evaluation was from a single program located at one comprehensive cancer center.

“These findings provide the oncology community with an opportunity to rethink cancer care as solely hospital- and clinic-based and instead reimagine care delivery that moves with the patient with key components provided at home,” said Mooney. “We plan to continue the development and evaluation of Huntsman at Home and extend care to admission from the emergency department.”

She added that, together with Flatiron Health, they are validating a tool to prospectively predict, on the basis of the likelihood of ED use, which patients may benefit from Huntsman at Home support. They also plan to extend care to patients who live at a distance from the cancer center and in rural communities, and may include chemotherapy infusion services.

Palliative Care Patients Prefer Home-Based Treatment

In a discussion of the paper, Lynne Wagner, PhD, a professor in the Department of Social Sciences and Health Policy with the Wake Forest School of Medicine, Winston-Salem, North Carolina, and a member of the Wake Forest Baptist Comprehensive Cancer Center, explained that some “aspects of healthcare are more translatable to a virtual or alternative delivery model than others. An area of cancer care greatly in need of innovation and quality improvement pertains to the management of oncologic emergencies.”

She pointed out that optimal care for oncologic emergencies requires the “intersection of oncology and emergency medicine specialists,” but there are often no well-defined processes for care coordination in place.

“Emergency department utilization could be reduced through greater precision with regard to risk stratification and early intervention and improved outpatient management, including improved symptom management,” said Wagner.

Wagner suggested that research should incorporate patient-reported outcomes so as to measure patient-centered benefits of home-based care. “Patients who are receiving palliative care services prefer home-based care, and it’s reasonable to anticipate this finding would extrapolate to the investigator’s target population,” she said. “However, there may also be unanticipated consequences, potentially including increased anxiety or increased burden on caretakers.”

In addition, the tangible and intangible costs associated with traveling to receive healthcare services and time away from work can be reduced with home-based care, and this should also be quantified. “The costs associated with COVID infection should be estimated to realize the full economic value of this care model, given significant reductions in cohort exposure afforded by home-based visits,” Wagner added.

The Huntsman at Home program is funded by the Huntsman Cancer Institute. The evaluation was funded by the Cambia Health Foundation. Mooney has a consulting or advisory role with Cognitive Medical System, Inc, and has patents, royalties, and other intellectual property for the development of Symptom Care at Home, a remote symptom-monitoring platform developed through research grants funded by the National Cancer Institute. No royalties have been received to date. Wagner has relationships with Celgene, Eli Lilly, Gilead Sciences, and Johnson & Johnson.
 

This article first appeared on Medscape.com.

Visits to the emergency department (ED) and hospitalizations are often frequent occurrences for cancer patients, but what if the “hospital” could be brought into the home instead?

A new American cohort study provides evidence that this can be a workable option for cancer patients. The authors report improved patient outcomes, with 56% lower odds of unplanned hospitalizations (P = .001), 45% lower odds of ED visits (P = .037), and 50% lower cumulative charges (P = .001), as compared with patients who received usual care.

“The oncology hospital-at-home model of care that extends acute-level care to the patient at home offers promise in addressing a long-term gap in cancer care service delivery,” said lead author Kathi Mooney, PhD, RN, interim senior director of population sciences at the Huntsman Cancer Institute and distinguished professor of nursing at the University of Utah, Salt Lake City. “In light of the current global pandemic, we are compelled to consider new ways to provide cancer care, and the oncology hospital-at-home model is on point to address critical elements of an improved cancer care delivery system.”

Mooney presented the findings during the virtual scientific program of the American Society of Clinical Oncology 2020 annual meeting (abstract 7000).

The hospital-at-home model of care provides hospital-level care in the comfort of the patient’s home and is a component of many healthcare systems worldwide. Although it was introduced in the United States more than 2 decades ago, it has not been widely adopted or studied specifically in oncology.

Most cancer treatment is provided on an outpatient basis, which means that patients experience significant adverse events, toxicities, and disease progression while they are at home. Thus, Mooney noted, patients tend to rely heavily on the ED and sometimes experience unplanned hospitalizations and 30-day readmissions.

“These care patterns are distressing to the patients and their families and tax healthcare resources,” she said. “They are even more concerning and salient as we endeavor to protect cancer patients and provide cancer care during a pandemic.”

Currently, strategies to evaluate and support cancer patients and caregivers at home are limited. In 2018, the Huntsman Cancer Institute implemented Huntsman at Home, a demonstration project to evaluate the utility of an oncology hospital-at-home model.
 

Significantly Fewer Unplanned Hospitalizations

Huntsman at Home is run by nurse practitioner and registered nurse teams who deliver acute-level care at home. Physicians provide backup support for both medical oncology and palliative care. Nurse practitioners also work directly with the patient’s oncology team to coordinate care needs, including services such as social work and physical therapy.

To evaluate the hospital-at-home model, Mooney and colleagues compared patients who were enrolled in the program with those who received usual care. The usual-care comparison group was drawn from patients who lived in the Salt Lake City area. These patients would have qualified for enrollment in the Huntsman at Home program, but they lived outside the 20-mile service area.

The cohort included 367 patients (169 Huntsman at Home patients and 198 usual-care patients). Of those patients, 77% had stage IV cancer. A range of cancer types was represented; the most common were colon, gynecologic, prostate, and lung cancers. As compared to the usual-care group, those in the home model were more likely to be women (61% vs 43%).

During the first 30 days after admission, Huntsman at Home patients had significantly fewer unplanned hospitalizations (19.5% vs 35.4%) and a shorter length of stay (1.4 vs 2.6 days). Their care was also less expensive. The estimated charges for the hospital-at-home patients was $10,238, compared with $21,363 for the usual-care patients. There was no real difference in stays in the intensive care unit between the two groups.

Mooney noted that since there have been few studies of the hospital-at-home model for oncology patients, the investigators’ initial focus was on patients at hospital discharge who needed continued acute-level care and those who had acute problems identified through their oncology care clinic. Therefore, patients were not admitted to the program directly from emergency services, and chemotherapy infusions were not provided, although these are “other areas to consider in an oncology hospital-at-home model.”

Other limitations of the study were that it was not a randomized trial, and the evaluation was from a single program located at one comprehensive cancer center.

“These findings provide the oncology community with an opportunity to rethink cancer care as solely hospital- and clinic-based and instead reimagine care delivery that moves with the patient with key components provided at home,” said Mooney. “We plan to continue the development and evaluation of Huntsman at Home and extend care to admission from the emergency department.”

She added that, together with Flatiron Health, they are validating a tool to prospectively predict, on the basis of the likelihood of ED use, which patients may benefit from Huntsman at Home support. They also plan to extend care to patients who live at a distance from the cancer center and in rural communities, and may include chemotherapy infusion services.

Palliative Care Patients Prefer Home-Based Treatment

In a discussion of the paper, Lynne Wagner, PhD, a professor in the Department of Social Sciences and Health Policy with the Wake Forest School of Medicine, Winston-Salem, North Carolina, and a member of the Wake Forest Baptist Comprehensive Cancer Center, explained that some “aspects of healthcare are more translatable to a virtual or alternative delivery model than others. An area of cancer care greatly in need of innovation and quality improvement pertains to the management of oncologic emergencies.”

She pointed out that optimal care for oncologic emergencies requires the “intersection of oncology and emergency medicine specialists,” but there are often no well-defined processes for care coordination in place.

“Emergency department utilization could be reduced through greater precision with regard to risk stratification and early intervention and improved outpatient management, including improved symptom management,” said Wagner.

Wagner suggested that research should incorporate patient-reported outcomes so as to measure patient-centered benefits of home-based care. “Patients who are receiving palliative care services prefer home-based care, and it’s reasonable to anticipate this finding would extrapolate to the investigator’s target population,” she said. “However, there may also be unanticipated consequences, potentially including increased anxiety or increased burden on caretakers.”

In addition, the tangible and intangible costs associated with traveling to receive healthcare services and time away from work can be reduced with home-based care, and this should also be quantified. “The costs associated with COVID infection should be estimated to realize the full economic value of this care model, given significant reductions in cohort exposure afforded by home-based visits,” Wagner added.

The Huntsman at Home program is funded by the Huntsman Cancer Institute. The evaluation was funded by the Cambia Health Foundation. Mooney has a consulting or advisory role with Cognitive Medical System, Inc, and has patents, royalties, and other intellectual property for the development of Symptom Care at Home, a remote symptom-monitoring platform developed through research grants funded by the National Cancer Institute. No royalties have been received to date. Wagner has relationships with Celgene, Eli Lilly, Gilead Sciences, and Johnson & Johnson.
 

This article first appeared on Medscape.com.

Visits to the emergency department (ED) and hospitalizations are often frequent occurrences for cancer patients, but what if the “hospital” could be brought into the home instead?

A new American cohort study provides evidence that this can be a workable option for cancer patients. The authors report improved patient outcomes, with 56% lower odds of unplanned hospitalizations (P = .001), 45% lower odds of ED visits (P = .037), and 50% lower cumulative charges (P = .001), as compared with patients who received usual care.

“The oncology hospital-at-home model of care that extends acute-level care to the patient at home offers promise in addressing a long-term gap in cancer care service delivery,” said lead author Kathi Mooney, PhD, RN, interim senior director of population sciences at the Huntsman Cancer Institute and distinguished professor of nursing at the University of Utah, Salt Lake City. “In light of the current global pandemic, we are compelled to consider new ways to provide cancer care, and the oncology hospital-at-home model is on point to address critical elements of an improved cancer care delivery system.”

Mooney presented the findings during the virtual scientific program of the American Society of Clinical Oncology 2020 annual meeting (abstract 7000).

The hospital-at-home model of care provides hospital-level care in the comfort of the patient’s home and is a component of many healthcare systems worldwide. Although it was introduced in the United States more than 2 decades ago, it has not been widely adopted or studied specifically in oncology.

Most cancer treatment is provided on an outpatient basis, which means that patients experience significant adverse events, toxicities, and disease progression while they are at home. Thus, Mooney noted, patients tend to rely heavily on the ED and sometimes experience unplanned hospitalizations and 30-day readmissions.

“These care patterns are distressing to the patients and their families and tax healthcare resources,” she said. “They are even more concerning and salient as we endeavor to protect cancer patients and provide cancer care during a pandemic.”

Currently, strategies to evaluate and support cancer patients and caregivers at home are limited. In 2018, the Huntsman Cancer Institute implemented Huntsman at Home, a demonstration project to evaluate the utility of an oncology hospital-at-home model.
 

Significantly Fewer Unplanned Hospitalizations

Huntsman at Home is run by nurse practitioner and registered nurse teams who deliver acute-level care at home. Physicians provide backup support for both medical oncology and palliative care. Nurse practitioners also work directly with the patient’s oncology team to coordinate care needs, including services such as social work and physical therapy.

To evaluate the hospital-at-home model, Mooney and colleagues compared patients who were enrolled in the program with those who received usual care. The usual-care comparison group was drawn from patients who lived in the Salt Lake City area. These patients would have qualified for enrollment in the Huntsman at Home program, but they lived outside the 20-mile service area.

The cohort included 367 patients (169 Huntsman at Home patients and 198 usual-care patients). Of those patients, 77% had stage IV cancer. A range of cancer types was represented; the most common were colon, gynecologic, prostate, and lung cancers. As compared to the usual-care group, those in the home model were more likely to be women (61% vs 43%).

During the first 30 days after admission, Huntsman at Home patients had significantly fewer unplanned hospitalizations (19.5% vs 35.4%) and a shorter length of stay (1.4 vs 2.6 days). Their care was also less expensive. The estimated charges for the hospital-at-home patients was $10,238, compared with $21,363 for the usual-care patients. There was no real difference in stays in the intensive care unit between the two groups.

Mooney noted that since there have been few studies of the hospital-at-home model for oncology patients, the investigators’ initial focus was on patients at hospital discharge who needed continued acute-level care and those who had acute problems identified through their oncology care clinic. Therefore, patients were not admitted to the program directly from emergency services, and chemotherapy infusions were not provided, although these are “other areas to consider in an oncology hospital-at-home model.”

Other limitations of the study were that it was not a randomized trial, and the evaluation was from a single program located at one comprehensive cancer center.

“These findings provide the oncology community with an opportunity to rethink cancer care as solely hospital- and clinic-based and instead reimagine care delivery that moves with the patient with key components provided at home,” said Mooney. “We plan to continue the development and evaluation of Huntsman at Home and extend care to admission from the emergency department.”

She added that, together with Flatiron Health, they are validating a tool to prospectively predict, on the basis of the likelihood of ED use, which patients may benefit from Huntsman at Home support. They also plan to extend care to patients who live at a distance from the cancer center and in rural communities, and may include chemotherapy infusion services.

Palliative Care Patients Prefer Home-Based Treatment

In a discussion of the paper, Lynne Wagner, PhD, a professor in the Department of Social Sciences and Health Policy with the Wake Forest School of Medicine, Winston-Salem, North Carolina, and a member of the Wake Forest Baptist Comprehensive Cancer Center, explained that some “aspects of healthcare are more translatable to a virtual or alternative delivery model than others. An area of cancer care greatly in need of innovation and quality improvement pertains to the management of oncologic emergencies.”

She pointed out that optimal care for oncologic emergencies requires the “intersection of oncology and emergency medicine specialists,” but there are often no well-defined processes for care coordination in place.

“Emergency department utilization could be reduced through greater precision with regard to risk stratification and early intervention and improved outpatient management, including improved symptom management,” said Wagner.

Wagner suggested that research should incorporate patient-reported outcomes so as to measure patient-centered benefits of home-based care. “Patients who are receiving palliative care services prefer home-based care, and it’s reasonable to anticipate this finding would extrapolate to the investigator’s target population,” she said. “However, there may also be unanticipated consequences, potentially including increased anxiety or increased burden on caretakers.”

In addition, the tangible and intangible costs associated with traveling to receive healthcare services and time away from work can be reduced with home-based care, and this should also be quantified. “The costs associated with COVID infection should be estimated to realize the full economic value of this care model, given significant reductions in cohort exposure afforded by home-based visits,” Wagner added.

The Huntsman at Home program is funded by the Huntsman Cancer Institute. The evaluation was funded by the Cambia Health Foundation. Mooney has a consulting or advisory role with Cognitive Medical System, Inc, and has patents, royalties, and other intellectual property for the development of Symptom Care at Home, a remote symptom-monitoring platform developed through research grants funded by the National Cancer Institute. No royalties have been received to date. Wagner has relationships with Celgene, Eli Lilly, Gilead Sciences, and Johnson & Johnson.
 

This article first appeared on Medscape.com.

A new retrospective study provides some of the strongest support yet for considering first-line stereotactic radiosurgery (SRS) over whole-brain radiotherapy (WBRT) in carefully selected patients with brain metastases from small-cell lung cancer (SCLC), the researchers say.

As expected, WBRT was superior to focused SRS in lengthening the time to disease progression in the brain. However, this advantage did not appear to provide an improvement in overall survival (OS).

“This study suggests that the trade-offs inherent to first-line SRS without WBRT, including a shorter time to new brain metastases without an apparent difference in overall survival, may be similar to other settings where SRS alone is already well established,” lead author Chad Rusthoven, MD, told Medscape Medical News.

Upfront SRS may be “particularly attractive for SCLC patients with limited brain metastases and those at a higher risk of developing neurocognitive toxicity from WBRT, including older patients and those with a poor baseline performance status,” said Rusthoven, of the Department of Radiation Oncology, University of Colorado School of Medicine, Aurora.

Results of the FIRE-SCLC study – the largest analysis of first-line SRS for patients with SCLC brain metastases – were published online June 4 in JAMA Oncology.

The coauthors of an editorial in JAMA Oncology say the FIRE-SCLC study investigators should be “commended for conducting this important work and also for highlighting the inherent limitations of retrospective data.”

“Even after multivariable adjustment, OS may not be directly compared between the SRS and WBRT groups because selection bias is likely,” caution Cecile Le Pechoux, MD, and Antonin Levy, MD, PhD, from Institut Gustave-Roussy in Villejuif, France.

“Impressive” Outcomes

The researchers analyzed the outcomes of 710 patients (mean age, 68.5 years; 75% men; Karnofsky Performance Status score, ≥90) who underwent first-line SRS without prior treatment with WBRT or prophylactic cranial irradiation. They compared the SRS outcomes with outcomes of a cohort of 219 patients treated with first-line WBRT for SCLC brain metastases.

The SRS outcomes are “encouraging,” with a median OS of 8.5 months, median time to central nervous system (CNS) progression (TTCP) of 8.1 months, and median CNS progression-free survival (PFS) of 5.0 months, the study investigators say.

The outcomes are “particularly impressive” in patients with a single brain metastasis (median OS and TTCP, 11.0 months and 11.7 months, respectively), they note.

They found no significant differences in OS or TTCP after SRS in patients with two to four lesions and those with five to 10 lesions.

Median OS was 8.7 months with two to four lesions, 8.0 months with five to 10 lesions, and 5.5 months with 11 or more lesions. Corresponding median TTCP was 6.8, 6.1, and 4.7 months.

Local failures after SRS were rare. Most CNS progression occurred in the form of new lesions, which is in line with what’s been shown with SRS in other settings.

In propensity score–matched analyses that compared SRS with WBRT, median OS was higher with SRS (6.5 months vs 5.2 months with WBRT; P = .003). Median TTCP was improved with WBRT (SRS, 9.0 months vs WBRT, not reached; hazard ratio, 0.38; 95% confidence interval, 0.26 – 0.55; P < .001), with no significant difference in CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79).

The results were similar in multivariable analyses that compared SRS and WBRT, including subgroup analyses that controlled for extracranial metastases and extracranial disease control status.

Benchmark Data

“Although these retrospective data should not be used to conclude that OS is superior with SRS, the findings of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP, are similar to other settings in which SRS alone is well established by multiple randomized clinical trials,” the researchers write.

These data, they say, provide a “benchmark for SRS outcomes and offer support to first-line SRS as a treatment option in carefully selected patients with small-cell lung cancer.”

In a news release, senior author Tyler Robin, MD, University of Colorado School of Medicine, notes that paradigms for the treatment of SCLC are “evolving,” with the integration of immunotherapy into SCLC management, less use of WBRT, and guideline updates advising routine brain MRI surveillance for all patients.

“These changes may be expected to increase the identification of small-cell lung cancer patients with limited brain metastases who may be candidates for first-line SRS,” said Robin.

SRS made mainstream headlines in 2015 when former President Jimmy Carter was successfully treated for melanoma brain metastases with it. At the time, SRS was relatively new. The approach is more targeted and less toxic than traditional WBRT. Carter was treated at Emory University in Atlanta, Georgia.

SRS is now widely available in the United States, but adoption has been slow, Rusthoven told Medscape Medical News.

“Delayed adoption of SRS for SCLC is related to a number of factors, including a concern for short-interval CNS progression with SCLC histology and the historical exclusion of SCLC patients from the landmark randomized trials that established SRS alone,” he said.

“We hope that this study will contribute to an increased interest in the role of SRS for carefully selected SCLC patients and that it will offer support to ongoing and developing prospective clinical trials evaluating first-line SRS alone for SCLC,” Rusthoven added.

Prospective Data “Eagerly” Needed

The French editorial writers say prospective data are “eagerly needed” for this patient population.

SRS, they conclude, “might be a promising treatment option” for patients with SCLC with brain metastases, but larger studies are needed, as prophylactic cranial irradiation or prophylactic-intent WBRT has been shown to improve survival. “Hopefully, the work of Rusthoven et al will be used for the development of further prospective trials in patients with SCLC with brain metastases,” they write.

The study was funded by a grant from the University of Colorado Cancer Center. Rusthoven has received research funding from Takeda outside the submitted work as well as honoraria for educational talks from Genentech and AstraZeneca outside this work. The original article contains a complete list of author disclosures. Le Pechoux has received institutional honoraria for participation in advisory boards from AstraZeneca, Nanobiotix, and Roche; institutional honoraria for participation to educational meetings from Amgen, AstraZeneca, Medscape, and Eli Lilly and Company; and personal honoraria from prIME Oncology for participation in educational meetings. Levy has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A new retrospective study provides some of the strongest support yet for considering first-line stereotactic radiosurgery (SRS) over whole-brain radiotherapy (WBRT) in carefully selected patients with brain metastases from small-cell lung cancer (SCLC), the researchers say.

As expected, WBRT was superior to focused SRS in lengthening the time to disease progression in the brain. However, this advantage did not appear to provide an improvement in overall survival (OS).

“This study suggests that the trade-offs inherent to first-line SRS without WBRT, including a shorter time to new brain metastases without an apparent difference in overall survival, may be similar to other settings where SRS alone is already well established,” lead author Chad Rusthoven, MD, told Medscape Medical News.

Upfront SRS may be “particularly attractive for SCLC patients with limited brain metastases and those at a higher risk of developing neurocognitive toxicity from WBRT, including older patients and those with a poor baseline performance status,” said Rusthoven, of the Department of Radiation Oncology, University of Colorado School of Medicine, Aurora.

Results of the FIRE-SCLC study – the largest analysis of first-line SRS for patients with SCLC brain metastases – were published online June 4 in JAMA Oncology.

The coauthors of an editorial in JAMA Oncology say the FIRE-SCLC study investigators should be “commended for conducting this important work and also for highlighting the inherent limitations of retrospective data.”

“Even after multivariable adjustment, OS may not be directly compared between the SRS and WBRT groups because selection bias is likely,” caution Cecile Le Pechoux, MD, and Antonin Levy, MD, PhD, from Institut Gustave-Roussy in Villejuif, France.

“Impressive” Outcomes

The researchers analyzed the outcomes of 710 patients (mean age, 68.5 years; 75% men; Karnofsky Performance Status score, ≥90) who underwent first-line SRS without prior treatment with WBRT or prophylactic cranial irradiation. They compared the SRS outcomes with outcomes of a cohort of 219 patients treated with first-line WBRT for SCLC brain metastases.

The SRS outcomes are “encouraging,” with a median OS of 8.5 months, median time to central nervous system (CNS) progression (TTCP) of 8.1 months, and median CNS progression-free survival (PFS) of 5.0 months, the study investigators say.

The outcomes are “particularly impressive” in patients with a single brain metastasis (median OS and TTCP, 11.0 months and 11.7 months, respectively), they note.

They found no significant differences in OS or TTCP after SRS in patients with two to four lesions and those with five to 10 lesions.

Median OS was 8.7 months with two to four lesions, 8.0 months with five to 10 lesions, and 5.5 months with 11 or more lesions. Corresponding median TTCP was 6.8, 6.1, and 4.7 months.

Local failures after SRS were rare. Most CNS progression occurred in the form of new lesions, which is in line with what’s been shown with SRS in other settings.

In propensity score–matched analyses that compared SRS with WBRT, median OS was higher with SRS (6.5 months vs 5.2 months with WBRT; P = .003). Median TTCP was improved with WBRT (SRS, 9.0 months vs WBRT, not reached; hazard ratio, 0.38; 95% confidence interval, 0.26 – 0.55; P < .001), with no significant difference in CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79).

The results were similar in multivariable analyses that compared SRS and WBRT, including subgroup analyses that controlled for extracranial metastases and extracranial disease control status.

Benchmark Data

“Although these retrospective data should not be used to conclude that OS is superior with SRS, the findings of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP, are similar to other settings in which SRS alone is well established by multiple randomized clinical trials,” the researchers write.

These data, they say, provide a “benchmark for SRS outcomes and offer support to first-line SRS as a treatment option in carefully selected patients with small-cell lung cancer.”

In a news release, senior author Tyler Robin, MD, University of Colorado School of Medicine, notes that paradigms for the treatment of SCLC are “evolving,” with the integration of immunotherapy into SCLC management, less use of WBRT, and guideline updates advising routine brain MRI surveillance for all patients.

“These changes may be expected to increase the identification of small-cell lung cancer patients with limited brain metastases who may be candidates for first-line SRS,” said Robin.

SRS made mainstream headlines in 2015 when former President Jimmy Carter was successfully treated for melanoma brain metastases with it. At the time, SRS was relatively new. The approach is more targeted and less toxic than traditional WBRT. Carter was treated at Emory University in Atlanta, Georgia.

SRS is now widely available in the United States, but adoption has been slow, Rusthoven told Medscape Medical News.

“Delayed adoption of SRS for SCLC is related to a number of factors, including a concern for short-interval CNS progression with SCLC histology and the historical exclusion of SCLC patients from the landmark randomized trials that established SRS alone,” he said.

“We hope that this study will contribute to an increased interest in the role of SRS for carefully selected SCLC patients and that it will offer support to ongoing and developing prospective clinical trials evaluating first-line SRS alone for SCLC,” Rusthoven added.

Prospective Data “Eagerly” Needed

The French editorial writers say prospective data are “eagerly needed” for this patient population.

SRS, they conclude, “might be a promising treatment option” for patients with SCLC with brain metastases, but larger studies are needed, as prophylactic cranial irradiation or prophylactic-intent WBRT has been shown to improve survival. “Hopefully, the work of Rusthoven et al will be used for the development of further prospective trials in patients with SCLC with brain metastases,” they write.

The study was funded by a grant from the University of Colorado Cancer Center. Rusthoven has received research funding from Takeda outside the submitted work as well as honoraria for educational talks from Genentech and AstraZeneca outside this work. The original article contains a complete list of author disclosures. Le Pechoux has received institutional honoraria for participation in advisory boards from AstraZeneca, Nanobiotix, and Roche; institutional honoraria for participation to educational meetings from Amgen, AstraZeneca, Medscape, and Eli Lilly and Company; and personal honoraria from prIME Oncology for participation in educational meetings. Levy has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A new retrospective study provides some of the strongest support yet for considering first-line stereotactic radiosurgery (SRS) over whole-brain radiotherapy (WBRT) in carefully selected patients with brain metastases from small-cell lung cancer (SCLC), the researchers say.

As expected, WBRT was superior to focused SRS in lengthening the time to disease progression in the brain. However, this advantage did not appear to provide an improvement in overall survival (OS).

“This study suggests that the trade-offs inherent to first-line SRS without WBRT, including a shorter time to new brain metastases without an apparent difference in overall survival, may be similar to other settings where SRS alone is already well established,” lead author Chad Rusthoven, MD, told Medscape Medical News.

Upfront SRS may be “particularly attractive for SCLC patients with limited brain metastases and those at a higher risk of developing neurocognitive toxicity from WBRT, including older patients and those with a poor baseline performance status,” said Rusthoven, of the Department of Radiation Oncology, University of Colorado School of Medicine, Aurora.

Results of the FIRE-SCLC study – the largest analysis of first-line SRS for patients with SCLC brain metastases – were published online June 4 in JAMA Oncology.

The coauthors of an editorial in JAMA Oncology say the FIRE-SCLC study investigators should be “commended for conducting this important work and also for highlighting the inherent limitations of retrospective data.”

“Even after multivariable adjustment, OS may not be directly compared between the SRS and WBRT groups because selection bias is likely,” caution Cecile Le Pechoux, MD, and Antonin Levy, MD, PhD, from Institut Gustave-Roussy in Villejuif, France.

“Impressive” Outcomes

The researchers analyzed the outcomes of 710 patients (mean age, 68.5 years; 75% men; Karnofsky Performance Status score, ≥90) who underwent first-line SRS without prior treatment with WBRT or prophylactic cranial irradiation. They compared the SRS outcomes with outcomes of a cohort of 219 patients treated with first-line WBRT for SCLC brain metastases.

The SRS outcomes are “encouraging,” with a median OS of 8.5 months, median time to central nervous system (CNS) progression (TTCP) of 8.1 months, and median CNS progression-free survival (PFS) of 5.0 months, the study investigators say.

The outcomes are “particularly impressive” in patients with a single brain metastasis (median OS and TTCP, 11.0 months and 11.7 months, respectively), they note.

They found no significant differences in OS or TTCP after SRS in patients with two to four lesions and those with five to 10 lesions.

Median OS was 8.7 months with two to four lesions, 8.0 months with five to 10 lesions, and 5.5 months with 11 or more lesions. Corresponding median TTCP was 6.8, 6.1, and 4.7 months.

Local failures after SRS were rare. Most CNS progression occurred in the form of new lesions, which is in line with what’s been shown with SRS in other settings.

In propensity score–matched analyses that compared SRS with WBRT, median OS was higher with SRS (6.5 months vs 5.2 months with WBRT; P = .003). Median TTCP was improved with WBRT (SRS, 9.0 months vs WBRT, not reached; hazard ratio, 0.38; 95% confidence interval, 0.26 – 0.55; P < .001), with no significant difference in CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79).

The results were similar in multivariable analyses that compared SRS and WBRT, including subgroup analyses that controlled for extracranial metastases and extracranial disease control status.

Benchmark Data

“Although these retrospective data should not be used to conclude that OS is superior with SRS, the findings of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP, are similar to other settings in which SRS alone is well established by multiple randomized clinical trials,” the researchers write.

These data, they say, provide a “benchmark for SRS outcomes and offer support to first-line SRS as a treatment option in carefully selected patients with small-cell lung cancer.”

In a news release, senior author Tyler Robin, MD, University of Colorado School of Medicine, notes that paradigms for the treatment of SCLC are “evolving,” with the integration of immunotherapy into SCLC management, less use of WBRT, and guideline updates advising routine brain MRI surveillance for all patients.

“These changes may be expected to increase the identification of small-cell lung cancer patients with limited brain metastases who may be candidates for first-line SRS,” said Robin.

SRS made mainstream headlines in 2015 when former President Jimmy Carter was successfully treated for melanoma brain metastases with it. At the time, SRS was relatively new. The approach is more targeted and less toxic than traditional WBRT. Carter was treated at Emory University in Atlanta, Georgia.

SRS is now widely available in the United States, but adoption has been slow, Rusthoven told Medscape Medical News.

“Delayed adoption of SRS for SCLC is related to a number of factors, including a concern for short-interval CNS progression with SCLC histology and the historical exclusion of SCLC patients from the landmark randomized trials that established SRS alone,” he said.

“We hope that this study will contribute to an increased interest in the role of SRS for carefully selected SCLC patients and that it will offer support to ongoing and developing prospective clinical trials evaluating first-line SRS alone for SCLC,” Rusthoven added.

Prospective Data “Eagerly” Needed

The French editorial writers say prospective data are “eagerly needed” for this patient population.

SRS, they conclude, “might be a promising treatment option” for patients with SCLC with brain metastases, but larger studies are needed, as prophylactic cranial irradiation or prophylactic-intent WBRT has been shown to improve survival. “Hopefully, the work of Rusthoven et al will be used for the development of further prospective trials in patients with SCLC with brain metastases,” they write.

The study was funded by a grant from the University of Colorado Cancer Center. Rusthoven has received research funding from Takeda outside the submitted work as well as honoraria for educational talks from Genentech and AstraZeneca outside this work. The original article contains a complete list of author disclosures. Le Pechoux has received institutional honoraria for participation in advisory boards from AstraZeneca, Nanobiotix, and Roche; institutional honoraria for participation to educational meetings from Amgen, AstraZeneca, Medscape, and Eli Lilly and Company; and personal honoraria from prIME Oncology for participation in educational meetings. Levy has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

sworcester@mdedge.com

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

sworcester@mdedge.com

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

Adjuvant gefitinib provides no overall survival (OS) benefit over standard chemotherapy for EGFR-mutant, resected, stage II-IIIA non–small cell lung cancer (NSCLC), according to final results from the phase 3 ADJUVANT trial.

The median OS was 75.5 months in patients randomized to adjuvant gefitinib and 62.8 months in patients randomized to vinorelbine plus cisplatin.

Yi-Long Wu, MD, of Guangdong Lung Cancer Institute in Guangzhou, China, reported these results as part of the American Society of Clinical Oncology virtual scientific program.

Prior results from this trial had shown a disease-free survival (DFS) benefit with gefitinib, but this did not translate to an OS benefit at the final analysis, Dr. Wu said.

He noted, however, that the median OS of 75.5 months in the gefitinib arm “was one of the best in resected EGFR-mutant non–small cell lung cancer, compared with historical data.”

The findings also suggest a possible benefit with at least 18 months of gefitinib and show that adjuvant EGFR tyrosine kinase inhibitors (TKIs) should be considered the optimal therapy to improve DFS and achieve potentially better OS in this setting, Dr. Wu said.
 

Study details and DFS

The ADJUVANT trial (NCT01405079) randomized 222 patients, aged 18-75 years, with EGFR-mutant, stage II-IIIA (N1-N2) NSCLC who had undergone complete resection. Patients were enrolled at 27 sites between September 2011 and April 2014.

The patients were randomized 1:1 to receive 250 mg of gefitinib once daily for 24 months, or 25 mg/m² of vinorelbine on days 1 and 8 plus 75 mg/m² of cisplatin on day 1 every 3 weeks for 4 cycles.

The intent-to-treat (ITT) population included 111 patients in each arm. The per-protocol population included 106 patients in the gefitinib arm and 87 patients in the chemotherapy arm.

Primary results from this trial showed a significant improvement in DFS with gefitinib (Lancet Oncol. 2018 Jan;19[1]:139-48). That improvement was maintained in the final analysis.

The median DFS was 30.8 months in the gefitinib arm and 19.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The hazard ratio (HR) was 0.56 (P = .001) in the ITT population and 0.51 (P < .001) in the per-protocol population.

In the ITT population, the 5-year DFS rates were 22.6% in the gefitinib arm and 23.2% in the chemotherapy arm. In the per-protocol population, the 5-year DFS rates were 22.6% and 22.8%, respectively.

OS results

The median OS was 75.5 months in the gefitinib arm and 62.8 months in the chemotherapy arm for both the ITT and per-protocol populations. The HR was 0.92 in both the ITT (P = .674) and per-protocol populations (P = .686).

In the ITT population, the 5-year OS rates were 53.2% in the gefitinib arm and 51.2% in the chemotherapy arm. In the per-protocol population, the 5-year OS rates were 53.2% and 50.7%, respectively.

Subgroup analyses by age, gender, lymph node status, and EGFR mutation showed trends toward improved OS with gefitinib, but the differences were not statistically significant.

The researchers conducted a post hoc analysis to assess the effect of subsequent treatment on patient outcomes. The analysis showed that patients who received gefitinib with subsequent EGFR-TKIs had the best responses and OS.

The median OS was not reached among patients who received gefitinib and subsequent EGFR-TKIs, whereas the median OS ranged from 15.6 months to 62.8 months in other groups. The shortest OS was observed in patients who received adjuvant chemotherapy without subsequent therapy.

The duration of gefitinib treatment also appeared to affect OS. The median OS was 35.7 months in patients who received gefitinib for less than 18 months, and the median OS was not reached in patients who received gefitinib for 18 months or longer (HR, 0.38; P < .001).
 

Implications and potential next steps

Despite the lack of OS improvement with gefitinib, “all of the patients on this study did much, much better than historical non–small cell lung cancer not specified by the EGFR mutation, with 70 months median survival compared to 35 months median survival for N2-positive disease,” said invited discussant Christopher G. Azzoli, MD, director of thoracic oncology at Lifespan Cancer Institute at Brown University in Providence, R.I.

“But you can’t avoid noticing how the curves come back together in terms of disease-free survival when your effective treatment is limited to 24 months,” he added.

An apparent risk of late brain recurrence in the gefitinib arm is also a concern, Dr. Azzoli said. “So ... longer duration of treatment with a drug that has better control of CNS [central nervous system] disease, such as osimertinib, may improve both DFS and OS,” he added.

Only about 50% of patients in the chemotherapy arm received a TKI at recurrence. The post hoc analysis showing that TKI recipients had the best outcomes raises the question of whether “the survival benefit could be conferred by delivering a superior drug merely at recurrence, or is there benefit to earlier delivery of an effective drug,” Dr. Azzoli said.

Given the high cost of continuous therapy, biomarker refinement could help improve treatment decision-making, he said, noting that “early testing of blood DNA to detect cancer in the body as minimal residual disease is showing promise,” and that many phase 3 studies of EGFR-TKIs are ongoing.

The current trial was sponsored by the Guangdong Association of Clinical Trials. Dr. Wu disclosed relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Lilly, MSD Oncology, Pfizer, and Roche. Dr. Azzoli reported having no disclosures.

sworcester@mdedge.com

SOURCE: Wu Y et al. ASCO 2020, Abstract 9005.

The use of electronic nicotine delivery systems is associated with increased risk of cigarette smoking relapse among former smokers, results from a large longitudinal cohort study demonstrated.

ArminStautBerlin/Thinkstock

“For the many clinicians treating former smokers who have successfully quit all nicotine products, the implications are that use of [electronic nicotine delivery systems] should be discouraged, just as use of all other tobacco products is discouraged,” researchers led by Colm D. Everard, PhD, reported in a study published in JAMA Network Open (2020 Jun 5. doi: 10.1001/jamanetworkopen.2020.4813).

Dr. Everard, of the National Institute on Drug Abuse, and colleagues based their comments on results from a survey of adult former smokers who participated in Waves 1-4 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2018). They limited the analysis to 2,273 former cigarette smokers who self-reported reported no tobacco product use at Wave 1, and categorized them as recent former smokers (defined as having last smoked within the past 12 previous months) or as long-term former smokers (defined as having last smoked for longer ago than in the previous 12 months). The main outcome of interest was the self-reported current use of cigarettes at follow-up interviews, which was defined as every day or some days. Electronic nicotine delivery systems (ENDS) comprised e-cigarettes, e-cigars, e-pipes, and e-hookahs. Other tobacco products included cigars, pipe tobacco, hookahs, snus tobacco, other smokeless tobacco, and dissolvable tobacco.

Of the 2,273 adult former smokers, 52% were women, 60% were older than age 50, and 80% were non-Hispanic white. Adjusted hazard ratio (AHR) analysis revealed that the use of ENDS was associated with significant risk of cigarette smoking relapse among recent former smokers (AHR 1.63) and among long-term former smokers (AHR 3.79). The use of other tobacco products was associated with significant risk for cigarette smoking relapse among recent former smokers (AHR 1.97) and among long-term former smokers (AHR 3.82).

The authors acknowledged certain limitations of the study, including the fact that it did not assess different ENDS devices, different e-liquid nicotine levels, or frequency of ENDS use and their associations with cigarette smoking relapse. It also did not explore the mechanism by which ENDS use may lead to reestablishing or reinforcing nicotine-seeking behavior among former cigarette users. “Determining pharmacologic, behavioral, or some other explanation for these findings may require laboratory-based research,” they wrote.

The PATH Study is supported with federal funds from the National Institute on Drug Abuse, the National Institutes of Health, and the Food and Drug Administration and Department of Health and Human Services under a contract to Westat. One of the study authors, Wilson M. Compton, MD, reported having long-term stock holdings in General Electric, 3M, and Pfizer. The other authors reported having no financial disclosures.

dbrunk@mdedge.com

The use of electronic nicotine delivery systems is associated with increased risk of cigarette smoking relapse among former smokers, results from a large longitudinal cohort study demonstrated.

ArminStautBerlin/Thinkstock

“For the many clinicians treating former smokers who have successfully quit all nicotine products, the implications are that use of [electronic nicotine delivery systems] should be discouraged, just as use of all other tobacco products is discouraged,” researchers led by Colm D. Everard, PhD, reported in a study published in JAMA Network Open (2020 Jun 5. doi: 10.1001/jamanetworkopen.2020.4813).

Dr. Everard, of the National Institute on Drug Abuse, and colleagues based their comments on results from a survey of adult former smokers who participated in Waves 1-4 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2018). They limited the analysis to 2,273 former cigarette smokers who self-reported reported no tobacco product use at Wave 1, and categorized them as recent former smokers (defined as having last smoked within the past 12 previous months) or as long-term former smokers (defined as having last smoked for longer ago than in the previous 12 months). The main outcome of interest was the self-reported current use of cigarettes at follow-up interviews, which was defined as every day or some days. Electronic nicotine delivery systems (ENDS) comprised e-cigarettes, e-cigars, e-pipes, and e-hookahs. Other tobacco products included cigars, pipe tobacco, hookahs, snus tobacco, other smokeless tobacco, and dissolvable tobacco.

Of the 2,273 adult former smokers, 52% were women, 60% were older than age 50, and 80% were non-Hispanic white. Adjusted hazard ratio (AHR) analysis revealed that the use of ENDS was associated with significant risk of cigarette smoking relapse among recent former smokers (AHR 1.63) and among long-term former smokers (AHR 3.79). The use of other tobacco products was associated with significant risk for cigarette smoking relapse among recent former smokers (AHR 1.97) and among long-term former smokers (AHR 3.82).

The authors acknowledged certain limitations of the study, including the fact that it did not assess different ENDS devices, different e-liquid nicotine levels, or frequency of ENDS use and their associations with cigarette smoking relapse. It also did not explore the mechanism by which ENDS use may lead to reestablishing or reinforcing nicotine-seeking behavior among former cigarette users. “Determining pharmacologic, behavioral, or some other explanation for these findings may require laboratory-based research,” they wrote.

The PATH Study is supported with federal funds from the National Institute on Drug Abuse, the National Institutes of Health, and the Food and Drug Administration and Department of Health and Human Services under a contract to Westat. One of the study authors, Wilson M. Compton, MD, reported having long-term stock holdings in General Electric, 3M, and Pfizer. The other authors reported having no financial disclosures.

dbrunk@mdedge.com

The use of electronic nicotine delivery systems is associated with increased risk of cigarette smoking relapse among former smokers, results from a large longitudinal cohort study demonstrated.

ArminStautBerlin/Thinkstock

“For the many clinicians treating former smokers who have successfully quit all nicotine products, the implications are that use of [electronic nicotine delivery systems] should be discouraged, just as use of all other tobacco products is discouraged,” researchers led by Colm D. Everard, PhD, reported in a study published in JAMA Network Open (2020 Jun 5. doi: 10.1001/jamanetworkopen.2020.4813).

Dr. Everard, of the National Institute on Drug Abuse, and colleagues based their comments on results from a survey of adult former smokers who participated in Waves 1-4 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2018). They limited the analysis to 2,273 former cigarette smokers who self-reported reported no tobacco product use at Wave 1, and categorized them as recent former smokers (defined as having last smoked within the past 12 previous months) or as long-term former smokers (defined as having last smoked for longer ago than in the previous 12 months). The main outcome of interest was the self-reported current use of cigarettes at follow-up interviews, which was defined as every day or some days. Electronic nicotine delivery systems (ENDS) comprised e-cigarettes, e-cigars, e-pipes, and e-hookahs. Other tobacco products included cigars, pipe tobacco, hookahs, snus tobacco, other smokeless tobacco, and dissolvable tobacco.

Of the 2,273 adult former smokers, 52% were women, 60% were older than age 50, and 80% were non-Hispanic white. Adjusted hazard ratio (AHR) analysis revealed that the use of ENDS was associated with significant risk of cigarette smoking relapse among recent former smokers (AHR 1.63) and among long-term former smokers (AHR 3.79). The use of other tobacco products was associated with significant risk for cigarette smoking relapse among recent former smokers (AHR 1.97) and among long-term former smokers (AHR 3.82).

The authors acknowledged certain limitations of the study, including the fact that it did not assess different ENDS devices, different e-liquid nicotine levels, or frequency of ENDS use and their associations with cigarette smoking relapse. It also did not explore the mechanism by which ENDS use may lead to reestablishing or reinforcing nicotine-seeking behavior among former cigarette users. “Determining pharmacologic, behavioral, or some other explanation for these findings may require laboratory-based research,” they wrote.

The PATH Study is supported with federal funds from the National Institute on Drug Abuse, the National Institutes of Health, and the Food and Drug Administration and Department of Health and Human Services under a contract to Westat. One of the study authors, Wilson M. Compton, MD, reported having long-term stock holdings in General Electric, 3M, and Pfizer. The other authors reported having no financial disclosures.

dbrunk@mdedge.com

Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies.¹ Pulmonary NETs are rare, accounting for 1 to 2% of all invasive lung malignancies and involve about 20 to 25% of primary lung malignancies. ^2,3 Their prevalence has increased by an estimated 6% per year over the past 30 years.² Nonetheless, the time of diagnosis is frequently delayed because of nonspecific symptoms that may imitate other pulmonary conditions.

In the normal pleural space, there is a steady state in which there is a roughly equal rate of fluid formation and absorption. Any disequilibrium may produce a pleural effusion. Pleural fluids can be transudates or exudates. Transudates result from imbalances in hydrostatic and oncotic pressures in the pleural space. Exudates result primarily from pleural and/or lung inflammation or from impaired lymphatic drainage of the pleural space. Clinical manifestations include cough, wheezing, recurrent pneumonia, hemoptysis and pleural effusions. We present a case of a man who developed a large left pleural effusion with a pathology report suggesting a pulmonary NET as the etiology. Being aware of this rare entity may help improve prognosis by making an earlier diagnosis and starting treatment sooner.

Case Presentation

A 90-year-old man with a medical history of arterial hypertension, hyperlipidemia, type 2 diabetes mellitus, coronary artery disease, and vascular dementia presented to the emergency department with hypoactivity, poor appetite, productive cough, and shortness of breath. The patient was a former smoker (unknown pack-years) who quit smoking cigarettes 7 years prior. Vital signs showed sinus tachycardia and peripheral oxygen saturation of 90% at room air. The initial physical examination was remarkable for decreased breath sounds and crackles at the left lung base. Laboratory findings showed leukocytosis with neutrophilia and chronic normocytic anemia. Chest computed tomography (CT) showed a large left-sided pleural effusion occupying most of the left hemithorax with adjacent atelectatic lung, enlarged pretracheal, subcarinal, and left perihilar lymph nodes (Figure 1).

The patient was admitted to the internal medicine ward with the diagnosis of left pneumonic process and started on IV levofloxacin. However, despite 7 days of antibiotic therapy, the patient’s respiratory symptoms worsened. This clinical deterioration prompted pulmonary service consultation. Chest radiography demonstrated an enlarging left pleural effusion (Figure 2). A thoracentesis drained 1.2 L of serosanguineous pleural fluid. Pleural fluid analysis showed a cell count of 947/cm3 with 79% of lymphocytes, total protein 3.8 g/dL, lactic dehydrogenase (LDH) level 607 U/L, and glucose level 109 mg/dL. Serum total protein was 6.62 g/dL, LDH 666 U/L and glucose 92 mg/dL (Tables 1 and 2). Alanine transaminase (ALT) and aspartate aminotransferase (AST) were 11 U/L and 21 U/L, respectively. Using Light criteria, the pleural:serum protein ratio was 0.57, the pleural:serum LDH ratio was 0.91, and the pleural LDH was more than two-thirds of the serum LDH. These calculations were consistent with an exudative effusion. An infectious disease workup, including blood and pleural fluid cultures, was negative.

The pleural fluid concentrated cell block hematoxylin and eosin (H&E) staining showed chromatin, prominent nucleoli, and nuclear molding, which was compatible with high-grade lung NET (Figure 3). The cell block immunohistochemistry (IHC) was positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE) also consistent with a high-grade pulmonary NET (Figure 4). The proliferation marker protein Ki-67 labeling index (LI) showed a proliferation index > 20% (Figure 5). The patient did not have decision-making capacity given vascular dementia. Multiple attempts to contact the next of kin or family members were unsuccessful. Risks vs benefits were evaluated, and given the patient’s advanced age and multiple comorbidities, a conservative management approach under palliative care was chosen. For this reason, further genomic studies were not done.

Discussion

NETs are a group of neoplasms that differ in site, amount of cell propagation, and clinical manifestations.⁴ These tumors are rare with an estimated incidence of 25 to 50 per 100,000.4 The most commonly affected organ systems are the gastroenteropancreatic and the bronchopulmonary tracts, accounting for 60% and 25% of the tumors, respectively.4 The incidence is increasing over the past years in part because of novel diagnostic techniques.

The average age of diagnosis is between the fourth and sixth decades, affecting more women than men.⁵ Smoking has been identified as a possible culprit for the development of these neoplasms; nonetheless, the association is still not clear.⁴ For example, poorly differentiated pulmonary NETs have a strong association with smoking but not well-differentiated pulmonary NETs.²

Patients typically present with cough, wheezing, hemoptysis, and recurrent pneumonias, which are in part a consequence of obstruction caused by the mass.² Sometimes, obstruction may yield persistent pleural effusions. Hemoptysis may be seen secondary to the vascularity of pulmonary NETs.

The diagnosis is often delayed because patients are frequently treated for infection before being diagnosed with the malignancy, such as in our case. Radiologic image findings include round opacities, central masses, and atelectasis. Pulmonary NETs are frequently found incidentally as solitary lung nodules. The CT scan is the most common diagnostic modality and can provide information about the borders of the tumor, the location and surrounding structures, including the presence of atelectasis.⁵ Pulmonary NETs are usually centrally located in an accessible region for lung biopsy. In cases where the mass is not easily reachable, thoracentesis may provide the only available specimen.

The 2015 World Health Organization classification has identified 4 histologic types of pulmonary NETs, namely, typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC).⁶ The low-grade pulmonary NET, the typical carcinoid, is slow growing and has lower rates of metastasis. The intermediate-grade NET, the atypical carcinoid, is more aggressive. The highgrade NETs, the LCNEC and the SCLC, are aggressive and spread quickly to other places.⁶ Consequently, LCNEC and SCLC have higher mortalities with a 5-year survival, ranging from 13 to 57% and 5%, respectively.⁷

Tumors may be histomorphologically classified by H&E staining. The main characteristics that differentiate the low- and high-grade NETs are the presence of necrosis and the mitotic rate. Both categories form neuropeptides and have dense granular cores when seen with an electron microscopy^.6 The TC and AC have welldefined, organized histologic patterns, no necrosis, and scarce mitosis. On the other hand, the LCNEC and SCLC are poorly differentiated tumors with necrosis, atypia, and mitosis.6 LCNEC can be separated from SCLC and other tumors by IHC staining, whereas SCLC is primarily distinguished by morphology.

If the biopsy sample size is small, then IHC morphology and markers are helpful for subclassification.⁸ IHC is used to discern between neuroendocrine (NE) vs non-NE. The evaluation of pleural fluid includes preparation of cell blocks. Cell block staining is deemed better for IHC because it mimics a small biopsy that enables superior stains.⁹ The need for a pleural biopsy in cases where the cytology is negative depends on treatment aims, the kind of tumor, and the presence of metastasis.¹⁰ In almost 80% of cases, pleural biopsy and cytology are the only specimens obtained for analysis.Therefore, identification of these markers is practical for diagnosis.¹⁰ For this reason, pleural effusion samples are appropriate options to lung biopsy for molecular studies.¹⁰

Ki-67 LI in samples has the highest specificity and sensitivity for low-tointermediate- grade vs high-grade tumors. It is being used for guiding clinical and treatment decisions.⁶ In SCLC, the Ki-67 LI is not necessary for diagnosis but will be about 80%.¹¹ The tumor cells will show epithelial characteristics with positive cytokeratin AE1/AE3 and monoclonal antibody CAM5.² and neuroendocrine markers, including NCAM/CD56, chromogranin A, and synaptophysin.¹¹

Thyroid transcription factor-1 (TTF- 1) is positive in most cases. In LCNEC, the Ki-67 LI is between 40% and 80%. NCAM/ CD56, chromogranin A, and synaptophysin are present in 92 to 100%, 80 to 85%, and 50 to 60%, respectively.¹¹ TTF-1 is identified in half of the tumors. All these tumors express pancytokeratin (AE1/AE3), cytokeratin 7 or low-molecular-weight cytokeratin. Likewise, the carcinoids will show markers, such as chromogranin A, synaptophysin, CD56, and epithelial markers like pancytokeratin.¹¹ However, the high-molecular-weight cytokeratin and TTF-1 are negative. Furthermore, NSE is considered a good tumor marker in the diagnosis and prognosis of SCLC. NSE also has been reported in NSCLC. The level of NSE correlates with tumor burden, number of metastatic sites, and response to treatment. ¹² A potentially useful marker is the insulinoma-associated protein 1, which is a nuclear determinant of NE differentiation that stains all types of pulmonary NETs irrespective of the histology but does not stain adenocarcinoma or squamous cell carcinoma (SCC).⁶

Recently, genomic studies have identified gene alterations that have become standard of care for diagnosis and targeted therapies.⁸ For example, epidermal growth factor receptor (EGFR) and echinoderm microtubule- associated proteinlike 4, and anaplastic lymphoma kinase (EML4-ALK) mutations have been found in about 25% of lung adenocarcinomas. ⁸ Other abnormalities in LKB1/STK11, NF1, CDKN2A, SMARCA4 and KEAP1, KRAS, MET, ROS1, and RET have also been identified.8 On the other hand, SCC rarely have derangements in EGFR and EML4-ALK, but do show changes in RTKs, DDR2M, FGGRs, among others.8 In TC and AC, observed molecular alterations include MEN1 mutations, mTOR, and SSTRs pathway activation, and GC/ CEACAM1 and CD44/OTP expression.¹³ LCNEC and SCLC have shown TP53 and RB1 mutations and CDX2/VIL1/BAI3 expression. DLL3 expression and MET mutations may be present in SCLC.13 Last, chromatin remodeling gene mutations have been identified in all these lung NET types.¹³

Furthermore, neuropeptides and neuroamines may be measured in the blood and urine.¹⁴ Pulmonary NETs may be functional and secrete these substances, leading to systemic symptoms based on the released molecules.¹⁵ However, pulmonary NETs produce less serotonin than gastrointestinal NETs; therefore, carcinoid syndrome is less frequent in pulmonary NETs.¹⁶ Liver metastasis is often present when it occurs.⁵ Other possible clinical features include Cushing syndrome and acromegaly depending on the secreted hormones.⁵

In a recent metanalysis, serum LDH has been found to have a prognostic role in Ewing sarcoma, urologic cancers, malignant mesothelioma, among others.¹⁷ It demonstrated that a higher LDH concentration is associated with worse survival in patients with lung cancer.¹⁷ Serum LDH is an enzyme that catalyzes the reaction between lactic acid and pyruvic acid that typically takes place in anaerobic conditions.¹⁷ LDH levels are elevated in malignancies because tumors have an anaerobic environment. Elevated LDH levels correlate with the anaerobic metabolism in the tumor. Other studies also have noted that patients with high metastatic score have higher LDH levels.¹⁷ Therefore, LDH may reflect tumor extension.

In addition, other techniques, such as somatostatin- receptor imaging are specifically beneficial in tumors that express the somatostatin receptor.¹⁶ For this reason, this type of study is typically indicated in patients with known metastasis, not in patients with low-grade tumors. Abdominal CT scans are done because the liver is a common site for metastasis.

Our case report demonstrates how biomarkers help diagnose these potentially aggressive and life-threatening tumors that may present as a common condition such as a pleural effusion. Using a less invasive and quicker approach with thoracentesis rather than with lung biopsies is a diagnostic tool in this entity. IHC in cell blocks is a reasonable diagnostic method especially in patients in whom performing a lung biopsy is difficult.

Conclusions

The presence of a symptomatic and recurrent unilateral pleural effusion must urge physicians to consider thoracentesis with mindful use of biomarkers not only for therapeutic purposes, but also for diagnosis of a variety of etiologies, both benign and malignant.

Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies.¹ Pulmonary NETs are rare, accounting for 1 to 2% of all invasive lung malignancies and involve about 20 to 25% of primary lung malignancies. ^2,3 Their prevalence has increased by an estimated 6% per year over the past 30 years.² Nonetheless, the time of diagnosis is frequently delayed because of nonspecific symptoms that may imitate other pulmonary conditions.

In the normal pleural space, there is a steady state in which there is a roughly equal rate of fluid formation and absorption. Any disequilibrium may produce a pleural effusion. Pleural fluids can be transudates or exudates. Transudates result from imbalances in hydrostatic and oncotic pressures in the pleural space. Exudates result primarily from pleural and/or lung inflammation or from impaired lymphatic drainage of the pleural space. Clinical manifestations include cough, wheezing, recurrent pneumonia, hemoptysis and pleural effusions. We present a case of a man who developed a large left pleural effusion with a pathology report suggesting a pulmonary NET as the etiology. Being aware of this rare entity may help improve prognosis by making an earlier diagnosis and starting treatment sooner.

Case Presentation

A 90-year-old man with a medical history of arterial hypertension, hyperlipidemia, type 2 diabetes mellitus, coronary artery disease, and vascular dementia presented to the emergency department with hypoactivity, poor appetite, productive cough, and shortness of breath. The patient was a former smoker (unknown pack-years) who quit smoking cigarettes 7 years prior. Vital signs showed sinus tachycardia and peripheral oxygen saturation of 90% at room air. The initial physical examination was remarkable for decreased breath sounds and crackles at the left lung base. Laboratory findings showed leukocytosis with neutrophilia and chronic normocytic anemia. Chest computed tomography (CT) showed a large left-sided pleural effusion occupying most of the left hemithorax with adjacent atelectatic lung, enlarged pretracheal, subcarinal, and left perihilar lymph nodes (Figure 1).

The patient was admitted to the internal medicine ward with the diagnosis of left pneumonic process and started on IV levofloxacin. However, despite 7 days of antibiotic therapy, the patient’s respiratory symptoms worsened. This clinical deterioration prompted pulmonary service consultation. Chest radiography demonstrated an enlarging left pleural effusion (Figure 2). A thoracentesis drained 1.2 L of serosanguineous pleural fluid. Pleural fluid analysis showed a cell count of 947/cm3 with 79% of lymphocytes, total protein 3.8 g/dL, lactic dehydrogenase (LDH) level 607 U/L, and glucose level 109 mg/dL. Serum total protein was 6.62 g/dL, LDH 666 U/L and glucose 92 mg/dL (Tables 1 and 2). Alanine transaminase (ALT) and aspartate aminotransferase (AST) were 11 U/L and 21 U/L, respectively. Using Light criteria, the pleural:serum protein ratio was 0.57, the pleural:serum LDH ratio was 0.91, and the pleural LDH was more than two-thirds of the serum LDH. These calculations were consistent with an exudative effusion. An infectious disease workup, including blood and pleural fluid cultures, was negative.

The pleural fluid concentrated cell block hematoxylin and eosin (H&E) staining showed chromatin, prominent nucleoli, and nuclear molding, which was compatible with high-grade lung NET (Figure 3). The cell block immunohistochemistry (IHC) was positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE) also consistent with a high-grade pulmonary NET (Figure 4). The proliferation marker protein Ki-67 labeling index (LI) showed a proliferation index > 20% (Figure 5). The patient did not have decision-making capacity given vascular dementia. Multiple attempts to contact the next of kin or family members were unsuccessful. Risks vs benefits were evaluated, and given the patient’s advanced age and multiple comorbidities, a conservative management approach under palliative care was chosen. For this reason, further genomic studies were not done.

Discussion

NETs are a group of neoplasms that differ in site, amount of cell propagation, and clinical manifestations.⁴ These tumors are rare with an estimated incidence of 25 to 50 per 100,000.4 The most commonly affected organ systems are the gastroenteropancreatic and the bronchopulmonary tracts, accounting for 60% and 25% of the tumors, respectively.4 The incidence is increasing over the past years in part because of novel diagnostic techniques.

The average age of diagnosis is between the fourth and sixth decades, affecting more women than men.⁵ Smoking has been identified as a possible culprit for the development of these neoplasms; nonetheless, the association is still not clear.⁴ For example, poorly differentiated pulmonary NETs have a strong association with smoking but not well-differentiated pulmonary NETs.²

Patients typically present with cough, wheezing, hemoptysis, and recurrent pneumonias, which are in part a consequence of obstruction caused by the mass.² Sometimes, obstruction may yield persistent pleural effusions. Hemoptysis may be seen secondary to the vascularity of pulmonary NETs.

The diagnosis is often delayed because patients are frequently treated for infection before being diagnosed with the malignancy, such as in our case. Radiologic image findings include round opacities, central masses, and atelectasis. Pulmonary NETs are frequently found incidentally as solitary lung nodules. The CT scan is the most common diagnostic modality and can provide information about the borders of the tumor, the location and surrounding structures, including the presence of atelectasis.⁵ Pulmonary NETs are usually centrally located in an accessible region for lung biopsy. In cases where the mass is not easily reachable, thoracentesis may provide the only available specimen.

The 2015 World Health Organization classification has identified 4 histologic types of pulmonary NETs, namely, typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC).⁶ The low-grade pulmonary NET, the typical carcinoid, is slow growing and has lower rates of metastasis. The intermediate-grade NET, the atypical carcinoid, is more aggressive. The highgrade NETs, the LCNEC and the SCLC, are aggressive and spread quickly to other places.⁶ Consequently, LCNEC and SCLC have higher mortalities with a 5-year survival, ranging from 13 to 57% and 5%, respectively.⁷

Tumors may be histomorphologically classified by H&E staining. The main characteristics that differentiate the low- and high-grade NETs are the presence of necrosis and the mitotic rate. Both categories form neuropeptides and have dense granular cores when seen with an electron microscopy^.6 The TC and AC have welldefined, organized histologic patterns, no necrosis, and scarce mitosis. On the other hand, the LCNEC and SCLC are poorly differentiated tumors with necrosis, atypia, and mitosis.6 LCNEC can be separated from SCLC and other tumors by IHC staining, whereas SCLC is primarily distinguished by morphology.

If the biopsy sample size is small, then IHC morphology and markers are helpful for subclassification.⁸ IHC is used to discern between neuroendocrine (NE) vs non-NE. The evaluation of pleural fluid includes preparation of cell blocks. Cell block staining is deemed better for IHC because it mimics a small biopsy that enables superior stains.⁹ The need for a pleural biopsy in cases where the cytology is negative depends on treatment aims, the kind of tumor, and the presence of metastasis.¹⁰ In almost 80% of cases, pleural biopsy and cytology are the only specimens obtained for analysis.Therefore, identification of these markers is practical for diagnosis.¹⁰ For this reason, pleural effusion samples are appropriate options to lung biopsy for molecular studies.¹⁰

Ki-67 LI in samples has the highest specificity and sensitivity for low-tointermediate- grade vs high-grade tumors. It is being used for guiding clinical and treatment decisions.⁶ In SCLC, the Ki-67 LI is not necessary for diagnosis but will be about 80%.¹¹ The tumor cells will show epithelial characteristics with positive cytokeratin AE1/AE3 and monoclonal antibody CAM5.² and neuroendocrine markers, including NCAM/CD56, chromogranin A, and synaptophysin.¹¹

Thyroid transcription factor-1 (TTF- 1) is positive in most cases. In LCNEC, the Ki-67 LI is between 40% and 80%. NCAM/ CD56, chromogranin A, and synaptophysin are present in 92 to 100%, 80 to 85%, and 50 to 60%, respectively.¹¹ TTF-1 is identified in half of the tumors. All these tumors express pancytokeratin (AE1/AE3), cytokeratin 7 or low-molecular-weight cytokeratin. Likewise, the carcinoids will show markers, such as chromogranin A, synaptophysin, CD56, and epithelial markers like pancytokeratin.¹¹ However, the high-molecular-weight cytokeratin and TTF-1 are negative. Furthermore, NSE is considered a good tumor marker in the diagnosis and prognosis of SCLC. NSE also has been reported in NSCLC. The level of NSE correlates with tumor burden, number of metastatic sites, and response to treatment. ¹² A potentially useful marker is the insulinoma-associated protein 1, which is a nuclear determinant of NE differentiation that stains all types of pulmonary NETs irrespective of the histology but does not stain adenocarcinoma or squamous cell carcinoma (SCC).⁶

Recently, genomic studies have identified gene alterations that have become standard of care for diagnosis and targeted therapies.⁸ For example, epidermal growth factor receptor (EGFR) and echinoderm microtubule- associated proteinlike 4, and anaplastic lymphoma kinase (EML4-ALK) mutations have been found in about 25% of lung adenocarcinomas. ⁸ Other abnormalities in LKB1/STK11, NF1, CDKN2A, SMARCA4 and KEAP1, KRAS, MET, ROS1, and RET have also been identified.8 On the other hand, SCC rarely have derangements in EGFR and EML4-ALK, but do show changes in RTKs, DDR2M, FGGRs, among others.8 In TC and AC, observed molecular alterations include MEN1 mutations, mTOR, and SSTRs pathway activation, and GC/ CEACAM1 and CD44/OTP expression.¹³ LCNEC and SCLC have shown TP53 and RB1 mutations and CDX2/VIL1/BAI3 expression. DLL3 expression and MET mutations may be present in SCLC.13 Last, chromatin remodeling gene mutations have been identified in all these lung NET types.¹³

Furthermore, neuropeptides and neuroamines may be measured in the blood and urine.¹⁴ Pulmonary NETs may be functional and secrete these substances, leading to systemic symptoms based on the released molecules.¹⁵ However, pulmonary NETs produce less serotonin than gastrointestinal NETs; therefore, carcinoid syndrome is less frequent in pulmonary NETs.¹⁶ Liver metastasis is often present when it occurs.⁵ Other possible clinical features include Cushing syndrome and acromegaly depending on the secreted hormones.⁵

In a recent metanalysis, serum LDH has been found to have a prognostic role in Ewing sarcoma, urologic cancers, malignant mesothelioma, among others.¹⁷ It demonstrated that a higher LDH concentration is associated with worse survival in patients with lung cancer.¹⁷ Serum LDH is an enzyme that catalyzes the reaction between lactic acid and pyruvic acid that typically takes place in anaerobic conditions.¹⁷ LDH levels are elevated in malignancies because tumors have an anaerobic environment. Elevated LDH levels correlate with the anaerobic metabolism in the tumor. Other studies also have noted that patients with high metastatic score have higher LDH levels.¹⁷ Therefore, LDH may reflect tumor extension.

In addition, other techniques, such as somatostatin- receptor imaging are specifically beneficial in tumors that express the somatostatin receptor.¹⁶ For this reason, this type of study is typically indicated in patients with known metastasis, not in patients with low-grade tumors. Abdominal CT scans are done because the liver is a common site for metastasis.

Our case report demonstrates how biomarkers help diagnose these potentially aggressive and life-threatening tumors that may present as a common condition such as a pleural effusion. Using a less invasive and quicker approach with thoracentesis rather than with lung biopsies is a diagnostic tool in this entity. IHC in cell blocks is a reasonable diagnostic method especially in patients in whom performing a lung biopsy is difficult.

Conclusions

The presence of a symptomatic and recurrent unilateral pleural effusion must urge physicians to consider thoracentesis with mindful use of biomarkers not only for therapeutic purposes, but also for diagnosis of a variety of etiologies, both benign and malignant.

Neuroendocrine tumors (NETs) account for about 0.5% of all newly diagnosed malignancies.¹ Pulmonary NETs are rare, accounting for 1 to 2% of all invasive lung malignancies and involve about 20 to 25% of primary lung malignancies. ^2,3 Their prevalence has increased by an estimated 6% per year over the past 30 years.² Nonetheless, the time of diagnosis is frequently delayed because of nonspecific symptoms that may imitate other pulmonary conditions.

In the normal pleural space, there is a steady state in which there is a roughly equal rate of fluid formation and absorption. Any disequilibrium may produce a pleural effusion. Pleural fluids can be transudates or exudates. Transudates result from imbalances in hydrostatic and oncotic pressures in the pleural space. Exudates result primarily from pleural and/or lung inflammation or from impaired lymphatic drainage of the pleural space. Clinical manifestations include cough, wheezing, recurrent pneumonia, hemoptysis and pleural effusions. We present a case of a man who developed a large left pleural effusion with a pathology report suggesting a pulmonary NET as the etiology. Being aware of this rare entity may help improve prognosis by making an earlier diagnosis and starting treatment sooner.

Case Presentation

A 90-year-old man with a medical history of arterial hypertension, hyperlipidemia, type 2 diabetes mellitus, coronary artery disease, and vascular dementia presented to the emergency department with hypoactivity, poor appetite, productive cough, and shortness of breath. The patient was a former smoker (unknown pack-years) who quit smoking cigarettes 7 years prior. Vital signs showed sinus tachycardia and peripheral oxygen saturation of 90% at room air. The initial physical examination was remarkable for decreased breath sounds and crackles at the left lung base. Laboratory findings showed leukocytosis with neutrophilia and chronic normocytic anemia. Chest computed tomography (CT) showed a large left-sided pleural effusion occupying most of the left hemithorax with adjacent atelectatic lung, enlarged pretracheal, subcarinal, and left perihilar lymph nodes (Figure 1).

The patient was admitted to the internal medicine ward with the diagnosis of left pneumonic process and started on IV levofloxacin. However, despite 7 days of antibiotic therapy, the patient’s respiratory symptoms worsened. This clinical deterioration prompted pulmonary service consultation. Chest radiography demonstrated an enlarging left pleural effusion (Figure 2). A thoracentesis drained 1.2 L of serosanguineous pleural fluid. Pleural fluid analysis showed a cell count of 947/cm3 with 79% of lymphocytes, total protein 3.8 g/dL, lactic dehydrogenase (LDH) level 607 U/L, and glucose level 109 mg/dL. Serum total protein was 6.62 g/dL, LDH 666 U/L and glucose 92 mg/dL (Tables 1 and 2). Alanine transaminase (ALT) and aspartate aminotransferase (AST) were 11 U/L and 21 U/L, respectively. Using Light criteria, the pleural:serum protein ratio was 0.57, the pleural:serum LDH ratio was 0.91, and the pleural LDH was more than two-thirds of the serum LDH. These calculations were consistent with an exudative effusion. An infectious disease workup, including blood and pleural fluid cultures, was negative.

The pleural fluid concentrated cell block hematoxylin and eosin (H&E) staining showed chromatin, prominent nucleoli, and nuclear molding, which was compatible with high-grade lung NET (Figure 3). The cell block immunohistochemistry (IHC) was positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE) also consistent with a high-grade pulmonary NET (Figure 4). The proliferation marker protein Ki-67 labeling index (LI) showed a proliferation index > 20% (Figure 5). The patient did not have decision-making capacity given vascular dementia. Multiple attempts to contact the next of kin or family members were unsuccessful. Risks vs benefits were evaluated, and given the patient’s advanced age and multiple comorbidities, a conservative management approach under palliative care was chosen. For this reason, further genomic studies were not done.

Discussion

NETs are a group of neoplasms that differ in site, amount of cell propagation, and clinical manifestations.⁴ These tumors are rare with an estimated incidence of 25 to 50 per 100,000.4 The most commonly affected organ systems are the gastroenteropancreatic and the bronchopulmonary tracts, accounting for 60% and 25% of the tumors, respectively.4 The incidence is increasing over the past years in part because of novel diagnostic techniques.

The average age of diagnosis is between the fourth and sixth decades, affecting more women than men.⁵ Smoking has been identified as a possible culprit for the development of these neoplasms; nonetheless, the association is still not clear.⁴ For example, poorly differentiated pulmonary NETs have a strong association with smoking but not well-differentiated pulmonary NETs.²

Patients typically present with cough, wheezing, hemoptysis, and recurrent pneumonias, which are in part a consequence of obstruction caused by the mass.² Sometimes, obstruction may yield persistent pleural effusions. Hemoptysis may be seen secondary to the vascularity of pulmonary NETs.

The diagnosis is often delayed because patients are frequently treated for infection before being diagnosed with the malignancy, such as in our case. Radiologic image findings include round opacities, central masses, and atelectasis. Pulmonary NETs are frequently found incidentally as solitary lung nodules. The CT scan is the most common diagnostic modality and can provide information about the borders of the tumor, the location and surrounding structures, including the presence of atelectasis.⁵ Pulmonary NETs are usually centrally located in an accessible region for lung biopsy. In cases where the mass is not easily reachable, thoracentesis may provide the only available specimen.

The 2015 World Health Organization classification has identified 4 histologic types of pulmonary NETs, namely, typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC).⁶ The low-grade pulmonary NET, the typical carcinoid, is slow growing and has lower rates of metastasis. The intermediate-grade NET, the atypical carcinoid, is more aggressive. The highgrade NETs, the LCNEC and the SCLC, are aggressive and spread quickly to other places.⁶ Consequently, LCNEC and SCLC have higher mortalities with a 5-year survival, ranging from 13 to 57% and 5%, respectively.⁷

Tumors may be histomorphologically classified by H&E staining. The main characteristics that differentiate the low- and high-grade NETs are the presence of necrosis and the mitotic rate. Both categories form neuropeptides and have dense granular cores when seen with an electron microscopy^.6 The TC and AC have welldefined, organized histologic patterns, no necrosis, and scarce mitosis. On the other hand, the LCNEC and SCLC are poorly differentiated tumors with necrosis, atypia, and mitosis.6 LCNEC can be separated from SCLC and other tumors by IHC staining, whereas SCLC is primarily distinguished by morphology.

If the biopsy sample size is small, then IHC morphology and markers are helpful for subclassification.⁸ IHC is used to discern between neuroendocrine (NE) vs non-NE. The evaluation of pleural fluid includes preparation of cell blocks. Cell block staining is deemed better for IHC because it mimics a small biopsy that enables superior stains.⁹ The need for a pleural biopsy in cases where the cytology is negative depends on treatment aims, the kind of tumor, and the presence of metastasis.¹⁰ In almost 80% of cases, pleural biopsy and cytology are the only specimens obtained for analysis.Therefore, identification of these markers is practical for diagnosis.¹⁰ For this reason, pleural effusion samples are appropriate options to lung biopsy for molecular studies.¹⁰

Ki-67 LI in samples has the highest specificity and sensitivity for low-tointermediate- grade vs high-grade tumors. It is being used for guiding clinical and treatment decisions.⁶ In SCLC, the Ki-67 LI is not necessary for diagnosis but will be about 80%.¹¹ The tumor cells will show epithelial characteristics with positive cytokeratin AE1/AE3 and monoclonal antibody CAM5.² and neuroendocrine markers, including NCAM/CD56, chromogranin A, and synaptophysin.¹¹

Thyroid transcription factor-1 (TTF- 1) is positive in most cases. In LCNEC, the Ki-67 LI is between 40% and 80%. NCAM/ CD56, chromogranin A, and synaptophysin are present in 92 to 100%, 80 to 85%, and 50 to 60%, respectively.¹¹ TTF-1 is identified in half of the tumors. All these tumors express pancytokeratin (AE1/AE3), cytokeratin 7 or low-molecular-weight cytokeratin. Likewise, the carcinoids will show markers, such as chromogranin A, synaptophysin, CD56, and epithelial markers like pancytokeratin.¹¹ However, the high-molecular-weight cytokeratin and TTF-1 are negative. Furthermore, NSE is considered a good tumor marker in the diagnosis and prognosis of SCLC. NSE also has been reported in NSCLC. The level of NSE correlates with tumor burden, number of metastatic sites, and response to treatment. ¹² A potentially useful marker is the insulinoma-associated protein 1, which is a nuclear determinant of NE differentiation that stains all types of pulmonary NETs irrespective of the histology but does not stain adenocarcinoma or squamous cell carcinoma (SCC).⁶

Recently, genomic studies have identified gene alterations that have become standard of care for diagnosis and targeted therapies.⁸ For example, epidermal growth factor receptor (EGFR) and echinoderm microtubule- associated proteinlike 4, and anaplastic lymphoma kinase (EML4-ALK) mutations have been found in about 25% of lung adenocarcinomas. ⁸ Other abnormalities in LKB1/STK11, NF1, CDKN2A, SMARCA4 and KEAP1, KRAS, MET, ROS1, and RET have also been identified.8 On the other hand, SCC rarely have derangements in EGFR and EML4-ALK, but do show changes in RTKs, DDR2M, FGGRs, among others.8 In TC and AC, observed molecular alterations include MEN1 mutations, mTOR, and SSTRs pathway activation, and GC/ CEACAM1 and CD44/OTP expression.¹³ LCNEC and SCLC have shown TP53 and RB1 mutations and CDX2/VIL1/BAI3 expression. DLL3 expression and MET mutations may be present in SCLC.13 Last, chromatin remodeling gene mutations have been identified in all these lung NET types.¹³

Furthermore, neuropeptides and neuroamines may be measured in the blood and urine.¹⁴ Pulmonary NETs may be functional and secrete these substances, leading to systemic symptoms based on the released molecules.¹⁵ However, pulmonary NETs produce less serotonin than gastrointestinal NETs; therefore, carcinoid syndrome is less frequent in pulmonary NETs.¹⁶ Liver metastasis is often present when it occurs.⁵ Other possible clinical features include Cushing syndrome and acromegaly depending on the secreted hormones.⁵

In a recent metanalysis, serum LDH has been found to have a prognostic role in Ewing sarcoma, urologic cancers, malignant mesothelioma, among others.¹⁷ It demonstrated that a higher LDH concentration is associated with worse survival in patients with lung cancer.¹⁷ Serum LDH is an enzyme that catalyzes the reaction between lactic acid and pyruvic acid that typically takes place in anaerobic conditions.¹⁷ LDH levels are elevated in malignancies because tumors have an anaerobic environment. Elevated LDH levels correlate with the anaerobic metabolism in the tumor. Other studies also have noted that patients with high metastatic score have higher LDH levels.¹⁷ Therefore, LDH may reflect tumor extension.

In addition, other techniques, such as somatostatin- receptor imaging are specifically beneficial in tumors that express the somatostatin receptor.¹⁶ For this reason, this type of study is typically indicated in patients with known metastasis, not in patients with low-grade tumors. Abdominal CT scans are done because the liver is a common site for metastasis.

Our case report demonstrates how biomarkers help diagnose these potentially aggressive and life-threatening tumors that may present as a common condition such as a pleural effusion. Using a less invasive and quicker approach with thoracentesis rather than with lung biopsies is a diagnostic tool in this entity. IHC in cell blocks is a reasonable diagnostic method especially in patients in whom performing a lung biopsy is difficult.

Conclusions

The presence of a symptomatic and recurrent unilateral pleural effusion must urge physicians to consider thoracentesis with mindful use of biomarkers not only for therapeutic purposes, but also for diagnosis of a variety of etiologies, both benign and malignant.

The MET inhibitor tepotinib produced responses in about half of advanced non–small cell lung cancer (NSCLC) patients with confirmed MET exon 14–skipping mutations in an open-label, phase 2 study.

The objective response rate was 46.5% among the 99 patients followed for 9 or more months, as assessed by independent reviewers. There were no complete responders, according to the reviewers.

However, the response rate according to investigator assessment was 55.6%, including two responses that were judged to be complete.

The median duration of response was 11.1 months according to reviewers and 14 months according to investigators.

“The success of this trial, alongside other studies on the same class of drugs, establishes MET exon 14 as an actionable target for non–small cell lung cancer,” said senior author Xiuning Le, MD, PhD, assistant professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Le presented results from this trial as part of the American Society of Clinical Oncology virtual scientific program. Results were published simultaneously in the New England Journal of Medicine.

The trial, dubbed VISION, already won tepotinib approval in Japan to treat NSCLC patients with MET exon 14–skipping mutations. The Food and Drug Administration has granted tepotinib breakthrough status, and Merck, the drug’s manufacturer, plans to submit tepotinib for review this year.

The VISION trial enrolled 152 patients with NSCLC – 99 with at least 9 months of follow-up and 53 with shorter follow-up. The patients’ MET exon 14 mutations were confirmed by liquid or tissue biopsy.

The patients’ median age at baseline was 74 years, 54% were men, and almost half had no smoking history. Patients received tepotinib at 500 mg daily until disease progression or intolerable toxicity.

Overall, the VISION results “compare favorably” with those from studies of other MET inhibitors, the investigators wrote.

The 46.5% objective response rate (per independent reviewers) included the 99 patients with follow-up of at least 9 months who were liquid- or tissue-biopsy positive (combined group). The response rate was 48.5% among the 66 patients with positive liquid biopsies and 50% among the 60 patients with positive tissue biopsies.

The median progression-free survival was 8.5 months in the combined group, 8.5 months in the liquid-biopsy group, and 11 months in the tissue-biopsy group. The median overall survival was 17.1 months, 15.8 months, and 22.3 months, respectively.

The 11 patients with brain metastases at baseline had results that were in line with the other patients’ results. Patients with brain metastases had an objective response rate of 54.5%, a median response duration of 9.5 months, and a median progression-free survival of 10.9 months.

Overall, 88.8% of patients reported adverse events related to treatment, including peripheral edema in 63.2%, nausea in 25.7%, and diarrhea in 21.7%.

Grade 3-4 adverse events occurred in 27% of patients. Peripheral edema was the most common of these events, reported in 7.2% of patients.

“Proactive monitoring for peripheral edema is recommended and can be managed with temporary discontinuation of tepotinib or dose reduction,” the investigators wrote.

The death of a 79-year-old patient with respiratory failure and dyspnea, secondary to interstitial lung disease, was the only death considered to be treatment related.

The study was funded by Merck. Dr. Le and other investigators disclosed relationships, including employment, with the company.

aotto@mdedge.com

SOURCE: Le X et al. ASCO 2020, Abstract 9556.

The MET inhibitor tepotinib produced responses in about half of advanced non–small cell lung cancer (NSCLC) patients with confirmed MET exon 14–skipping mutations in an open-label, phase 2 study.

The objective response rate was 46.5% among the 99 patients followed for 9 or more months, as assessed by independent reviewers. There were no complete responders, according to the reviewers.

However, the response rate according to investigator assessment was 55.6%, including two responses that were judged to be complete.

The median duration of response was 11.1 months according to reviewers and 14 months according to investigators.

“The success of this trial, alongside other studies on the same class of drugs, establishes MET exon 14 as an actionable target for non–small cell lung cancer,” said senior author Xiuning Le, MD, PhD, assistant professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Le presented results from this trial as part of the American Society of Clinical Oncology virtual scientific program. Results were published simultaneously in the New England Journal of Medicine.

The trial, dubbed VISION, already won tepotinib approval in Japan to treat NSCLC patients with MET exon 14–skipping mutations. The Food and Drug Administration has granted tepotinib breakthrough status, and Merck, the drug’s manufacturer, plans to submit tepotinib for review this year.

The VISION trial enrolled 152 patients with NSCLC – 99 with at least 9 months of follow-up and 53 with shorter follow-up. The patients’ MET exon 14 mutations were confirmed by liquid or tissue biopsy.

The patients’ median age at baseline was 74 years, 54% were men, and almost half had no smoking history. Patients received tepotinib at 500 mg daily until disease progression or intolerable toxicity.

Overall, the VISION results “compare favorably” with those from studies of other MET inhibitors, the investigators wrote.

The 46.5% objective response rate (per independent reviewers) included the 99 patients with follow-up of at least 9 months who were liquid- or tissue-biopsy positive (combined group). The response rate was 48.5% among the 66 patients with positive liquid biopsies and 50% among the 60 patients with positive tissue biopsies.

The median progression-free survival was 8.5 months in the combined group, 8.5 months in the liquid-biopsy group, and 11 months in the tissue-biopsy group. The median overall survival was 17.1 months, 15.8 months, and 22.3 months, respectively.

The 11 patients with brain metastases at baseline had results that were in line with the other patients’ results. Patients with brain metastases had an objective response rate of 54.5%, a median response duration of 9.5 months, and a median progression-free survival of 10.9 months.

Overall, 88.8% of patients reported adverse events related to treatment, including peripheral edema in 63.2%, nausea in 25.7%, and diarrhea in 21.7%.

Grade 3-4 adverse events occurred in 27% of patients. Peripheral edema was the most common of these events, reported in 7.2% of patients.

“Proactive monitoring for peripheral edema is recommended and can be managed with temporary discontinuation of tepotinib or dose reduction,” the investigators wrote.

The death of a 79-year-old patient with respiratory failure and dyspnea, secondary to interstitial lung disease, was the only death considered to be treatment related.

The study was funded by Merck. Dr. Le and other investigators disclosed relationships, including employment, with the company.

aotto@mdedge.com

SOURCE: Le X et al. ASCO 2020, Abstract 9556.

The MET inhibitor tepotinib produced responses in about half of advanced non–small cell lung cancer (NSCLC) patients with confirmed MET exon 14–skipping mutations in an open-label, phase 2 study.

The objective response rate was 46.5% among the 99 patients followed for 9 or more months, as assessed by independent reviewers. There were no complete responders, according to the reviewers.

However, the response rate according to investigator assessment was 55.6%, including two responses that were judged to be complete.

The median duration of response was 11.1 months according to reviewers and 14 months according to investigators.

“The success of this trial, alongside other studies on the same class of drugs, establishes MET exon 14 as an actionable target for non–small cell lung cancer,” said senior author Xiuning Le, MD, PhD, assistant professor in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, Houston.

Dr. Le presented results from this trial as part of the American Society of Clinical Oncology virtual scientific program. Results were published simultaneously in the New England Journal of Medicine.

The trial, dubbed VISION, already won tepotinib approval in Japan to treat NSCLC patients with MET exon 14–skipping mutations. The Food and Drug Administration has granted tepotinib breakthrough status, and Merck, the drug’s manufacturer, plans to submit tepotinib for review this year.

The VISION trial enrolled 152 patients with NSCLC – 99 with at least 9 months of follow-up and 53 with shorter follow-up. The patients’ MET exon 14 mutations were confirmed by liquid or tissue biopsy.

The patients’ median age at baseline was 74 years, 54% were men, and almost half had no smoking history. Patients received tepotinib at 500 mg daily until disease progression or intolerable toxicity.

Overall, the VISION results “compare favorably” with those from studies of other MET inhibitors, the investigators wrote.

The 46.5% objective response rate (per independent reviewers) included the 99 patients with follow-up of at least 9 months who were liquid- or tissue-biopsy positive (combined group). The response rate was 48.5% among the 66 patients with positive liquid biopsies and 50% among the 60 patients with positive tissue biopsies.

The median progression-free survival was 8.5 months in the combined group, 8.5 months in the liquid-biopsy group, and 11 months in the tissue-biopsy group. The median overall survival was 17.1 months, 15.8 months, and 22.3 months, respectively.

The 11 patients with brain metastases at baseline had results that were in line with the other patients’ results. Patients with brain metastases had an objective response rate of 54.5%, a median response duration of 9.5 months, and a median progression-free survival of 10.9 months.

Overall, 88.8% of patients reported adverse events related to treatment, including peripheral edema in 63.2%, nausea in 25.7%, and diarrhea in 21.7%.

Grade 3-4 adverse events occurred in 27% of patients. Peripheral edema was the most common of these events, reported in 7.2% of patients.

“Proactive monitoring for peripheral edema is recommended and can be managed with temporary discontinuation of tepotinib or dose reduction,” the investigators wrote.

The death of a 79-year-old patient with respiratory failure and dyspnea, secondary to interstitial lung disease, was the only death considered to be treatment related.

The study was funded by Merck. Dr. Le and other investigators disclosed relationships, including employment, with the company.

aotto@mdedge.com

SOURCE: Le X et al. ASCO 2020, Abstract 9556.

In its updated cancer prevention guidelines, the American Cancer Society now recommends that “it is best not to drink alcohol.”

Previously, ACS suggested that, for those who consume alcoholic beverages, intake should be no more than one drink per day for women or two per day for men. That recommendation is still in place, but is now accompanied by this new, stronger directive.

The revised guidelines also place more emphasis on reducing the consumption of processed and red meat and highly processed foods, and on increasing physical activity.

But importantly, there is also a call for action from public, private, and community organizations to work to together to increase access to affordable, nutritious foods and physical activity.

“Making healthy choices can be challenging for many, and there are strategies included in the guidelines that communities can undertake to help reduce barriers to eating well and physical activity,” said Laura Makaroff, DO, American Cancer Society senior vice president. “Individual choice is an important part of a healthy lifestyle, but having the right policies and environmental factors to break down these barriers is also important, and that is something that clinicians can support.”

The guidelines were published in CA: A Cancer Journal for Clinicians.

The link between cancer and lifestyle factors has long been established, and for the past 4 decades, both government and leading nonprofit health organizations, including the ACS and the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), have released cancer prevention guidelines and recommendations that focus on managing weight, diet, physical activity, and alcohol consumption.

In 2012, the ACS issued guidelines on diet and physical activity, and their current guideline is largely based on the WCRF/AICR systematic reviews and Continuous Update Project reports, which were last updated in 2018. The ACS guidelines also incorporated systematic reviews conducted by the International Agency on Cancer Research (IARC) and the U.S. Department of Agriculture and the Department of Health and Human Services (USDA/HHS) and other analyses that were published since the WCRF/AICR recommendations were released.
 

Emphasis on three areas

The differences between the old guidelines and the update do not differ dramatically, but Makaroff highlighted a few areas that have increased emphasis.

Time spent being physically active is critical. The recommendation has changed to encourage adults to engage in 150-300 minutes (2.5-5 hours) of moderate-intensity physical activity, or 75-150 minutes (1.25-2.5 hours) of vigorous-intensity physical activity, or an equivalent combination, per week. Achieving or exceeding the upper limit of 300 minutes is optimal.

“That is more than what we have recommended in the past, along with the continued message that children and adolescents engage in at least 1 hour of moderate- or vigorous-intensity activity each day,” she told Medscape Medical News.

The ACS has also increased emphasis on reducing the consumption of processed and red meat. “This is part of a healthy eating pattern and making sure that people are eating food that is high in nutrients that help achieve and maintain a healthy body weight,” said Makaroff.

A healthy diet should include a variety of dark green, red, and orange vegetables; fiber-rich legumes; and fruits with a variety of colors and whole grains, according to the guidelines. Sugar-sweetened beverages, highly processed foods, and refined grain products should be limited or avoided.

The revised dietary recommendations reflect a shift from a “reductionist or nutrient-centric” approach to one that is more “holistic” and that focuses on dietary patterns. In contrast to a focus on individual nutrients and bioactive compounds, the new approach is more consistent with what and how people actually eat, ACS points out.

The third area that Makaroff highlighted is alcohol, where the recommendation is to avoid or limit consumption. “The current update says not to drink alcohol, which is in line with the scientific evidence, but for those people who choose to drink alcohol, to limit it to one drink per day for women and two drinks per day for men.”

Thus, the change here is that the previous guideline only recommended limiting alcohol consumption, while the update suggests that, optimally, it should be avoided completely.

The ACS has also called for community involvement to help implement these goals: “Public, private, and community organizations should work collaboratively at national, state, and local levels to develop, advocate for, and implement policy and environmental changes that increase access to affordable, nutritious foods; provide safe, enjoyable, and accessible opportunities for physical activity; and limit alcohol for all individuals.”
 

No smoking guns

Commenting on the guidelines, Steven K. Clinton, MD, PhD, associate director of the Center for Advanced Functional Foods Research and Entrepreneurship at the Ohio State University, Columbus, explained that he didn’t view the change in alcohol as that much of an evolution. “It’s been 8 years since they revised their overall guidelines, and during that time frame, there has been an enormous growth in the evidence that has been used by many organizations,” he said.

Clinton noted that the guidelines are consistent with the whole body of current scientific literature. “It’s very easy to go to the document and look for the ‘smoking gun’ – but the smoking gun is really not one thing,” he said. “It’s a pattern, and what dietitians and nutritionists are telling people is that you need to orchestrate a healthy lifestyle and diet, with a diet that has a foundation of fruits, vegetables, whole grains, and modest intake of refined grains and meat. You are orchestrating an entire pattern to get the maximum benefit.”

Makaroff is an employee of the ACS. Clinton has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In its updated cancer prevention guidelines, the American Cancer Society now recommends that “it is best not to drink alcohol.”

Previously, ACS suggested that, for those who consume alcoholic beverages, intake should be no more than one drink per day for women or two per day for men. That recommendation is still in place, but is now accompanied by this new, stronger directive.

The revised guidelines also place more emphasis on reducing the consumption of processed and red meat and highly processed foods, and on increasing physical activity.

But importantly, there is also a call for action from public, private, and community organizations to work to together to increase access to affordable, nutritious foods and physical activity.

“Making healthy choices can be challenging for many, and there are strategies included in the guidelines that communities can undertake to help reduce barriers to eating well and physical activity,” said Laura Makaroff, DO, American Cancer Society senior vice president. “Individual choice is an important part of a healthy lifestyle, but having the right policies and environmental factors to break down these barriers is also important, and that is something that clinicians can support.”

The guidelines were published in CA: A Cancer Journal for Clinicians.

The link between cancer and lifestyle factors has long been established, and for the past 4 decades, both government and leading nonprofit health organizations, including the ACS and the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), have released cancer prevention guidelines and recommendations that focus on managing weight, diet, physical activity, and alcohol consumption.

In 2012, the ACS issued guidelines on diet and physical activity, and their current guideline is largely based on the WCRF/AICR systematic reviews and Continuous Update Project reports, which were last updated in 2018. The ACS guidelines also incorporated systematic reviews conducted by the International Agency on Cancer Research (IARC) and the U.S. Department of Agriculture and the Department of Health and Human Services (USDA/HHS) and other analyses that were published since the WCRF/AICR recommendations were released.
 

Emphasis on three areas

The differences between the old guidelines and the update do not differ dramatically, but Makaroff highlighted a few areas that have increased emphasis.

Time spent being physically active is critical. The recommendation has changed to encourage adults to engage in 150-300 minutes (2.5-5 hours) of moderate-intensity physical activity, or 75-150 minutes (1.25-2.5 hours) of vigorous-intensity physical activity, or an equivalent combination, per week. Achieving or exceeding the upper limit of 300 minutes is optimal.

“That is more than what we have recommended in the past, along with the continued message that children and adolescents engage in at least 1 hour of moderate- or vigorous-intensity activity each day,” she told Medscape Medical News.

The ACS has also increased emphasis on reducing the consumption of processed and red meat. “This is part of a healthy eating pattern and making sure that people are eating food that is high in nutrients that help achieve and maintain a healthy body weight,” said Makaroff.

A healthy diet should include a variety of dark green, red, and orange vegetables; fiber-rich legumes; and fruits with a variety of colors and whole grains, according to the guidelines. Sugar-sweetened beverages, highly processed foods, and refined grain products should be limited or avoided.

The revised dietary recommendations reflect a shift from a “reductionist or nutrient-centric” approach to one that is more “holistic” and that focuses on dietary patterns. In contrast to a focus on individual nutrients and bioactive compounds, the new approach is more consistent with what and how people actually eat, ACS points out.

The third area that Makaroff highlighted is alcohol, where the recommendation is to avoid or limit consumption. “The current update says not to drink alcohol, which is in line with the scientific evidence, but for those people who choose to drink alcohol, to limit it to one drink per day for women and two drinks per day for men.”

Thus, the change here is that the previous guideline only recommended limiting alcohol consumption, while the update suggests that, optimally, it should be avoided completely.

The ACS has also called for community involvement to help implement these goals: “Public, private, and community organizations should work collaboratively at national, state, and local levels to develop, advocate for, and implement policy and environmental changes that increase access to affordable, nutritious foods; provide safe, enjoyable, and accessible opportunities for physical activity; and limit alcohol for all individuals.”
 

No smoking guns

Commenting on the guidelines, Steven K. Clinton, MD, PhD, associate director of the Center for Advanced Functional Foods Research and Entrepreneurship at the Ohio State University, Columbus, explained that he didn’t view the change in alcohol as that much of an evolution. “It’s been 8 years since they revised their overall guidelines, and during that time frame, there has been an enormous growth in the evidence that has been used by many organizations,” he said.

Clinton noted that the guidelines are consistent with the whole body of current scientific literature. “It’s very easy to go to the document and look for the ‘smoking gun’ – but the smoking gun is really not one thing,” he said. “It’s a pattern, and what dietitians and nutritionists are telling people is that you need to orchestrate a healthy lifestyle and diet, with a diet that has a foundation of fruits, vegetables, whole grains, and modest intake of refined grains and meat. You are orchestrating an entire pattern to get the maximum benefit.”

Makaroff is an employee of the ACS. Clinton has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In its updated cancer prevention guidelines, the American Cancer Society now recommends that “it is best not to drink alcohol.”

Previously, ACS suggested that, for those who consume alcoholic beverages, intake should be no more than one drink per day for women or two per day for men. That recommendation is still in place, but is now accompanied by this new, stronger directive.

The revised guidelines also place more emphasis on reducing the consumption of processed and red meat and highly processed foods, and on increasing physical activity.

But importantly, there is also a call for action from public, private, and community organizations to work to together to increase access to affordable, nutritious foods and physical activity.

“Making healthy choices can be challenging for many, and there are strategies included in the guidelines that communities can undertake to help reduce barriers to eating well and physical activity,” said Laura Makaroff, DO, American Cancer Society senior vice president. “Individual choice is an important part of a healthy lifestyle, but having the right policies and environmental factors to break down these barriers is also important, and that is something that clinicians can support.”

The guidelines were published in CA: A Cancer Journal for Clinicians.

The link between cancer and lifestyle factors has long been established, and for the past 4 decades, both government and leading nonprofit health organizations, including the ACS and the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), have released cancer prevention guidelines and recommendations that focus on managing weight, diet, physical activity, and alcohol consumption.

In 2012, the ACS issued guidelines on diet and physical activity, and their current guideline is largely based on the WCRF/AICR systematic reviews and Continuous Update Project reports, which were last updated in 2018. The ACS guidelines also incorporated systematic reviews conducted by the International Agency on Cancer Research (IARC) and the U.S. Department of Agriculture and the Department of Health and Human Services (USDA/HHS) and other analyses that were published since the WCRF/AICR recommendations were released.
 

Emphasis on three areas

The differences between the old guidelines and the update do not differ dramatically, but Makaroff highlighted a few areas that have increased emphasis.

Time spent being physically active is critical. The recommendation has changed to encourage adults to engage in 150-300 minutes (2.5-5 hours) of moderate-intensity physical activity, or 75-150 minutes (1.25-2.5 hours) of vigorous-intensity physical activity, or an equivalent combination, per week. Achieving or exceeding the upper limit of 300 minutes is optimal.

“That is more than what we have recommended in the past, along with the continued message that children and adolescents engage in at least 1 hour of moderate- or vigorous-intensity activity each day,” she told Medscape Medical News.

The ACS has also increased emphasis on reducing the consumption of processed and red meat. “This is part of a healthy eating pattern and making sure that people are eating food that is high in nutrients that help achieve and maintain a healthy body weight,” said Makaroff.

A healthy diet should include a variety of dark green, red, and orange vegetables; fiber-rich legumes; and fruits with a variety of colors and whole grains, according to the guidelines. Sugar-sweetened beverages, highly processed foods, and refined grain products should be limited or avoided.

The revised dietary recommendations reflect a shift from a “reductionist or nutrient-centric” approach to one that is more “holistic” and that focuses on dietary patterns. In contrast to a focus on individual nutrients and bioactive compounds, the new approach is more consistent with what and how people actually eat, ACS points out.

The third area that Makaroff highlighted is alcohol, where the recommendation is to avoid or limit consumption. “The current update says not to drink alcohol, which is in line with the scientific evidence, but for those people who choose to drink alcohol, to limit it to one drink per day for women and two drinks per day for men.”

Thus, the change here is that the previous guideline only recommended limiting alcohol consumption, while the update suggests that, optimally, it should be avoided completely.

The ACS has also called for community involvement to help implement these goals: “Public, private, and community organizations should work collaboratively at national, state, and local levels to develop, advocate for, and implement policy and environmental changes that increase access to affordable, nutritious foods; provide safe, enjoyable, and accessible opportunities for physical activity; and limit alcohol for all individuals.”
 

No smoking guns

Commenting on the guidelines, Steven K. Clinton, MD, PhD, associate director of the Center for Advanced Functional Foods Research and Entrepreneurship at the Ohio State University, Columbus, explained that he didn’t view the change in alcohol as that much of an evolution. “It’s been 8 years since they revised their overall guidelines, and during that time frame, there has been an enormous growth in the evidence that has been used by many organizations,” he said.

Clinton noted that the guidelines are consistent with the whole body of current scientific literature. “It’s very easy to go to the document and look for the ‘smoking gun’ – but the smoking gun is really not one thing,” he said. “It’s a pattern, and what dietitians and nutritionists are telling people is that you need to orchestrate a healthy lifestyle and diet, with a diet that has a foundation of fruits, vegetables, whole grains, and modest intake of refined grains and meat. You are orchestrating an entire pattern to get the maximum benefit.”

Makaroff is an employee of the ACS. Clinton has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Deciding which cancer patients need immediate treatment and who can safely wait is an uncomfortable assessment for cancer clinicians during the COVID-19 pandemic.

In early April, as the COVID-19 surge was bearing down on New York City, those treatment decisions were “a juggling act every single day,” Jonathan Yang, MD, PhD, a radiation oncologist from New York’s Memorial Sloan Kettering Cancer Center, told Medscape Medical News.

Eventually, a glut of guidelines, recommendations, and expert opinions aimed at helping oncologists emerged. The tools help navigate the complicated risk-benefit analysis of their patient’s risk of infection by SARS-CoV-2 and delaying therapy.

Now, a new tool, which appears to be the first of its kind, quantifies that risk-benefit analysis. But its presence immediately raises the question: can it help?
 

Three-Tier Systems Are Not Very Sophisticated

OncCOVID, a free tool that was launched May 26 by the University of Michigan, allows physicians to individualize risk estimates for delaying treatment of up to 25 early- to late-stage cancers. It includes more than 45 patient characteristics, such as age, location, cancer type, cancer stage, treatment plan, underlying medical conditions, and proposed length of delay in care.

Combining these personal details with data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) registry and the National Cancer Database, the Michigan app then estimates a patient’s 5- or 10-year survival with immediate vs delayed treatment and weighs that against their risk for COVID-19 using data from the Johns Hopkins Coronavirus Resource Center.

“We thought, isn’t it better to at least provide some evidence-based quantification, rather than a back-of-the-envelope three-tier system that is just sort of ‘made up’?“ explained one of the developers, Daniel Spratt, MD, associate professor of radiation oncology at Michigan Medicine.

Spratt explained that almost every organization, professional society, and government has created something like a three-tier system. Tier 1 represents urgent cases and patients who need immediate treatment. For tier 2, treatment can be delayed weeks or a month, and with tier 3, it can be delayed until the pandemic is over or it’s deemed safe.

“[This system] sounds good at first glance, but in cancer, we’re always talking about personalized medicine, and it’s mind-blowing that these tier systems are only based on urgency and prognosis,” he told Medscape Medical News.

Spratt offered an example. Consider a patient with a very aggressive brain tumor ― that patient is in tier 1 and should undergo treatment immediately. But will the treatment actually help? And how helpful would the procedure be if, say, the patient is 80 years old and, if infected, would have a 30% to 50% chance of dying from the coronavirus?

“If the model says this guy has a 5% harm and this one has 30% harm, you can use that to help prioritize,” summarized Spratt.

The app can generate risk estimates for patients living anywhere in the world and has already been accessed by people from 37 countries. However, Spratt cautions that it is primarily “designed and calibrated for the US.

“The estimates are based on very large US registries, and though it’s probably somewhat similar across much of the world, there’s probably certain cancer types that are more region specific ― especially something like stomach cancer or certain types of head and neck cancer in parts of Asia, for example,” he said.

Although the app’s COVID-19 data are specific to the county level in the United States, elsewhere in the world, it is only country specific.

“We’re using the best data we have for coronavirus, but everyone knows we still have large data gaps,” he acknowledged.
 

How Accurate?

Asked to comment on the app, Richard Bleicher, MD, leader of the Breast Cancer Program at Fox Chase Cancer Center, Philadelphia, praised the effort and the goal but had some concerns.

“Several questions arise, most important of which is, How accurate is this, and how has this been validated, if at all ― especially as it is too soon to see the outcomes of patients affected in this pandemic?” he told Medscape Medical News.

“We are imposing delays on a broad scale because of the coronavirus, and we are getting continuously changing data as we test more patients. But both situations are novel and may not be accurately represented by the data being pulled, because the datasets use patients from a few years ago, and confounders in these datasets may not apply to this situation,” Bleicher continued.

Although acknowledging the “value in delineating the risk of dying from cancer vs the risk of dying from the SARS-CoV-2 pandemic,” Bleicher urged caution in using the tool to make individual patient decisions.

“We need to remember that the best of modeling ... can be wildly inaccurate and needs to be validated using patients having the circumstances in question. ... This won’t be possible until long after the pandemic is completed, and so the model’s accuracy remains unknown.”

That sentiment was echoed by Giampaolo Bianchini, MD, head of the Breast Cancer Group, Department of Medical Oncology, Ospedale San Raffaele, in Milan, Italy.

“Arbitrarily postponing and modifying treatment strategies including surgery, radiation therapy, and medical therapy without properly balancing the risk/benefit ratio may lead to significantly worse cancer-related outcomes, which largely exceed the actual risks for COVID,” he wrote in an email.

“The OncCOVID app is a remarkable attempt to fill the gap between perception and estimation,” he said. The app provides side by side the COVID-19 risk estimation and the consequences of arbitrary deviation from the standard of care, observed Bianchini.

However, he pointed out weaknesses, including the fact that the “data generated in literature are not always of high quality and do not take into consideration relevant characteristics of the disease and treatment benefit. It should for sure be used, but then also interpreted with caution.”

Another Italian group responded more positively.

“In our opinion, it could be a useful tool for clinicians,” wrote colleagues Alessio Cortelinni and Giampiero Porzio, both medical oncologists at San Salvatore Hospital and the University of L’Aquila, in Italy. “This Web app might assist clinicians in balancing the risk/benefit ratio of being treated and/or access to the outpatient cancer center for each kind of patient (both early and advanced stages), in order to make a more tailored counseling,” they wrote in an email. “Importantly, the Web app might help those clinicians who work ‘alone,’ in peripheral centers, without resources, colleagues, and multidisciplinary tumor boards on whom they can rely.”

Bleicher, who was involved in the COVID-19 Breast Cancer Consortium’s recommendations for prioritizing breast cancer treatment, summarized that the app “may end up being close or accurate, but we won’t know except in hindsight.”
 

This article first appeared on Medscape.com.

Deciding which cancer patients need immediate treatment and who can safely wait is an uncomfortable assessment for cancer clinicians during the COVID-19 pandemic.

In early April, as the COVID-19 surge was bearing down on New York City, those treatment decisions were “a juggling act every single day,” Jonathan Yang, MD, PhD, a radiation oncologist from New York’s Memorial Sloan Kettering Cancer Center, told Medscape Medical News.

Eventually, a glut of guidelines, recommendations, and expert opinions aimed at helping oncologists emerged. The tools help navigate the complicated risk-benefit analysis of their patient’s risk of infection by SARS-CoV-2 and delaying therapy.

Now, a new tool, which appears to be the first of its kind, quantifies that risk-benefit analysis. But its presence immediately raises the question: can it help?
 

Three-Tier Systems Are Not Very Sophisticated

OncCOVID, a free tool that was launched May 26 by the University of Michigan, allows physicians to individualize risk estimates for delaying treatment of up to 25 early- to late-stage cancers. It includes more than 45 patient characteristics, such as age, location, cancer type, cancer stage, treatment plan, underlying medical conditions, and proposed length of delay in care.

Combining these personal details with data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) registry and the National Cancer Database, the Michigan app then estimates a patient’s 5- or 10-year survival with immediate vs delayed treatment and weighs that against their risk for COVID-19 using data from the Johns Hopkins Coronavirus Resource Center.

“We thought, isn’t it better to at least provide some evidence-based quantification, rather than a back-of-the-envelope three-tier system that is just sort of ‘made up’?“ explained one of the developers, Daniel Spratt, MD, associate professor of radiation oncology at Michigan Medicine.

Spratt explained that almost every organization, professional society, and government has created something like a three-tier system. Tier 1 represents urgent cases and patients who need immediate treatment. For tier 2, treatment can be delayed weeks or a month, and with tier 3, it can be delayed until the pandemic is over or it’s deemed safe.

“[This system] sounds good at first glance, but in cancer, we’re always talking about personalized medicine, and it’s mind-blowing that these tier systems are only based on urgency and prognosis,” he told Medscape Medical News.

Spratt offered an example. Consider a patient with a very aggressive brain tumor ― that patient is in tier 1 and should undergo treatment immediately. But will the treatment actually help? And how helpful would the procedure be if, say, the patient is 80 years old and, if infected, would have a 30% to 50% chance of dying from the coronavirus?

“If the model says this guy has a 5% harm and this one has 30% harm, you can use that to help prioritize,” summarized Spratt.

The app can generate risk estimates for patients living anywhere in the world and has already been accessed by people from 37 countries. However, Spratt cautions that it is primarily “designed and calibrated for the US.

“The estimates are based on very large US registries, and though it’s probably somewhat similar across much of the world, there’s probably certain cancer types that are more region specific ― especially something like stomach cancer or certain types of head and neck cancer in parts of Asia, for example,” he said.

Although the app’s COVID-19 data are specific to the county level in the United States, elsewhere in the world, it is only country specific.

“We’re using the best data we have for coronavirus, but everyone knows we still have large data gaps,” he acknowledged.
 

How Accurate?

Asked to comment on the app, Richard Bleicher, MD, leader of the Breast Cancer Program at Fox Chase Cancer Center, Philadelphia, praised the effort and the goal but had some concerns.

“Several questions arise, most important of which is, How accurate is this, and how has this been validated, if at all ― especially as it is too soon to see the outcomes of patients affected in this pandemic?” he told Medscape Medical News.

“We are imposing delays on a broad scale because of the coronavirus, and we are getting continuously changing data as we test more patients. But both situations are novel and may not be accurately represented by the data being pulled, because the datasets use patients from a few years ago, and confounders in these datasets may not apply to this situation,” Bleicher continued.

Although acknowledging the “value in delineating the risk of dying from cancer vs the risk of dying from the SARS-CoV-2 pandemic,” Bleicher urged caution in using the tool to make individual patient decisions.

“We need to remember that the best of modeling ... can be wildly inaccurate and needs to be validated using patients having the circumstances in question. ... This won’t be possible until long after the pandemic is completed, and so the model’s accuracy remains unknown.”

That sentiment was echoed by Giampaolo Bianchini, MD, head of the Breast Cancer Group, Department of Medical Oncology, Ospedale San Raffaele, in Milan, Italy.

“Arbitrarily postponing and modifying treatment strategies including surgery, radiation therapy, and medical therapy without properly balancing the risk/benefit ratio may lead to significantly worse cancer-related outcomes, which largely exceed the actual risks for COVID,” he wrote in an email.

“The OncCOVID app is a remarkable attempt to fill the gap between perception and estimation,” he said. The app provides side by side the COVID-19 risk estimation and the consequences of arbitrary deviation from the standard of care, observed Bianchini.

However, he pointed out weaknesses, including the fact that the “data generated in literature are not always of high quality and do not take into consideration relevant characteristics of the disease and treatment benefit. It should for sure be used, but then also interpreted with caution.”

Another Italian group responded more positively.

“In our opinion, it could be a useful tool for clinicians,” wrote colleagues Alessio Cortelinni and Giampiero Porzio, both medical oncologists at San Salvatore Hospital and the University of L’Aquila, in Italy. “This Web app might assist clinicians in balancing the risk/benefit ratio of being treated and/or access to the outpatient cancer center for each kind of patient (both early and advanced stages), in order to make a more tailored counseling,” they wrote in an email. “Importantly, the Web app might help those clinicians who work ‘alone,’ in peripheral centers, without resources, colleagues, and multidisciplinary tumor boards on whom they can rely.”

Bleicher, who was involved in the COVID-19 Breast Cancer Consortium’s recommendations for prioritizing breast cancer treatment, summarized that the app “may end up being close or accurate, but we won’t know except in hindsight.”
 

This article first appeared on Medscape.com.

Deciding which cancer patients need immediate treatment and who can safely wait is an uncomfortable assessment for cancer clinicians during the COVID-19 pandemic.

In early April, as the COVID-19 surge was bearing down on New York City, those treatment decisions were “a juggling act every single day,” Jonathan Yang, MD, PhD, a radiation oncologist from New York’s Memorial Sloan Kettering Cancer Center, told Medscape Medical News.

Eventually, a glut of guidelines, recommendations, and expert opinions aimed at helping oncologists emerged. The tools help navigate the complicated risk-benefit analysis of their patient’s risk of infection by SARS-CoV-2 and delaying therapy.

Now, a new tool, which appears to be the first of its kind, quantifies that risk-benefit analysis. But its presence immediately raises the question: can it help?
 

Three-Tier Systems Are Not Very Sophisticated

OncCOVID, a free tool that was launched May 26 by the University of Michigan, allows physicians to individualize risk estimates for delaying treatment of up to 25 early- to late-stage cancers. It includes more than 45 patient characteristics, such as age, location, cancer type, cancer stage, treatment plan, underlying medical conditions, and proposed length of delay in care.

Combining these personal details with data from the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) registry and the National Cancer Database, the Michigan app then estimates a patient’s 5- or 10-year survival with immediate vs delayed treatment and weighs that against their risk for COVID-19 using data from the Johns Hopkins Coronavirus Resource Center.

“We thought, isn’t it better to at least provide some evidence-based quantification, rather than a back-of-the-envelope three-tier system that is just sort of ‘made up’?“ explained one of the developers, Daniel Spratt, MD, associate professor of radiation oncology at Michigan Medicine.

Spratt explained that almost every organization, professional society, and government has created something like a three-tier system. Tier 1 represents urgent cases and patients who need immediate treatment. For tier 2, treatment can be delayed weeks or a month, and with tier 3, it can be delayed until the pandemic is over or it’s deemed safe.

“[This system] sounds good at first glance, but in cancer, we’re always talking about personalized medicine, and it’s mind-blowing that these tier systems are only based on urgency and prognosis,” he told Medscape Medical News.

Spratt offered an example. Consider a patient with a very aggressive brain tumor ― that patient is in tier 1 and should undergo treatment immediately. But will the treatment actually help? And how helpful would the procedure be if, say, the patient is 80 years old and, if infected, would have a 30% to 50% chance of dying from the coronavirus?

“If the model says this guy has a 5% harm and this one has 30% harm, you can use that to help prioritize,” summarized Spratt.

The app can generate risk estimates for patients living anywhere in the world and has already been accessed by people from 37 countries. However, Spratt cautions that it is primarily “designed and calibrated for the US.

“The estimates are based on very large US registries, and though it’s probably somewhat similar across much of the world, there’s probably certain cancer types that are more region specific ― especially something like stomach cancer or certain types of head and neck cancer in parts of Asia, for example,” he said.

Although the app’s COVID-19 data are specific to the county level in the United States, elsewhere in the world, it is only country specific.

“We’re using the best data we have for coronavirus, but everyone knows we still have large data gaps,” he acknowledged.
 

How Accurate?

Asked to comment on the app, Richard Bleicher, MD, leader of the Breast Cancer Program at Fox Chase Cancer Center, Philadelphia, praised the effort and the goal but had some concerns.

“Several questions arise, most important of which is, How accurate is this, and how has this been validated, if at all ― especially as it is too soon to see the outcomes of patients affected in this pandemic?” he told Medscape Medical News.

“We are imposing delays on a broad scale because of the coronavirus, and we are getting continuously changing data as we test more patients. But both situations are novel and may not be accurately represented by the data being pulled, because the datasets use patients from a few years ago, and confounders in these datasets may not apply to this situation,” Bleicher continued.

Although acknowledging the “value in delineating the risk of dying from cancer vs the risk of dying from the SARS-CoV-2 pandemic,” Bleicher urged caution in using the tool to make individual patient decisions.

“We need to remember that the best of modeling ... can be wildly inaccurate and needs to be validated using patients having the circumstances in question. ... This won’t be possible until long after the pandemic is completed, and so the model’s accuracy remains unknown.”

That sentiment was echoed by Giampaolo Bianchini, MD, head of the Breast Cancer Group, Department of Medical Oncology, Ospedale San Raffaele, in Milan, Italy.

“Arbitrarily postponing and modifying treatment strategies including surgery, radiation therapy, and medical therapy without properly balancing the risk/benefit ratio may lead to significantly worse cancer-related outcomes, which largely exceed the actual risks for COVID,” he wrote in an email.

“The OncCOVID app is a remarkable attempt to fill the gap between perception and estimation,” he said. The app provides side by side the COVID-19 risk estimation and the consequences of arbitrary deviation from the standard of care, observed Bianchini.

However, he pointed out weaknesses, including the fact that the “data generated in literature are not always of high quality and do not take into consideration relevant characteristics of the disease and treatment benefit. It should for sure be used, but then also interpreted with caution.”

Another Italian group responded more positively.

“In our opinion, it could be a useful tool for clinicians,” wrote colleagues Alessio Cortelinni and Giampiero Porzio, both medical oncologists at San Salvatore Hospital and the University of L’Aquila, in Italy. “This Web app might assist clinicians in balancing the risk/benefit ratio of being treated and/or access to the outpatient cancer center for each kind of patient (both early and advanced stages), in order to make a more tailored counseling,” they wrote in an email. “Importantly, the Web app might help those clinicians who work ‘alone,’ in peripheral centers, without resources, colleagues, and multidisciplinary tumor boards on whom they can rely.”

Bleicher, who was involved in the COVID-19 Breast Cancer Consortium’s recommendations for prioritizing breast cancer treatment, summarized that the app “may end up being close or accurate, but we won’t know except in hindsight.”
 

This article first appeared on Medscape.com.