Lung Cancer

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Cigarette smoking is an independent risk factor for lung cancer and atherosclerotic cardiovascular disease (ASCVD).^1-3 The National Lung Screening Trial (NLST) demonstrated both lung cancer mortality reduction with the use of surveillance low-dose computed tomography (LDCT) and ASCVD as the most common cause of death among smokers.^4,5 ASCVD remains the leading cause of death in the lung cancer screening (LCS) population.^2,3 After publication of the NLST results, the US Preventive Services Task Force (USPSTF) established LCS eligibility among smokers and the Center for Medicare and Medicaid Services approved payment for annual LDCT in this group.^1,6,7

Recently LDCT has been proposed as an adjunct diagnostic tool for detecting coronary artery calcium (CAC), which is independently associated with ASCVD and mortality.^8-13 CAC scores have been recommended by the 2019 American College of Cardiology/American Heart Association cholesterol treatment guidelines and shown to be cost-effective in guiding statin therapy for patients with borderline to intermediate ASCVD risk.^14-16 While CAC is conventionally quantified using electrocardiogram (ECG)-gated CT, these scans are not routinely performed in clinical practice because preventive CAC screening is neither recommended by the USPSTF nor covered by most insurance providers.^17,18 LDCT, conversely, is reimbursable and a well-validated ASCVD risk predictor.^18,19

In this study, we aimed to determine the validity of LDCT in identifying CAC among the military LCS population and whether it would impact statin recommendations based on 10-year ASCVD risk.

Methods

Participants were recruited from a retrospective cohort of 563 Military Health System (MHS) beneficiaries who received LCS with LDCT at Naval Medical Center Portsmouth (NMCP) in Virginia between January 1, 2019, and December 31, 2020. The 2013 USPSTF LCS guidelines were followed as the 2021 guidelines had not been published before the start of the study; thus, eligible participants included adults aged 55 to 80 years with at least a 30-pack-year smoking history and currently smoked or had quit within 15 years from the date of study consent.^6,7

Between November 2020 and May 2021, study investigators screened 287 patient records and recruited 190 participants by telephone, starting with individuals who had the most recent LDCT and working backward until reaching the predetermined 170 subjects who had undergone in-office consents before ECG-gated CT scans. Since LDCT was not obtained simultaneously with the ECG-gated CT, participants were required to complete their gated CT within 24 months of their last LDCT. Of the 190 subjects initially recruited, those who were ineligible for LCS (n = 4), had a history of angioplasty, stent, or bypass revascularization procedure (n = 4), did not complete their ECG-gated CT within the specified time frame (n = 8), or withdrew from the study (n = 4) were excluded. While gated CT scans were scored for CAC in the present time, LDCT (previously only read for general lung pathology) was not scored until after participant consent. Patients were peripherally followed, via health record reviews, for 3 months after their gated CT to document any additional imaging ordered by their primary care practitioners. The study was approved by the NMCP Institutional Review Board.

Coronary Artery Calcification Scoring

We performed CT scans using Siemens SOMATOM Flash, a second-generation dual-source scanner; and GE LightSpeed VCT, a single-source, 64-slice scanner. A step-and-shoot prospective trigger technique was used, and contiguous axial images were reconstructed at 2.5-mm or 3-mm intervals for CAC quantification using the Agatston method.²⁰ ECG-gated CT scans were electrocardiographically triggered at mid-diastole (70% of the R-R interval). Radiation dose reduction techniques involved adjustments of the mA according to body mass index and iterative reconstruction. LDCT scans were performed without ECG gating. We reconstructed contiguous axial images at 1-mm intervals for evaluation of the lung parenchyma. Similar dose-reduction techniques were used, to limit radiation exposure for each LDCT scan to < 1.5 mSv, per established guidelines.²¹ CAC on LDCT was also scored using the Agatston method. CAC was scored on the 2 scan types by different blinded reviewers.

Covariates

We reviewed outpatient health records to obtain participants’ age, sex, medical history, statin use, smoking status (current or former), and pack-years. International Classification of Diseases, Tenth Revision codes within medical encounters were used to document prevalent hypertension, hyperlipidemia, and diabetes mellitus. Participants’ most recent low-density lipoprotein value (within 24 months of ECG-gated CT) was recorded and 10-year ASCVD risk scores were calculated using the pooled cohorts equation.

Statistical Analysis

A power analysis performed before study initiation determined that a prospective sample size of 170 would be sufficient to provide strength of correlation between CAC scores calculated from ECG-gated CT and LDCT and achieve a statistical power of at least 80%. The Wilcoxon rank sum and Fisher exact tests were used to evaluate differences in continuous and categorical CAC scores, respectively. Given skewed distributions, Spearman rank correlations and Kendall W coefficient of concordance were respectively used to evaluate correlation and concordance of CAC scores between the 2 scan types. κ statistics were used to rate agreement between categorical CAC scores. Bland-Altman analysis was performed to determine the bias and limits of agreement between ECG-gated CT and LDCT.²² For categorical CAC score analysis, participants were categorized into 5 groups according to standard Agatston score cut-off points. We defined the 5 categories of CAC for both scan types based on previous analysis from Rumberger and colleagues: CAC = 0 (absent), CAC = 1-10 (minimal), CAC = 11-100 (mild), CAC = 101-400 (moderate), CAC > 400 (severe).²³ Of note, LDCT reports at NMCP include a visual CAC score using these qualitative descriptors that were available to LDCT reviewers. Analyses were conducted using SAS version 9.4 and Microsoft Excel; P values < .05 were considered statistically significant.

Results

The 170 participants had a mean (SD) age of 62.1 (4.6) years and were 70.6% male (Table 1). Hyperlipidemia was the most prevalent cardiac risk factor with almost 70% of participants on a statin. There was no incidence of ischemic ASCVD during follow-up, although 1 participant was later diagnosed with lung cancer after evaluation of suspicious pulmonary findings on ECG-gated CT. CAC was identified on both scan types in 126 participants; however, LDCT was discordant with gated CT in identifying CAC in 24 subjects (P < .001).

The correlation between CAC scores on ECG-gated CT and LDCT was 0.945 (P < .001) and the concordance was 0.643, indicating moderate agreement between CAC scores on the 2 different scans (Figure 1). Median CAC scores were significantly higher on ECG-gated CT when compared with LDCT (107.5 vs 48.1 Agatston units, respectively; P < .05). Table 2 shows the CAC score characteristics for both scan types. The κ statistic for agreement between categorical CAC scores on ECG-gated CT compared with LDCT was 0.49 (SEκ= 0.05; 95% CI, -0.73-1.71), and the weighted κ statistic was 0.71, indicating moderate to substantial agreement between the 2 scans using the specified cutoff points. The Bland-Altman analysis presented a mean bias of 111.45 Agatston units, with limits of agreement between -268.64 and 491.54, as shown in Figure 2, suggesting that CAC scores on ECG-gated CT were, on average, about 111 units higher than those on LDCT. Finally, there were 24 participants with CAC seen on ECG-gated CT but none identified on LDCT (P < .001); of this cohort 20 were already on a statin, and of the remaining 4 individuals, 1 met statin criteria based on a > 20% ASCVD risk score alone (regardless of CAC score), 1 with an intermediate risk score met statin criteria based on CAC score reporting, 1 did not meet criteria due to a low-risk score, and the last had no reportable ASCVD risk score.

Discussion

In this study population of recruited MHS beneficiaries, there was a strong correlation and moderate to substantial agreement between CAC scores calculated from LDCT and conventional ECG-gated CT. The number of nonstatin participants who met statin criteria and would have benefited from additional CAC score reporting was statistically significant as compared to their statin counterparts who no longer met the criteria.

CAC screening using nongated CT has become an increasingly available and consistently reproducible means for stratifying ASCVD risk and guiding statin therapy in individuals with equivocal ASCVD risk scores.^24-26 As has been demonstrated in previous studies, our study additionally highlights the effective use of LDCT in not only identifying CAC, but also in beneficially impacting statin decisions in the high-risk smoking population.^24-26 Our results also showed LDCT missed CAC in participants, the majority of which were already on a statin, and only 1 nonstatin individual benefited from additional CAC reporting. CAC scoring on LDCT should be an adjunct, not a substitute, for ASCVD risk stratification to help guide statin management.^25,27

Our results may provide cost considerate implications for preventive CAC screening. While TRICARE covers the cost of ECG-gated CT for MHS beneficiaries, the same is not true of most nonmilitary insurance providers. Concerns about cancer risk from radiation exposure may also lead to hesitation about receiving additional CTs in the smoking population. Since the LCS population already receives annual LDCT, these scans can also be used for CAC scoring to help primary care professionals risk stratify their patients, as has been previously shown.^28-31 Clinicians should consider implementing CAC scoring with annual LDCT scans, which would curtail further risks and expenses from CAC-specified scans.

Although CAC is scored visually and routinely reported in the body of LDCT reports at our facility, this is not a universal practice and was performed in only 44% of subjects with known CAC by a previous study.³² In 2007, there were 600,000 CAC scoring scans and > 9 million routine chest CTs performed in the United States.³³ Based on our results and the growing consensus in the existing literature, CAC scoring on nongated CT is not only valid and reliable, but also can estimate ASCVD risk and subsequent mortality.^34-36 Routine chest CTs remain an available resource for providing additional ASCVD risk stratification.

As we demonstrated, median CAC scores on LDCT were on average significantly lower than those from gated CT. This could be due to slice thickness variability between the GE and Siemens scanners or CAC progression between the time of the retrospective LDCT and prospective ECG-gated CT. Aside from this potential limitation, LDCT has been shown to have a high level of agreement with gated CT in predicting CAC, both visually and by the Agatston technique.^37-39 Our results further support previous recommendations of utilizing CAC score categories when determining ASCVD risk from LDCT and that establishing scoring cutoff points warrants further development for potential standardization.^37-39 Readers should be mindful that LDCT may still be less sensitive and underestimate low CAC levels and that ECG-gated CT may occasionally be more optimal in determining ASCVD risk when considering the negative predictive value of CAC.⁴⁰

Limitations

Our study cohort was composed of MHS beneficiaries. Compared with the general population, these individuals may have greater access to care and be more likely to receive statins after preventive screenings. Additional studies may be required to assess CAC-associated statin eligibility among the general population. As discussed previously LDCT was not performed concomitantly with the ECG-gated CT. Although there was moderate to substantial CAC agreement between the 2 scan types, the timing difference could have led to absolute differences in CAC scores across both scan types and impacted the ability to detect low-level CAC on LDCT. CAC values should be interpreted based on the respective scan type.

Conclusions

LDCT is a reliable diagnostic alternative to ECG-gated CT in predicting CAC. CAC scores from LDCT are highly correlated and concordant with those from gated CT and can help guide statin management in individuals with intermediate ASCVD risk. The proposed duality of LDCT to assess ASCVD risk in addition to lung cancer can reduce the need for unnecessary scans while optimizing preventive clinical care. While coronary calcium and elevated CAC scores can facilitate clinical decision making to initiate statin therapy for intermediate-risk patients, physicians must still determine whether additional cardiac testing is warranted to avoid unnecessary procedures and health care costs. Smokers undergoing annual LDCT may benefit from standardized CAC scoring to help further stratify ASCVD risk while limiting the expense and radiation of additional scans.

Acknowledgments

The authors thank Ms. Lorie Gower for her contributions to the study.

Background

There are no studies in oncologic literature that report biomarker alterations in Vietnam War veterans with lung cancers. Our study elucidates genetic mutations in veterans with lung cancer exposed to Agent Orange (AO) and compares them to non-Agent Orange exposed (NAO) veterans.

Methods

We collected data of veterans with lung cancers from VA Central California Health Care System who had NGS testing via Foundation One CDx from January 2007 to January 2022. We collected data of AO versus NAO veterans including age, race, gender, smoking and exposure history, histologic subtypes, treatment modalities, PDL-1, and molecular mutations. Median PFS and OS were calculated between AO and NAO in all veterans and adenocarcinoma group after first-line therapy in months by Kaplan-Meier R log-rank test.

Results

There were total of 58 lung cancer veterans, 27 AO and 31 NAO. 33 (56.9%) veterans had adenocarcinoma (20 AO vs 13 NAO). Veterans were White (81%), male (93%) and all had tobacco exposure. The median age at diagnosis was 72 years in both groups. 65.5% had stage III-IV disease. Veterans with AO adenocarcinoma had more early stage I-II disease (50%) as compared to NAO (16%). The AO group had more PDL1 expression (TPS > 1%). 15/31 (48.4%) NAO received immunotherapy vs 7/27 (25.9%) AO. 104 molecular mutations were identified. Veterans with AO had more ROS1, MET, and NRAS while NAO had more EGFR, KRAS, and NF1 mutations. In adenocarcinoma group, AO had more MET and less KRAS while NAO has more KRAS, TP53, and EGFR. The median PFS and OS for all veterans with AO vs NAO were 8 mo vs 6 mo and 12 mo vs 10 mo, respectively (non-significant [NS]). In adenocarcinoma group the median PFS and OS for AO vs NAO veterans were 8 mo vs 4 mo and 11.75 mo vs 6 mo, respectively (NS).

Conclusions

Our study is the first to report molecular biomarkers in AO and NAO veterans with lung cancers. We found different markers between the groups. The median PFS and OS of AO and adenocarcinoma AO veterans were longer due to early stage diagnoses while NAO vetera

Background

There are no studies in oncologic literature that report biomarker alterations in Vietnam War veterans with lung cancers. Our study elucidates genetic mutations in veterans with lung cancer exposed to Agent Orange (AO) and compares them to non-Agent Orange exposed (NAO) veterans.

Methods

We collected data of veterans with lung cancers from VA Central California Health Care System who had NGS testing via Foundation One CDx from January 2007 to January 2022. We collected data of AO versus NAO veterans including age, race, gender, smoking and exposure history, histologic subtypes, treatment modalities, PDL-1, and molecular mutations. Median PFS and OS were calculated between AO and NAO in all veterans and adenocarcinoma group after first-line therapy in months by Kaplan-Meier R log-rank test.

Results

There were total of 58 lung cancer veterans, 27 AO and 31 NAO. 33 (56.9%) veterans had adenocarcinoma (20 AO vs 13 NAO). Veterans were White (81%), male (93%) and all had tobacco exposure. The median age at diagnosis was 72 years in both groups. 65.5% had stage III-IV disease. Veterans with AO adenocarcinoma had more early stage I-II disease (50%) as compared to NAO (16%). The AO group had more PDL1 expression (TPS > 1%). 15/31 (48.4%) NAO received immunotherapy vs 7/27 (25.9%) AO. 104 molecular mutations were identified. Veterans with AO had more ROS1, MET, and NRAS while NAO had more EGFR, KRAS, and NF1 mutations. In adenocarcinoma group, AO had more MET and less KRAS while NAO has more KRAS, TP53, and EGFR. The median PFS and OS for all veterans with AO vs NAO were 8 mo vs 6 mo and 12 mo vs 10 mo, respectively (non-significant [NS]). In adenocarcinoma group the median PFS and OS for AO vs NAO veterans were 8 mo vs 4 mo and 11.75 mo vs 6 mo, respectively (NS).

Conclusions

Our study is the first to report molecular biomarkers in AO and NAO veterans with lung cancers. We found different markers between the groups. The median PFS and OS of AO and adenocarcinoma AO veterans were longer due to early stage diagnoses while NAO vetera

Background

There are no studies in oncologic literature that report biomarker alterations in Vietnam War veterans with lung cancers. Our study elucidates genetic mutations in veterans with lung cancer exposed to Agent Orange (AO) and compares them to non-Agent Orange exposed (NAO) veterans.

Methods

We collected data of veterans with lung cancers from VA Central California Health Care System who had NGS testing via Foundation One CDx from January 2007 to January 2022. We collected data of AO versus NAO veterans including age, race, gender, smoking and exposure history, histologic subtypes, treatment modalities, PDL-1, and molecular mutations. Median PFS and OS were calculated between AO and NAO in all veterans and adenocarcinoma group after first-line therapy in months by Kaplan-Meier R log-rank test.

Results

There were total of 58 lung cancer veterans, 27 AO and 31 NAO. 33 (56.9%) veterans had adenocarcinoma (20 AO vs 13 NAO). Veterans were White (81%), male (93%) and all had tobacco exposure. The median age at diagnosis was 72 years in both groups. 65.5% had stage III-IV disease. Veterans with AO adenocarcinoma had more early stage I-II disease (50%) as compared to NAO (16%). The AO group had more PDL1 expression (TPS > 1%). 15/31 (48.4%) NAO received immunotherapy vs 7/27 (25.9%) AO. 104 molecular mutations were identified. Veterans with AO had more ROS1, MET, and NRAS while NAO had more EGFR, KRAS, and NF1 mutations. In adenocarcinoma group, AO had more MET and less KRAS while NAO has more KRAS, TP53, and EGFR. The median PFS and OS for all veterans with AO vs NAO were 8 mo vs 6 mo and 12 mo vs 10 mo, respectively (non-significant [NS]). In adenocarcinoma group the median PFS and OS for AO vs NAO veterans were 8 mo vs 4 mo and 11.75 mo vs 6 mo, respectively (NS).

Conclusions

Our study is the first to report molecular biomarkers in AO and NAO veterans with lung cancers. We found different markers between the groups. The median PFS and OS of AO and adenocarcinoma AO veterans were longer due to early stage diagnoses while NAO vetera

Nearly 123,000 cancer deaths – or almost 30% of all cancer deaths – in the United States in 2019 were linked to cigarette smoking, a new analysis suggests.

That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.

“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.

AtnoYdur/Thinkstock

Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.

The study was published online in the International Journal of Cancer.

Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.

To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.

Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.

By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).

Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.

The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.

The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.

Ending the ‘scourge of tobacco’

To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.

Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.

In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”

To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.

These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.

“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.

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

Nearly 123,000 cancer deaths – or almost 30% of all cancer deaths – in the United States in 2019 were linked to cigarette smoking, a new analysis suggests.

That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.

“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.

AtnoYdur/Thinkstock

Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.

The study was published online in the International Journal of Cancer.

Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.

To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.

Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.

By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).

Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.

The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.

The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.

Ending the ‘scourge of tobacco’

To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.

Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.

In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”

To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.

These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.

“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.

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

Nearly 123,000 cancer deaths – or almost 30% of all cancer deaths – in the United States in 2019 were linked to cigarette smoking, a new analysis suggests.

That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.

“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.

AtnoYdur/Thinkstock

Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.

The study was published online in the International Journal of Cancer.

Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.

To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.

Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.

By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).

Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.

The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.

The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.

Ending the ‘scourge of tobacco’

To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.

Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.

In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”

To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.

These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.

“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.

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

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

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

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

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

Lung disease as an adverse effect of the targeted cancer drug trastuzumab deruxtecan (T-DXd, Enhertu) is not negligible, although the benefit-to-risk relationship with use of the drug is still positive, say researchers who report a review of early clinical trials with the drug.

T-DXd is a monoclonal antibody that targets HER2. It is approved for use in HER2-positive breast, gastric, and lung cancers.

In the new study, investigators analyzed data from early clinical trials that involved patients with advanced cancers who had been heavily pretreated. They found an incidence of just over 15% for interstitial lung disease (ILD)/pneumonitis associated with the drug. Most patients (77.4%) had grade 1 or 2 ILD, but 2.2% of patients had grade 5 ILD.

“Interstitial lung disease is a known risk factor in patients treated with antibody conjugates for cancer,” commented lead author Charles Powell, MD, Icahn School of Medicine at Mount Sinai, New York. This adverse effect can lead to lung fibrosis and can become severe, life threatening, and even fatal, the authors warned.

The authors also discussed management of the event, which involves corticosteroids, and recommended that any patient who develops ILD of grade 3 or higher be hospitalized.

Close monitoring and proactive management may reduce the risk of ILD, they suggested.

Indeed, the incidence of this adverse effect was lower in a later phase 3 trial of the drug (10.5% in the DESTINY-Breast03 trial) and that the adverse events were less severe in this patient population (none of these events were of grade 4 or 5).

“Increased knowledge ... and implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines” may have resulted in this adverse effect being identified early and treated before it progressed, they commented.

ILD is highlighted in a boxed warning on the product label.

The study was published online in ESMO Open.

In their review, the investigators evaluated nine early-stage monotherapy clinical trials (phases 1 and 2) involving a total of 1,150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%, other cancers, 3.0%).

These patients had advanced cancer and had been heavily pretreated with a median of four prior lines of therapy. They received one or more doses of at least 5.4 mg/kg of T-DXd.

Nearly half of the cohort were treated for more than 6 months. A total of 276 potential ILD/pneumonitis events were sent for adjudication; of those, 85% were adjudicated as ILD/pneumonitis.

The overall incidence of adjudicated ILD/pneumonitis events was 15.4%; most were low-grade events. Some 87% of patients experienced their first ILD event within 12 months of treatment. The median time to experiencing an ILD/pneumonitis event was 5.4 months.

Some of the patients who developed grade 1 ILD/pneumonitis were treated and the adverse event resolved. These patients were then rechallenged with the drug. Only 3 of the 47 rechallenged patients experienced recurrence of ILD/pneumonitis, the authors noted.

“Rechallenge with T-DXd after complete resolution of grade 1 events is possible and warrants further investigation,” they commented. They cautioned, however, that rechallenge is not recommended for all patients, at least not for those with grade 2 or higher ILD/pneumonitis.

Overall, the authors concluded that the “benefit-risk of T-DXd treatment is positive,” but they warned that some patients may be at increased risk of developing ILD/pneumonitis

Baseline factors that increase the risk of developing an ILD/pneumonitis event include the following: being younger than 65 years, receiving a T-DXd dose of more than6.4 mg/kg, having a baseline oxygen saturation level of less than 95%, having moderate to severe renal impairment, and having lung comorbidities. In addition, patients who had initially been diagnosed with cancer more than 4 years before receiving the drug were at higher risk of developing ILD/pneumonitis.

“Using learnings from the early clinical trials experience, physician education and patient management protocols were revised and disseminated by the study sponsors [and] more recent trial data in earlier lines of therapy has demonstrated lower rates of ILD events, suggesting close monitoring and proactive management of ILD/pneumonitis is warranted for all patients,” Dr. Powell said in a statement.

The T-DXd clinical trials were sponsored by AstraZeneca and Daiichi Sankyo. Dr. Powell has received fees from Daiichi Sankyo, AstraZeneca, and Voluntis.

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

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

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

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

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

The field of radiation oncology has rapidly evolved in recent years, thanks in large part to findings from randomized clinical trials (RCTs) that have helped shift therapeutic standards, a review of the literature shows.

The authors assessed all RCTs involving radiotherapy from 2018 to 2021, with the goal of identifying the latest practice-changing data, emerging concepts, and areas that require further study.

Highlights from this research reveal how high-tech radiotherapy, such as hypofractionation and stereotactic body radiotherapy, has improved care for many patients, how personalized radiotherapy using image-based guidance has helped tailor treatments, and how endpoints that focus on quality of life and patient satisfaction are emerging.

For instance, Charles B. Simone II, MD, FACRO, who was not involved in the current work, pointed to “a proliferation of trials assessing hypofractionation in the curative setting and stereotactic body radiation therapy in the curative and poly- and oligometastatic settings that have allowed for increased patient convenience and dose intensification, respectively.”

Dr. Simone, chief medical officer, New York Proton Center, Memorial Sloan Kettering Cancer Center, also noted that the first personalized radiotherapy trials using imaging and biological markers have “the profound potential to individualize treatment and improve patient outcomes.”

The review was published in the European Journal of Cancer.
 

An evolving field

Given the fast-changing landscape for cancer therapeutics and a deluge of research studies, the authors wanted to understand the most notable advances established in recent trials as well as caveats to some approaches and emerging areas to watch.

In the review, Sophie Espenel, MD, from the department of radiation oncology, Gustave Roussy Cancer Campus, Villejuif, France, and colleagues identified 1,347 radiotherapy RCTs that were conducted from January 2018 to December 2021. Of these, the authors selected 110 large phase 2 or 3 RCTs that contained data showing practice-changing or emerging concepts.

Overall, the studies showed “great dynamism” in radiation oncology research and covered a wide range of radiotherapy practices, according to Dr. Espenel and coauthors.

A central area of research has focused on radioimmunotherapy, an approach that aims to enhance the antitumor immune response. One RCT in the preoperative setting showed, for instance, that concurrent stereotactic body radiotherapy delivered at 24 Gy over eight fractions, along with the anti–PD-L1 agent durvalumab, increased major pathologic complete response rates almost eightfold in comparison with durvalumab alone for patients with early-stage lung cancer (53.3% vs. 6.7%).

Although promising, not all trials that evaluated a concurrent chemoradiotherapy-immunotherapy strategy showed positive results. One RCT of locally advanced head and neck squamous cell carcinoma, for instance, found that median progression-free survival was not reached when adding the anti–PD-L1 avelumab to chemoradiotherapy. In addition, trials in the metastatic setting have shown conflicting results, the authors note.

Another topic of interest is that of newer radiosensitizers. A trial that evaluated high-risk locoregionally advanced head and neck squamous cell carcinoma highlighted the efficacy of xevinapant, a pro-apoptotic agent that inhibits apoptosis proteins. Xevinapant was used for the first time in conjunction with a standard high-dose cisplatin chemoradiotherapy. In this study, locoregional control at 18 months was achieved for 54% of patients who received xevinapant vs. 33% of those who received standard care. The toxicity profiles were similar.

The use of high-tech radiotherapy is gaining ground. It allows patients to receive more targeted treatments at lower doses and in shorter time frames. One trial found, for instance, that a more hypofractionated adjuvant whole breast approach, using 26 Gy in five fractions over a week, is as effective and safe as 40 Gy in 15 fractions over 3 weeks. The researchers found that there was no difference in the incidence of locoregional relapses, disease-free survival, and overall survival between the regimens.

Dr. Simone also noted that advanced treatment modalities, such as intensity-modulated radiotherapy, stereotactic radiosurgery, and proton therapy, have the potential to improve patient-reported adverse events and clinical outcomes. “I have seen this both in my clinical practice and in several recent publications,” he says.

Personalization of radiotherapy is also an emerging area that may allow for more tailored treatments with improved outcomes. The authors highlighted a study that found that PMSA PET-CT was better than conventional CT for accurately staging prostate cancer. This approach was also less expensive and led to less radiation exposure.

On the basis of this research, “PMSA PET-CT has since become the [standard of care] for prostate cancer staging,” the authors explain.

Dr. Espenel and colleagues note that as patients survive longer, quality of life and patient satisfaction are increasingly becoming endpoints in RCTs. Experts are focusing more attention on sequelae of treatments and advances in technology that can spare critical organs from radiation and reduce overall treatment time.

Shared decision-making is becoming increasingly possible in many cases as well. For example, with some clinical trials that involved different treatment modalities, outcomes were equivalent, but toxicity profiles differed, allowing patients to choose therapeutic options tailored to their preferences.

Overall, these data demonstrate “a great dynamism of radiation oncology research in most primary tumor types,” the researchers write.

The study received no outside financial support. The authors have disclosed no relevant financial relationships. Dr. Simone is chair of the American Society for Radiation Oncology Lung Resource Panel and the American Society for Radiation Oncology Veteran Affairs Radiation Oncology Quality Surveillance Blue Ribbon Lung Panel and has received honorarium from Varian Medical Systems.

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

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

Lung cancer has been the leading cause of cancer-related mortality for decades. It is also predicted to remain as the leading cause of cancer-related mortality through 2030.¹ Platinum-based chemotherapy, including carboplatin and paclitaxel, was introduced 3 decades ago and revolutionized the management of advanced non–small cell lung cancer (NSCLC). A more recent advancement has been mutant epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors.¹ EGFR is a transmembrane protein that functions by transducing essential growth factor signaling from the extracellular milieu to the cell. As 60% of the advanced NSCLC expresses this receptor, blocking the mutant EGFR receptor was a groundbreaking development in the management of advanced NSCLC.² Development of mutant EGFR-TK inhibitors has revolutionized the management of advanced NSCLC. This study was conducted to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced NSCLC.

Methods 

This meta-analysis was conducted according to Cochrane Collaboration guidelines and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The findings are summarized in the PRISMA flow diagram (Figure 1). Two authors (MZ and MM) performed a systematic literature search using databases such as MEDLINE (via PubMed), Embase, and Cochrane Library using the medical search terms and their respective entry words with the following search strategy: safety, “mutant EGFR-TK inhibitors,” advanced, “non–small cell,” “lung cancer,” “adverse effect,” and literature. Additionally, unpublished trials were identified from clinicaltrials.gov, and references of all pertinent articles were also scrutinized to ensure the inclusion of all relevant studies. The search was completed on June 1, 2021, and we only included studies available in English. Two authors (MM and MZ) independently screened the search results in a 2-step process based on predetermined inclusion/exclusion criteria. First, 890 articles were evaluated for relevance on title and abstract level, followed by full-text screening of the final list of 140 articles. Any disagreements were resolved by discussion or third-party review, and a total of 9 articles were included in the study.

The following eligibility criteria were used: original articles reporting adverse effects (AEs) of mutant EGFR-TK inhibitors in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy. All the patients included in the study had an EGFR mutation but randomly assigned to either treatment or control group. All articles with subjective data on mutant EGFR-TK inhibitors AEs in patients with advanced NSCLC compared with control groups receiving platinum-based chemotherapy were included in the analysis. Only 9 articles qualified the aforementioned selection criteria for eligibility. All qualifying studies were nationwide inpatient or pooled clinical trials data. The reasons for exclusion of the other 71 articles were irrelevant (n = 31), duplicate (n = 13), reviews (n = 14), and poor data reporting (n = 12). Out of the 9 included studies, 9 studies showed correlation of AEs, including rash, diarrhea, nausea, and fatigue. Seven studies showed correlation of AEs including neutropenia, anorexia, and vomiting. Six studies showed correlation of anemia, cough, and stomatitis. Five studies showed correlation of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leucopenia. Four studies showed correlation of fever between mutant EGFR-TK inhibitors and platinum-based chemotherapy.

The primary endpoints were reported AEs including rash, diarrhea, elevated ALT, elevated AST, stomatitis, nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever, respectively. Data on baseline characteristics and clinical outcomes were then extracted, and summary tables were created. Summary estimates of the clinical endpoints were then calculated with risk ratio (RR) and 95% confidence intervals (CIs) using the random-effects model. Heterogeneity between studies was examined with the Cochran Q I² statistic which can be defined as low (25% to 50%), moderate (50% to 75%), or high (> 75%). Statistical analysis was performed using Comprehensive Meta-Analysis Software CMA Version 3.0.

Results

A total of 9 studies including 3415 patients (1775 in EGFR-TK inhibitor treatment group while 1640 patients in platinum-based chemotherapy control group) were included in the study. All 9 studies were phase III randomized control clinical trials conducted to compare the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. Mean age was 61 years in both treatment and control groups. Further details on study and participant characteristics and safety profile including AEs are summarized in Tables 1 and 2. No evidence of publication bias was found.

Rash developed in 45.8% of patients in the treatment group receiving mutant EGFR-TK inhibitors vs only 5.6% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 7.38 with the 95% CI noted, which was statistically significant, confirming higher rash event rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 2).

Diarrhea occurred in 33.6% of patients in the mutant EGFR-TK inhibitors treatment group vs 13.5% of patients in the control group receiving platinum-based chemotherapy. Overall RR of 2.63 and 95% CI was noted, which was statistically significant, confirming higher diarrheal rates in patients receiving EGFR-TK inhibitors for their advanced NSCLC (Figure 3).

Discussion

Despite the advancement in the treatment of metastatic NSCLC, lung cancer stays as most common cause of cancer-related death in North America and European countries, as patients usually have an advanced disease at the time of diagnosis.³ In the past, platinum-based chemotherapy remained the standard of care for most of the patients affected with advanced NSCLC, but the higher recurrence rate and increase in frequency and intensity of AEs with platinum-based chemotherapy led to the development of targeted therapy for NSCLC, one of which includes mutant EGFR-TK inhibitors, including erlotinib, gefitinib, dacomitinib, lapatinib, and osimertinib.⁴

Smoking is the most common reversible risk factor associated with lung cancer. The EURTAC trial was the first perspective study in this regard, which compared safety and efficacy of mutant EGFR-TK inhibitors with platinum-based chemotherapy. Results analyzed in this study were in favor of mutant EGFR-TK inhibitors except in the group of former smokers.⁵ On the contrary, the OPTIMAL trial showed results in favor of mutant EGFR-TK inhibitors both in active and former smokers; this trial also confirmed the efficacy of mutant EGFR-TK inhibitors in European and Asian populations, confirming the rationale for routine testing of EGFR mutation in all the patients being diagnosed with advanced NSCLC.⁶ Similarly, osimertinib is one of the most recent mutant EGFR-TK inhibitors developed for the treatment of advanced NSCLC in patients with EGFR-positive receptors.

According to the FLAURA trial, patients receiving osimertinib showed significantly longer progression-free survival compared with platinum-based chemotherapy and early mutant EGFR-TK inhibitors. Median progression-free survival was noted to be 18.9 months, which showed 54% lower risk of disease progression in the treatment group receiving osimertinib.⁷ The ARCHER study emphasized a significant improvement in overall survival as well as progression-free survival among a patient population receiving dacomitinib compared with platinum-based chemotherapy.^8,9

Being a potent targeted therapy, mutant EGFR-TK inhibitors do come with some AEs including diarrhea, which was seen in 33.6% of the patients receiving mutant EGFR-TK inhibitors in our study vs 53% in the chemotherapy group, as was observed in the study conducted by Pless and colleagues.¹⁰ Similarly, only 16.5% of patients receiving mutant EGFR-TK inhibitors developed nausea compared with 66% being observed in patients receiving chemotherapy. Correspondingly, only a small fraction of patients (9.7%) receiving mutant EGFR-TK inhibitors developed leucopenia, which was 10 times less reported in mutant EGFR-TK inhibitors compared with patients receiving chemotherapy having a percentage of 100%. A similar trend was reported for neutropenia and anemia in mutant EGFR-TK inhibitors with an incidence of 6.1% and 8.7%, compared with the platinum-based chemotherapy group in which the incidence was found to be 80% and 100%, respectively. It was concluded that platinum-based chemotherapy had played a vital role in the treatment of advanced NSCLC but at an expense of serious and severe AEs which led to discontinuation or withdrawal of treatment, leading to relapse and recurrence of lung cancer.^10,11

Zhong and colleagues conducted a phase 2 randomized clinical trial comparing mutant EGFR-TK inhibitors with platinum-based chemotherapy. They concluded that in patients receiving platinum-based chemotherapy, incidence of rash, vomiting, anorexia, neutropenia, and nausea were 29.4%, 47%, 41.2%, 55.8%, and 32.4% compared with 45.8%, 11%, 21.3%, 6.1%, and 16.5%, respectively, reported in patients receiving mutant EGFR-TK inhibitors for their advanced NSCLC.¹²

Another study was conducted in 2019 by Noronha and colleagues to determine the impact of platinum-based chemotherapy combined with gefitinib on patients with advanced NSCLC.¹³ They concluded that 70% of the patients receiving combination treatment developed rash, which was significantly higher compared with 45.8% patients receiving the mutant EGFR-TK inhibitors alone in our study. Also, 56% of patients receiving combination therapy developed diarrhea vs 33.6% of patients receiving mutant EGFR-TK inhibitors only. Similarly, 96% of patients in the combination therapy group developed some degree of anemia compared with only 8.7% patients in the mutant EGFR-TK inhibitors group included in our study. In the same way, neutropenia was observed in 55% of patients receiving combination therapy vs 6.1% in patients receiving mutant EGFR-TK inhibitors solely. They concluded that mutant EGFR-TK inhibitors when combined with platinum-based chemotherapy increase the incidence of AEs of chemotherapy by many folds.^13,14

Kato and colleagues conducted a study to determine the impact on AEs when erlotinib was combined with anti–vascular endothelial growth factor (VEGF) inhibitors like bevacizumab, they stated that 98.7% of patient in combination therapy developed rash, the incidence of which was only 45.8% in patients receiving mutant EGFR-TK inhibitors as was observed in our study. Similar trends were noticed with other AEs, including diarrhea, fatigue, nausea, and elevated liver enzymes.¹⁵

Conclusions

Our study focused on the safety profile of mutant EGFR-TK inhibitors vs platinum-based chemotherapy in the treatment of advanced NSCLC. Mutant EGFR-TK inhibitors are safer than platinum-based chemotherapy when compared for nausea, leucopenia, fatigue, neutropenia, anorexia, anemia, cough, vomiting, and fever. On the other end, mutant EGFR-TK inhibitors cause slightly higher AEs, including rash, diarrhea, elevated AST and ALT levels, and stomatitis. However, considering that the development of mutant EGFR-TK inhibitors laid a foundation of targeted therapy, we recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. AEs caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until the patient is symptomatic.

In 2016, as vice president, Joe Biden launched the Cancer Moonshot program just 1 year after his son Beau died from glioblastoma multiforme. His objective, he said, was to “cure” cancer, but to get close to that goal, researchers from two leading National Cancer Institute-designated cancer centers say an infusion of new funding for cancer research is needed to get cancer research just back up to pre-COVID-19 pandemic levels.

There has been a significant decrease in the launch of new clinical trials for cancer and biologic therapies since 2020. “That can affect every aspect of our research operation. It really affected our capacity to continue to move forward at a fast pace. It will require a behemoth effort to get back to pre-COVID times,” said Tanios S. Bekaii-Saab, MD, leader of the gastrointestinal cancer program at Mayo Clinic in Phoenix.

Congress passed the 21st Century Cures Act in 2016 authorizing $1.8 billion for Cancer Moonshot over 7 years. More recently, the program received $194 million from the $6.9 billion National Cancer Institute budget in FY 2022.

Joseph Alvarnas, MD, a hematologist oncologist and vice president of government affairs at City of Hope, Duarte, Calif., sees the Moonshot budget as a potential shortcoming.

“The priorities are well founded and based on what we would think are the most important things to cover, but, if we’re going to achieve these extraordinarily ambitious goals of halving cancer mortality and serving communities more equitably, it’s going to need more funding positioned at making these things real,” he said.

Moonshot is being positioned as an opportunity to double down on efforts started in 2016, but treating cancer is complex and goes well beyond funding new research.

“We know that we have amazing research and progress around innovations that will drive us toward the goal of reducing the death rate from cancer. But we also know that we have tools that aren’t reaching all parts of the country, so we have a great opportunity to make sure that we’re doing all we can to prevent, detect and treat cancer,” Dr. Carnival said.
 

Can cancer be cured?

The Biden administration relaunched Moonshot in 2022 with newly defined goals: Cut the rate of cancer-related deaths in half within 25 years; improve the experience of people with cancer, cancer survivors, and their families; and “end cancer as we know it,” President Biden said in a press conference in February.

Cancer is the second leading cause of death in the United States after heart disease, but it may indeed be possible to cut the total number of cancer-related deaths in half over the next 25 years.

“As a hematologist who’s been involved in both research and clinical care, I think it’s important to realize this is actually doable. Between 1990 and 2020 cancer mortality rates decreased by 31%, and in the last American Cancer Society’s annual report, mortality rates dropped by the largest percentages for 2 consecutive years in a row. The question shifts now from ‘Is this possible? to ‘How do we ensure that it’s possible?’ The spirit of Cancer Moonshot 2.0 is identifying the multiple paths to move this effort forward,” Dr. Alvarnas said.

But without a significant infusion of cash for research, it’s doubtful cancer-related deaths will drop by 50% over the next 25 years.

“There are a lot of big and lofty goals in Cancer Moonshot, and the words ‘ending cancer,’ well those are big words,” Dr. Bekaii-Saab said. “The reality is how do we measure in 25 years the impact of this today? I think it will require significantly more funding over the next few years to achieve the goals set by the Moonshot. Otherwise it will be a 7-year done deal that will accrue a lot of great numbers but won’t make a dent in those goals for the next 25 years. To stop it at some point and not invest more into it, we will probably lose most of the benefit.”

Closing the loop on data sharing

Moonshot has been instrumental in fostering research collaborations by encouraging data sharing among scientists.

“It also brought together a new way for the National Cancer Institute and Department of Energy to drive progress on some of the big data initiatives. The initial Cancer Moonshot infused a sense of urgency and hope into this effort,” said Danielle Carnival, PhD, coordinator of Cancer Moonshot.

Between 2017 and 2022, Cancer Moonshot created more than 70 consortiums or programs, and funded about 240 research projects. Its fundamental goals of improving data sharing and encouraging collaboration are very important, Dr. Bekaii-Saab said.

“Because, historically, what happens with cancer is that researchers compete for resources...and they become very protective of their data. Sharing gets more difficult, collaborations become more onerous, and it becomes counterproductive,” he said.

Dr. Bekaii-Saab highlighted two networks created specifically for data sharing. They include the Human Tumor Atlas for cellular, morphological, and molecular tumor data, and PDXNet, a patient derived xenograft research network.
 

A shift in funding priorities?

Cancer funding has been stagnant for years. When adjusted for growth, it hasn’t had a significant infusion of funding since at least 2003—at least in relative terms, Dr. Bekaii-Saab said. “This affects a lot of the things we do, including NCI-funded clinical trials. It pushes us to work with the private sector, which is not necessarily a detriment, but it doesn’t advance the academic mission at the same level. So, overall, I wouldn’t call it tragic, but I do think we’re falling behind,” he said.

“I think when we do the process for the budget for FY24 and after we’ve had time to really explore the best ideas and build the foundation for some of these new aspects of the Cancer Moonshot, we hope to have something more concrete going toward these efforts,” Dr. Carnival said.

But in addition to funding, Dr. Alvarnas says, it is equally important to address gaps in care. Not all patients have access to existing cancer treatments.

“The great challenge to us in the 2020s is not only about developing new and more effective technologies, but also in doing a better job of getting existing life-saving treatments into the hands of underserved populations. One of the really positive challenges set forth by the Biden administration is the idea that financing care equity is as important, if not more so, than advancing technologies. If there’s been stagnation, it’s because from a government and resourcing point of view, that priority has been ineffectively supported financially.”
 

The pandemic stymies cancer research

The pandemic has had a significant impact on cancer research. As in other fields, it disrupted ongoing research, but it may have also contributed to the loss of employees who resigned in what’s been called the “Great Resignation.” “A lot of employees just decided to change jobs in the middle of the pandemic, which led to a cancer research staffing crisis,” Dr. Bekaii-Saab said.

“We all recognized that turning so much of the attention of the entire biomedical research engine and health system to the COVID-19 pandemic would have an impact across cancer research, screenings and care,” Dr. Carnival said. “There is work to do to get us back to whole, but from a research perspective, we’ve seen a reorientation of the trial networks we were using for COVID-19 research, back to their initial purpose. Some of those are cancer and oncology networks, so we’re excited about that and fully believe that we can catch up.”

But then there’s also the impact the pandemic has had on cancer patients who delayed their care at the primary level. This, Dr. Bekaii-Saab fears, will lead to more patients presenting with more advanced disease in years to come. “One of the biggest problems was that a lot of patients delayed their care at the primary level. My biggest concern is that in the years to come we will see a lot more patients presenting with more advanced cancer.”

In 2016, as vice president, Joe Biden launched the Cancer Moonshot program just 1 year after his son Beau died from glioblastoma multiforme. His objective, he said, was to “cure” cancer, but to get close to that goal, researchers from two leading National Cancer Institute-designated cancer centers say an infusion of new funding for cancer research is needed to get cancer research just back up to pre-COVID-19 pandemic levels.

There has been a significant decrease in the launch of new clinical trials for cancer and biologic therapies since 2020. “That can affect every aspect of our research operation. It really affected our capacity to continue to move forward at a fast pace. It will require a behemoth effort to get back to pre-COVID times,” said Tanios S. Bekaii-Saab, MD, leader of the gastrointestinal cancer program at Mayo Clinic in Phoenix.

Congress passed the 21st Century Cures Act in 2016 authorizing $1.8 billion for Cancer Moonshot over 7 years. More recently, the program received $194 million from the $6.9 billion National Cancer Institute budget in FY 2022.

Joseph Alvarnas, MD, a hematologist oncologist and vice president of government affairs at City of Hope, Duarte, Calif., sees the Moonshot budget as a potential shortcoming.

“The priorities are well founded and based on what we would think are the most important things to cover, but, if we’re going to achieve these extraordinarily ambitious goals of halving cancer mortality and serving communities more equitably, it’s going to need more funding positioned at making these things real,” he said.

Moonshot is being positioned as an opportunity to double down on efforts started in 2016, but treating cancer is complex and goes well beyond funding new research.

“We know that we have amazing research and progress around innovations that will drive us toward the goal of reducing the death rate from cancer. But we also know that we have tools that aren’t reaching all parts of the country, so we have a great opportunity to make sure that we’re doing all we can to prevent, detect and treat cancer,” Dr. Carnival said.
 

Can cancer be cured?

The Biden administration relaunched Moonshot in 2022 with newly defined goals: Cut the rate of cancer-related deaths in half within 25 years; improve the experience of people with cancer, cancer survivors, and their families; and “end cancer as we know it,” President Biden said in a press conference in February.

Cancer is the second leading cause of death in the United States after heart disease, but it may indeed be possible to cut the total number of cancer-related deaths in half over the next 25 years.

“As a hematologist who’s been involved in both research and clinical care, I think it’s important to realize this is actually doable. Between 1990 and 2020 cancer mortality rates decreased by 31%, and in the last American Cancer Society’s annual report, mortality rates dropped by the largest percentages for 2 consecutive years in a row. The question shifts now from ‘Is this possible? to ‘How do we ensure that it’s possible?’ The spirit of Cancer Moonshot 2.0 is identifying the multiple paths to move this effort forward,” Dr. Alvarnas said.

But without a significant infusion of cash for research, it’s doubtful cancer-related deaths will drop by 50% over the next 25 years.

“There are a lot of big and lofty goals in Cancer Moonshot, and the words ‘ending cancer,’ well those are big words,” Dr. Bekaii-Saab said. “The reality is how do we measure in 25 years the impact of this today? I think it will require significantly more funding over the next few years to achieve the goals set by the Moonshot. Otherwise it will be a 7-year done deal that will accrue a lot of great numbers but won’t make a dent in those goals for the next 25 years. To stop it at some point and not invest more into it, we will probably lose most of the benefit.”

Closing the loop on data sharing

Moonshot has been instrumental in fostering research collaborations by encouraging data sharing among scientists.

“It also brought together a new way for the National Cancer Institute and Department of Energy to drive progress on some of the big data initiatives. The initial Cancer Moonshot infused a sense of urgency and hope into this effort,” said Danielle Carnival, PhD, coordinator of Cancer Moonshot.

Between 2017 and 2022, Cancer Moonshot created more than 70 consortiums or programs, and funded about 240 research projects. Its fundamental goals of improving data sharing and encouraging collaboration are very important, Dr. Bekaii-Saab said.

“Because, historically, what happens with cancer is that researchers compete for resources...and they become very protective of their data. Sharing gets more difficult, collaborations become more onerous, and it becomes counterproductive,” he said.

Dr. Bekaii-Saab highlighted two networks created specifically for data sharing. They include the Human Tumor Atlas for cellular, morphological, and molecular tumor data, and PDXNet, a patient derived xenograft research network.
 

A shift in funding priorities?

Cancer funding has been stagnant for years. When adjusted for growth, it hasn’t had a significant infusion of funding since at least 2003—at least in relative terms, Dr. Bekaii-Saab said. “This affects a lot of the things we do, including NCI-funded clinical trials. It pushes us to work with the private sector, which is not necessarily a detriment, but it doesn’t advance the academic mission at the same level. So, overall, I wouldn’t call it tragic, but I do think we’re falling behind,” he said.

“I think when we do the process for the budget for FY24 and after we’ve had time to really explore the best ideas and build the foundation for some of these new aspects of the Cancer Moonshot, we hope to have something more concrete going toward these efforts,” Dr. Carnival said.

But in addition to funding, Dr. Alvarnas says, it is equally important to address gaps in care. Not all patients have access to existing cancer treatments.

“The great challenge to us in the 2020s is not only about developing new and more effective technologies, but also in doing a better job of getting existing life-saving treatments into the hands of underserved populations. One of the really positive challenges set forth by the Biden administration is the idea that financing care equity is as important, if not more so, than advancing technologies. If there’s been stagnation, it’s because from a government and resourcing point of view, that priority has been ineffectively supported financially.”
 

The pandemic stymies cancer research

The pandemic has had a significant impact on cancer research. As in other fields, it disrupted ongoing research, but it may have also contributed to the loss of employees who resigned in what’s been called the “Great Resignation.” “A lot of employees just decided to change jobs in the middle of the pandemic, which led to a cancer research staffing crisis,” Dr. Bekaii-Saab said.

“We all recognized that turning so much of the attention of the entire biomedical research engine and health system to the COVID-19 pandemic would have an impact across cancer research, screenings and care,” Dr. Carnival said. “There is work to do to get us back to whole, but from a research perspective, we’ve seen a reorientation of the trial networks we were using for COVID-19 research, back to their initial purpose. Some of those are cancer and oncology networks, so we’re excited about that and fully believe that we can catch up.”

But then there’s also the impact the pandemic has had on cancer patients who delayed their care at the primary level. This, Dr. Bekaii-Saab fears, will lead to more patients presenting with more advanced disease in years to come. “One of the biggest problems was that a lot of patients delayed their care at the primary level. My biggest concern is that in the years to come we will see a lot more patients presenting with more advanced cancer.”

In 2016, as vice president, Joe Biden launched the Cancer Moonshot program just 1 year after his son Beau died from glioblastoma multiforme. His objective, he said, was to “cure” cancer, but to get close to that goal, researchers from two leading National Cancer Institute-designated cancer centers say an infusion of new funding for cancer research is needed to get cancer research just back up to pre-COVID-19 pandemic levels.

There has been a significant decrease in the launch of new clinical trials for cancer and biologic therapies since 2020. “That can affect every aspect of our research operation. It really affected our capacity to continue to move forward at a fast pace. It will require a behemoth effort to get back to pre-COVID times,” said Tanios S. Bekaii-Saab, MD, leader of the gastrointestinal cancer program at Mayo Clinic in Phoenix.

Congress passed the 21st Century Cures Act in 2016 authorizing $1.8 billion for Cancer Moonshot over 7 years. More recently, the program received $194 million from the $6.9 billion National Cancer Institute budget in FY 2022.

Joseph Alvarnas, MD, a hematologist oncologist and vice president of government affairs at City of Hope, Duarte, Calif., sees the Moonshot budget as a potential shortcoming.

“The priorities are well founded and based on what we would think are the most important things to cover, but, if we’re going to achieve these extraordinarily ambitious goals of halving cancer mortality and serving communities more equitably, it’s going to need more funding positioned at making these things real,” he said.

Moonshot is being positioned as an opportunity to double down on efforts started in 2016, but treating cancer is complex and goes well beyond funding new research.

“We know that we have amazing research and progress around innovations that will drive us toward the goal of reducing the death rate from cancer. But we also know that we have tools that aren’t reaching all parts of the country, so we have a great opportunity to make sure that we’re doing all we can to prevent, detect and treat cancer,” Dr. Carnival said.
 

Can cancer be cured?

The Biden administration relaunched Moonshot in 2022 with newly defined goals: Cut the rate of cancer-related deaths in half within 25 years; improve the experience of people with cancer, cancer survivors, and their families; and “end cancer as we know it,” President Biden said in a press conference in February.

Cancer is the second leading cause of death in the United States after heart disease, but it may indeed be possible to cut the total number of cancer-related deaths in half over the next 25 years.

“As a hematologist who’s been involved in both research and clinical care, I think it’s important to realize this is actually doable. Between 1990 and 2020 cancer mortality rates decreased by 31%, and in the last American Cancer Society’s annual report, mortality rates dropped by the largest percentages for 2 consecutive years in a row. The question shifts now from ‘Is this possible? to ‘How do we ensure that it’s possible?’ The spirit of Cancer Moonshot 2.0 is identifying the multiple paths to move this effort forward,” Dr. Alvarnas said.

But without a significant infusion of cash for research, it’s doubtful cancer-related deaths will drop by 50% over the next 25 years.

“There are a lot of big and lofty goals in Cancer Moonshot, and the words ‘ending cancer,’ well those are big words,” Dr. Bekaii-Saab said. “The reality is how do we measure in 25 years the impact of this today? I think it will require significantly more funding over the next few years to achieve the goals set by the Moonshot. Otherwise it will be a 7-year done deal that will accrue a lot of great numbers but won’t make a dent in those goals for the next 25 years. To stop it at some point and not invest more into it, we will probably lose most of the benefit.”

Closing the loop on data sharing

Moonshot has been instrumental in fostering research collaborations by encouraging data sharing among scientists.

“It also brought together a new way for the National Cancer Institute and Department of Energy to drive progress on some of the big data initiatives. The initial Cancer Moonshot infused a sense of urgency and hope into this effort,” said Danielle Carnival, PhD, coordinator of Cancer Moonshot.

Between 2017 and 2022, Cancer Moonshot created more than 70 consortiums or programs, and funded about 240 research projects. Its fundamental goals of improving data sharing and encouraging collaboration are very important, Dr. Bekaii-Saab said.

“Because, historically, what happens with cancer is that researchers compete for resources...and they become very protective of their data. Sharing gets more difficult, collaborations become more onerous, and it becomes counterproductive,” he said.

Dr. Bekaii-Saab highlighted two networks created specifically for data sharing. They include the Human Tumor Atlas for cellular, morphological, and molecular tumor data, and PDXNet, a patient derived xenograft research network.
 

A shift in funding priorities?

Cancer funding has been stagnant for years. When adjusted for growth, it hasn’t had a significant infusion of funding since at least 2003—at least in relative terms, Dr. Bekaii-Saab said. “This affects a lot of the things we do, including NCI-funded clinical trials. It pushes us to work with the private sector, which is not necessarily a detriment, but it doesn’t advance the academic mission at the same level. So, overall, I wouldn’t call it tragic, but I do think we’re falling behind,” he said.

“I think when we do the process for the budget for FY24 and after we’ve had time to really explore the best ideas and build the foundation for some of these new aspects of the Cancer Moonshot, we hope to have something more concrete going toward these efforts,” Dr. Carnival said.

But in addition to funding, Dr. Alvarnas says, it is equally important to address gaps in care. Not all patients have access to existing cancer treatments.

“The great challenge to us in the 2020s is not only about developing new and more effective technologies, but also in doing a better job of getting existing life-saving treatments into the hands of underserved populations. One of the really positive challenges set forth by the Biden administration is the idea that financing care equity is as important, if not more so, than advancing technologies. If there’s been stagnation, it’s because from a government and resourcing point of view, that priority has been ineffectively supported financially.”
 

The pandemic stymies cancer research

The pandemic has had a significant impact on cancer research. As in other fields, it disrupted ongoing research, but it may have also contributed to the loss of employees who resigned in what’s been called the “Great Resignation.” “A lot of employees just decided to change jobs in the middle of the pandemic, which led to a cancer research staffing crisis,” Dr. Bekaii-Saab said.

“We all recognized that turning so much of the attention of the entire biomedical research engine and health system to the COVID-19 pandemic would have an impact across cancer research, screenings and care,” Dr. Carnival said. “There is work to do to get us back to whole, but from a research perspective, we’ve seen a reorientation of the trial networks we were using for COVID-19 research, back to their initial purpose. Some of those are cancer and oncology networks, so we’re excited about that and fully believe that we can catch up.”

But then there’s also the impact the pandemic has had on cancer patients who delayed their care at the primary level. This, Dr. Bekaii-Saab fears, will lead to more patients presenting with more advanced disease in years to come. “One of the biggest problems was that a lot of patients delayed their care at the primary level. My biggest concern is that in the years to come we will see a lot more patients presenting with more advanced cancer.”

Lung cancer screening has been a success story in high-income countries, leading to a shift in diagnoses to earlier stages and a reduction in mortality among eligible groups.

A new report shows that middle- and low-income countries are being left out. “We do have good screening programs and some national ones, even in smaller European countries and in Canada, but in low- and middle-income countries where the mortality rates and the incidence of lung cancer is higher than in high-income countries, these programs are not implemented either at all or not implemented nationwide. This is a huge problem in the world,” said Milena Cavic, PhD, who presented the interim results on behalf of the diagnostics working group of the International Association for the Study of Lung Cancer early detection and screening committee at a press conference on Aug. 7 at the World Conference on Lung Cancer. Dr. Cavic is a senior research associate at the Institute for Oncology and Radiology of Serbia in Belgrade.

“It’s definitely a work in progress, and it’s also about raising awareness of the problem. In several parts of Asia, in Taiwan, in Korea, smoking is not the major, or at least, not the only reason for getting lung cancer. The other reasons are family history and also environmental factors like cooking fires, etc. So, the criteria we have for screening in Western countries are not one to one implementable in these countries,” said Rudolf Huber, MD, PhD, a respiratory physician at Ludwig Maximilian University of Munich and a coauthor of the report.

The report also pointed out the lack of recommendations for lung cancer screening in middle- and low-income countries. One approach would be to produce recommendations for countries with similar infrastructures and health resources, as well as primary risk factors such as smoking or cooking fires. “We have to adapt it to the various situations,” said Dr. Huber.

Another possibility is to rework existing recommendations for high income countries to adapt them to low- and middle-income countries. In the coming year, the working group will conduct a modeling study of Serbia, China, South Africa, and Columbia. It will look at population-specific and geographic factors from each country to produce country-specific models. “It will be interesting to see if these models will give us new recommendations for countries like this. So we can derive something from the high-income countries, but it will need to be adapted very, very much,” said Dr. Cavic.

The report highlighted some of the disparities between countries. CT scanners are far more common in high-income countries. Japan leads the way at 111.5 per million residents, followed by Australia at 70.2, Iceland at 47.6, and the United States at 44.9. At the other end is Columbia with 1.3, which trails Mexico at 5.9, Hungary at 9.4, and the United Kingdom at 9.5. However, the authors point out that there is no consensus on the optimum number of CT scanners per capita, since too few can lead to lack of access and too many can result in overuse. In fact, the greatest number of CT scans performed per capita was in the United States (278.5 per million), followed by Iceland (234.4), Japan (230.8), and Korea (228.1).

Lung cancer screening can be at odds with other health priorities, especially in low-income countries. These can include HIV, tuberculosis, and granulomatous diseases. But that could also provide an opportunity, according to Dr. Huber. “For example, in South Africa, tuberculosis programs are done by chest x-ray. We now have data that [allows us to] detect nodules by artificial intelligence, so one of the things we are thinking about is whether we could even use chest x-ray to get an earlier detection. At the end, it may be that in some countries it’s possible to do the classical CT screening, while in other countries we have to adapt to other options – probably chest x-ray using artificial intelligence or computer-aided diagnosis. And, then a consequent program for following up and managing the incidentally diagnosed nodules.”

The group is hoping to explore the environmental factors that could affect lung cancer risk in middle- and low-income countries. That is difficult to do, however, because smoking data can be hard to come by in many countries, and there is general uncertainty about what other risk factors may exist, though air pollution is a clear suspect. “It is something we are hoping to focus on in the future because there is a subgroup of individuals without a smoking history who are at high risk. It would be really good to find this high-risk population that should actually be screened in the future,” Dr. Cavic said.

Some countries have no data on lung cancer screening. For example, only South Africa is represented from Africa, and data is missing from many countries in Asia. The diagnostics working group of the IASLC early detection and screening committee has created a survey to gather information on the availability of lung cancer screening and its effect on diagnosis and treatment in countries throughout the world.

Dr. Cavic and Dr. Huber reported no relevant financial disclosures. The meeting was sponsored by the IASLC.

Lung cancer screening has been a success story in high-income countries, leading to a shift in diagnoses to earlier stages and a reduction in mortality among eligible groups.

A new report shows that middle- and low-income countries are being left out. “We do have good screening programs and some national ones, even in smaller European countries and in Canada, but in low- and middle-income countries where the mortality rates and the incidence of lung cancer is higher than in high-income countries, these programs are not implemented either at all or not implemented nationwide. This is a huge problem in the world,” said Milena Cavic, PhD, who presented the interim results on behalf of the diagnostics working group of the International Association for the Study of Lung Cancer early detection and screening committee at a press conference on Aug. 7 at the World Conference on Lung Cancer. Dr. Cavic is a senior research associate at the Institute for Oncology and Radiology of Serbia in Belgrade.

“It’s definitely a work in progress, and it’s also about raising awareness of the problem. In several parts of Asia, in Taiwan, in Korea, smoking is not the major, or at least, not the only reason for getting lung cancer. The other reasons are family history and also environmental factors like cooking fires, etc. So, the criteria we have for screening in Western countries are not one to one implementable in these countries,” said Rudolf Huber, MD, PhD, a respiratory physician at Ludwig Maximilian University of Munich and a coauthor of the report.

The report also pointed out the lack of recommendations for lung cancer screening in middle- and low-income countries. One approach would be to produce recommendations for countries with similar infrastructures and health resources, as well as primary risk factors such as smoking or cooking fires. “We have to adapt it to the various situations,” said Dr. Huber.

Another possibility is to rework existing recommendations for high income countries to adapt them to low- and middle-income countries. In the coming year, the working group will conduct a modeling study of Serbia, China, South Africa, and Columbia. It will look at population-specific and geographic factors from each country to produce country-specific models. “It will be interesting to see if these models will give us new recommendations for countries like this. So we can derive something from the high-income countries, but it will need to be adapted very, very much,” said Dr. Cavic.

The report highlighted some of the disparities between countries. CT scanners are far more common in high-income countries. Japan leads the way at 111.5 per million residents, followed by Australia at 70.2, Iceland at 47.6, and the United States at 44.9. At the other end is Columbia with 1.3, which trails Mexico at 5.9, Hungary at 9.4, and the United Kingdom at 9.5. However, the authors point out that there is no consensus on the optimum number of CT scanners per capita, since too few can lead to lack of access and too many can result in overuse. In fact, the greatest number of CT scans performed per capita was in the United States (278.5 per million), followed by Iceland (234.4), Japan (230.8), and Korea (228.1).

Lung cancer screening can be at odds with other health priorities, especially in low-income countries. These can include HIV, tuberculosis, and granulomatous diseases. But that could also provide an opportunity, according to Dr. Huber. “For example, in South Africa, tuberculosis programs are done by chest x-ray. We now have data that [allows us to] detect nodules by artificial intelligence, so one of the things we are thinking about is whether we could even use chest x-ray to get an earlier detection. At the end, it may be that in some countries it’s possible to do the classical CT screening, while in other countries we have to adapt to other options – probably chest x-ray using artificial intelligence or computer-aided diagnosis. And, then a consequent program for following up and managing the incidentally diagnosed nodules.”

The group is hoping to explore the environmental factors that could affect lung cancer risk in middle- and low-income countries. That is difficult to do, however, because smoking data can be hard to come by in many countries, and there is general uncertainty about what other risk factors may exist, though air pollution is a clear suspect. “It is something we are hoping to focus on in the future because there is a subgroup of individuals without a smoking history who are at high risk. It would be really good to find this high-risk population that should actually be screened in the future,” Dr. Cavic said.

Some countries have no data on lung cancer screening. For example, only South Africa is represented from Africa, and data is missing from many countries in Asia. The diagnostics working group of the IASLC early detection and screening committee has created a survey to gather information on the availability of lung cancer screening and its effect on diagnosis and treatment in countries throughout the world.

Dr. Cavic and Dr. Huber reported no relevant financial disclosures. The meeting was sponsored by the IASLC.

Lung cancer screening has been a success story in high-income countries, leading to a shift in diagnoses to earlier stages and a reduction in mortality among eligible groups.

A new report shows that middle- and low-income countries are being left out. “We do have good screening programs and some national ones, even in smaller European countries and in Canada, but in low- and middle-income countries where the mortality rates and the incidence of lung cancer is higher than in high-income countries, these programs are not implemented either at all or not implemented nationwide. This is a huge problem in the world,” said Milena Cavic, PhD, who presented the interim results on behalf of the diagnostics working group of the International Association for the Study of Lung Cancer early detection and screening committee at a press conference on Aug. 7 at the World Conference on Lung Cancer. Dr. Cavic is a senior research associate at the Institute for Oncology and Radiology of Serbia in Belgrade.

“It’s definitely a work in progress, and it’s also about raising awareness of the problem. In several parts of Asia, in Taiwan, in Korea, smoking is not the major, or at least, not the only reason for getting lung cancer. The other reasons are family history and also environmental factors like cooking fires, etc. So, the criteria we have for screening in Western countries are not one to one implementable in these countries,” said Rudolf Huber, MD, PhD, a respiratory physician at Ludwig Maximilian University of Munich and a coauthor of the report.

The report also pointed out the lack of recommendations for lung cancer screening in middle- and low-income countries. One approach would be to produce recommendations for countries with similar infrastructures and health resources, as well as primary risk factors such as smoking or cooking fires. “We have to adapt it to the various situations,” said Dr. Huber.

Another possibility is to rework existing recommendations for high income countries to adapt them to low- and middle-income countries. In the coming year, the working group will conduct a modeling study of Serbia, China, South Africa, and Columbia. It will look at population-specific and geographic factors from each country to produce country-specific models. “It will be interesting to see if these models will give us new recommendations for countries like this. So we can derive something from the high-income countries, but it will need to be adapted very, very much,” said Dr. Cavic.

The report highlighted some of the disparities between countries. CT scanners are far more common in high-income countries. Japan leads the way at 111.5 per million residents, followed by Australia at 70.2, Iceland at 47.6, and the United States at 44.9. At the other end is Columbia with 1.3, which trails Mexico at 5.9, Hungary at 9.4, and the United Kingdom at 9.5. However, the authors point out that there is no consensus on the optimum number of CT scanners per capita, since too few can lead to lack of access and too many can result in overuse. In fact, the greatest number of CT scans performed per capita was in the United States (278.5 per million), followed by Iceland (234.4), Japan (230.8), and Korea (228.1).

Lung cancer screening can be at odds with other health priorities, especially in low-income countries. These can include HIV, tuberculosis, and granulomatous diseases. But that could also provide an opportunity, according to Dr. Huber. “For example, in South Africa, tuberculosis programs are done by chest x-ray. We now have data that [allows us to] detect nodules by artificial intelligence, so one of the things we are thinking about is whether we could even use chest x-ray to get an earlier detection. At the end, it may be that in some countries it’s possible to do the classical CT screening, while in other countries we have to adapt to other options – probably chest x-ray using artificial intelligence or computer-aided diagnosis. And, then a consequent program for following up and managing the incidentally diagnosed nodules.”

The group is hoping to explore the environmental factors that could affect lung cancer risk in middle- and low-income countries. That is difficult to do, however, because smoking data can be hard to come by in many countries, and there is general uncertainty about what other risk factors may exist, though air pollution is a clear suspect. “It is something we are hoping to focus on in the future because there is a subgroup of individuals without a smoking history who are at high risk. It would be really good to find this high-risk population that should actually be screened in the future,” Dr. Cavic said.

Some countries have no data on lung cancer screening. For example, only South Africa is represented from Africa, and data is missing from many countries in Asia. The diagnostics working group of the IASLC early detection and screening committee has created a survey to gather information on the availability of lung cancer screening and its effect on diagnosis and treatment in countries throughout the world.

Dr. Cavic and Dr. Huber reported no relevant financial disclosures. The meeting was sponsored by the IASLC.