Clinical Edge Journal Scan

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Key clinical point: A substantial proportion of patients with psoriatic arthritis (PsA) achieved resolution of enthesitis within a year of initiating nonsteroidal anti-inflammatory drugs (NSAID) or disease-modifying antirheumatic drugs (DMARD), although the odds were lower in patients with high joint disease activity at baseline.

Major finding: Complete resolution of enthesitis was achieved by 86.12% of patients within a mean period of 8.73 months from therapy initiation, with higher joint activity at baseline being associated with a lower chance of enthesitis resolution (odds ratio 0.97; P = .01).

Study details: Findings are from a retrospective analysis of prospectively collected data of 526 patients with PsA and enthesitis who received no treatment/only NSAID (n = 142), conventional DMARD ± NSAID but without targeted DMARD (n = 196), or targeted DMARD with or without other medications (n = 188).

Disclosures: Dr. Mathew and Dr. Chandran received funding from the National Psoriasis Foundation and University of Toronto, respectively. The authors declared no conflicts of interest.

Source: Mathew AJ et al. Effectiveness of disease modifying anti-rheumatic drugs for enthesitis in a prospective longitudinal psoriatic arthritis cohort. J Rheumatol. 2022 (Jun 1). Doi: 10.3899/jrheum.211231

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less then a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients — those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose. Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had. There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well. Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine. The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients. A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance. The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3. In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment of migraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment. The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans. The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2) to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptan insufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcome on the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired). In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of a gepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications. There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less then a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients — those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose. Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had. There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well. Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine. The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients. A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance. The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3. In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment of migraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment. The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans. The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2) to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptan insufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcome on the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired). In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of a gepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications. There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Many of our patients with refractory migraine do not respond to first-line acute or preventive treatments, and, almost by definition, first- and second-line treatments have failed in the majority of patients on calcitonin gene-related peptide (CGRP) antagonist medications. Three studies this month highlight the efficacy of CGRP monoclonal antibody (mAb) and small-molecule medications in this population specifically.

After an initial first dose of a CGRP mAb treatment, many patients ask whether a suboptimal response necessitates switching to another agent or whether a second (or third) dose should be given first. Eptinezumab is an intravenously administered mAb that is repeated every 12 weeks. Schim and colleagues present post hoc data for patients who initially had a minimally beneficial response to eptinezumab and received a second dose at week 13.
 

The authors define a suboptimal response as having less then a 50% decrease in monthly migraine days after 12 weeks. There were two pooled samples of patients — those who received 100 mg eptinezumab and those who received a 300 mg dose. Approximately 45% of patients in the pivotal trials of eptinezumab (PROMISE-1 and -2) were considered suboptimal responders, and 33%-37% of those suboptimal responders had a more than 50% decrease of their monthly migraine days after a second dose (week 24).
 

Further analysis determined predictive factors that favored a second dose response. The most prominent (and arguably most obvious) predictive factor was a favorable response after the first dose; the greater percent change in monthly migraine days after the first dose was proportional to the response after the second dose. Change in the Headache Impact Test (HIT-6) disability score after the first dose was also seen to be a strong predictive factor for improvement after the second dose.

When we discuss continuation of medications with our patients, especially when they have a suboptimal response, we should first keep in mind the degree of improvement that the patient initially had. There can be benefit from further treatment with the same medication; however, if the response truly was minimal, it may be better to consider another treatment option.

Practically every patient taking a preventive medication is taking at least one acute medication as well. Even the best preventive medication is not a guarantee that further exacerbations will not occur, and our patients will still need some acute treatment option even when their preventive medications are very effective. The study by Ambrosini and colleagues specifically shows how effective a preventive medication can be, specifically in allowing the patient to use fewer acute medications over time in a population of patients who have been resistant to two to four treatments.
 

Galcanezumab is a once-monthly mAb for the prevention of migraine. The authors of this study compared the acute use of medications for migraine in both the randomized and open-label stages of a study assessing treatment-refractory patients. A total of 462 patients were enrolled who were all resistant to two to four standard-of-care migraine-preventive medications that had been stopped either because of lack of efficacy or tolerance. The double-blind stage lasted 3 months; the open-label stage lasted another 3 months.
 

The treatment group was seen to use significantly fewer acute medications after just the first month and continued to improve through month 3. In the open-label phase, a similar improvement was noted in patients transitioning from placebo. In addition to acute medication use, emergency department use for migraine treatment was decreased significantly as well, by more than two thirds in month 3.

Migraine prevention will always remain the key ingredient for improvement for patients with higher frequencies of migraine, and adequate prevention will allow for the lower use of acute medications, and for less healthcare system use in general.
 

Most practitioners recommend migraine-specific medications for the acute treatment of migraine. Since the advent of sumatriptan, this has usually meant a triptan medication. However, a significant percentage of the population (up to 44% in one study) are either intolerant to, contraindicated for, or respond insufficiently to triptan medications. This can either be due to a strong triptan side effect (worsened nausea; tightness/soreness of the muscles of the chest, shoulders, and neck), having cardiovascular risk factors, or not responding adequately 2 hours after treatment. The study by Lipton and colleagues specifically assessed the efficacy of ubrogepant in this population.
 

Ubrogepant is a small-molecule CGRP antagonist for the acute treatment of migraine. Although somewhat controversial, most practitioners use ubrogepant in patients with some cardiovascular risk, a situation where they would be more likely to avoid the use of triptans. The study authors pooled post hoc data from the pivotal ubrogepant trials (ACHIEVE-1 and -2) to isolate patients with insufficient response to triptans, and their primary outcome was improvement in function 2 hours after medication dose.
 

Participants in the pivotal trials were separated into three groups: triptan responders, triptan insufficient responders, and triptan-naive patients. Triptan response was defined as achieving pain freedom 2 hours after medication dose. Both those who had an insufficient response and those who no longer use the triptan owing to intolerance or contraindications were included in the group with insufficient triptan response. Function improvement was defined as the primary outcome on the basis of a 4-point response scale (0 = no disability, 1 = mildly impaired, 2 = moderately impaired, 3 = severely impaired). In addition, patients were asked to report scores of satisfaction with the medication (yes or no) at 2 and 24 hours and their impression of overall change at 2 hours using a 7-point scale.
 

The population group of triptan insufficient responders (451 patients) had significant improvement in the primary outcome functional disability at 2, 4, and 7 hours after receipt of medications, but there was no statistical difference at 1 hour. This was similar when comparing those with intolerance to triptans, insufficient response to triptans, or contraindications for triptans. The secondary outcomes of satisfaction and global impression of change were also statistically improved in the insufficient-responders group. No additional tolerance issues or adverse events were noted in this group either.

It would certainly be worth considering the use of a gepant acute medication, such as ubrogepant, in patients who are intolerant to or inadequately treated by triptan medications. There still is much to learn about cardiovascular risk and the use of CGRP antagonists, and although no adverse events were noted, more data may be necessary to widely prescribe this class in higher-risk patients.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c < 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c < 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c < 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

In another recent prospective study, Cabeza and colleagues noted that ocrelizumab-treated PWMS who received a third SARS-CoV-2 vaccine dose had a boosted T-cell response, but there was no additive effect on the maximal T-cell response. The study included PWMS taking DMT (ocrelizumab, n = 24; fingolimod, n = 12; or no DMT, n = 10) and healthy controls (n = 12), all of whom received three SARS-CoV-2 vaccine doses (BioNTech-Pfizer or Moderna). The SARS-CoV-2–specific T-cell response in patients treated with ocrelizumab was comparable to that in PWMS who were not treated with DMT and to that in healthy controls after the second SARS-CoV-2 vaccination. However, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

The relationship and interplay of both T-cell and B-cell responses to viral infection is important to understand and appreciate. However, for PWMS who have had, do have, or will experience breakthrough infection, early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in PWMS treated with fingolimod or ocrelizumab. Manzano and colleagues reported on an observational study including 23 PWMS, most of whom had completed the initial COVID-19 vaccine series before infection and were either untreated or treated with fingolimod+ ocrelizumab and then received anti–SARS-CoV2 mAbs (bamlanivimab + etesevimab, casirivimab + imdevimab, sotrovimab, or an undocumented formulation) for treatment of active COVID-19. In this study, 74% of PWMS were able to be managed as outpatients (median duration to mAb receipt, 4 days), and 48% of PWMS recovered from COVID-19 within 7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 (median follow-up, 18 days). No adverse events or deaths were reported in this series.

Pivotal trials and package insert information affect DMT choice and dosing, the timing of ongoing treatment, and the awareness of efficacy and potential adverse reactions. Foley and colleagues  demonstrated that switching to once-every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every 4 weeks (QW4) was safe, without any clinically meaningful loss of efficacy in most patients with relapsing-remitting MS (RRMS). In the phase 3b NOVA trial (N = 499), patients with RRMS receiving stable intravenous natalizumab QW4 dosing were randomly assigned to continue QW4 (n = 248) or switch to QW6 (n = 251) natalizumab dosing. The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) with natalizumab QW6 vs 0.05 (95% CI 0.01-0.22) with natalizumab QW4, with only two of the PWMS developing 25 or more lesions; this contributed to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Both DMT choice and vaccine-related antibody production matter. Various DMT have different and problematic impact on antibody production and response, and unrecognized immune deficiency or poor antibody response are problematic as variant COVID-19 strains continue to evolve. Protection against both MS disease activity and infections from variants remain a complex issue. Establishing and maintaining protection are important. Identifying PWMS who are at high risk for poor or sustained antibody response is important in addition to the ongoing effective treatment of MS. The landscape of available DMT choice, treatment paradigms, and COVID-19 variants and COVID-19 family protection continues to evolve.

In another recent prospective study, Cabeza and colleagues noted that ocrelizumab-treated PWMS who received a third SARS-CoV-2 vaccine dose had a boosted T-cell response, but there was no additive effect on the maximal T-cell response. The study included PWMS taking DMT (ocrelizumab, n = 24; fingolimod, n = 12; or no DMT, n = 10) and healthy controls (n = 12), all of whom received three SARS-CoV-2 vaccine doses (BioNTech-Pfizer or Moderna). The SARS-CoV-2–specific T-cell response in patients treated with ocrelizumab was comparable to that in PWMS who were not treated with DMT and to that in healthy controls after the second SARS-CoV-2 vaccination. However, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

The relationship and interplay of both T-cell and B-cell responses to viral infection is important to understand and appreciate. However, for PWMS who have had, do have, or will experience breakthrough infection, early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in PWMS treated with fingolimod or ocrelizumab. Manzano and colleagues reported on an observational study including 23 PWMS, most of whom had completed the initial COVID-19 vaccine series before infection and were either untreated or treated with fingolimod+ ocrelizumab and then received anti–SARS-CoV2 mAbs (bamlanivimab + etesevimab, casirivimab + imdevimab, sotrovimab, or an undocumented formulation) for treatment of active COVID-19. In this study, 74% of PWMS were able to be managed as outpatients (median duration to mAb receipt, 4 days), and 48% of PWMS recovered from COVID-19 within 7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 (median follow-up, 18 days). No adverse events or deaths were reported in this series.

Pivotal trials and package insert information affect DMT choice and dosing, the timing of ongoing treatment, and the awareness of efficacy and potential adverse reactions. Foley and colleagues  demonstrated that switching to once-every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every 4 weeks (QW4) was safe, without any clinically meaningful loss of efficacy in most patients with relapsing-remitting MS (RRMS). In the phase 3b NOVA trial (N = 499), patients with RRMS receiving stable intravenous natalizumab QW4 dosing were randomly assigned to continue QW4 (n = 248) or switch to QW6 (n = 251) natalizumab dosing. The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) with natalizumab QW6 vs 0.05 (95% CI 0.01-0.22) with natalizumab QW4, with only two of the PWMS developing 25 or more lesions; this contributed to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Both DMT choice and vaccine-related antibody production matter. Various DMT have different and problematic impact on antibody production and response, and unrecognized immune deficiency or poor antibody response are problematic as variant COVID-19 strains continue to evolve. Protection against both MS disease activity and infections from variants remain a complex issue. Establishing and maintaining protection are important. Identifying PWMS who are at high risk for poor or sustained antibody response is important in addition to the ongoing effective treatment of MS. The landscape of available DMT choice, treatment paradigms, and COVID-19 variants and COVID-19 family protection continues to evolve.

In another recent prospective study, Cabeza and colleagues noted that ocrelizumab-treated PWMS who received a third SARS-CoV-2 vaccine dose had a boosted T-cell response, but there was no additive effect on the maximal T-cell response. The study included PWMS taking DMT (ocrelizumab, n = 24; fingolimod, n = 12; or no DMT, n = 10) and healthy controls (n = 12), all of whom received three SARS-CoV-2 vaccine doses (BioNTech-Pfizer or Moderna). The SARS-CoV-2–specific T-cell response in patients treated with ocrelizumab was comparable to that in PWMS who were not treated with DMT and to that in healthy controls after the second SARS-CoV-2 vaccination. However, the third SARS-CoV-2 vaccination had no additive effect on T-cell response, but it did induce a booster response (P < .05).

The relationship and interplay of both T-cell and B-cell responses to viral infection is important to understand and appreciate. However, for PWMS who have had, do have, or will experience breakthrough infection, early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in PWMS treated with fingolimod or ocrelizumab. Manzano and colleagues reported on an observational study including 23 PWMS, most of whom had completed the initial COVID-19 vaccine series before infection and were either untreated or treated with fingolimod+ ocrelizumab and then received anti–SARS-CoV2 mAbs (bamlanivimab + etesevimab, casirivimab + imdevimab, sotrovimab, or an undocumented formulation) for treatment of active COVID-19. In this study, 74% of PWMS were able to be managed as outpatients (median duration to mAb receipt, 4 days), and 48% of PWMS recovered from COVID-19 within 7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 (median follow-up, 18 days). No adverse events or deaths were reported in this series.

Pivotal trials and package insert information affect DMT choice and dosing, the timing of ongoing treatment, and the awareness of efficacy and potential adverse reactions. Foley and colleagues  demonstrated that switching to once-every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every 4 weeks (QW4) was safe, without any clinically meaningful loss of efficacy in most patients with relapsing-remitting MS (RRMS). In the phase 3b NOVA trial (N = 499), patients with RRMS receiving stable intravenous natalizumab QW4 dosing were randomly assigned to continue QW4 (n = 248) or switch to QW6 (n = 251) natalizumab dosing. The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) with natalizumab QW6 vs 0.05 (95% CI 0.01-0.22) with natalizumab QW4, with only two of the PWMS developing 25 or more lesions; this contributed to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Both DMT choice and vaccine-related antibody production matter. Various DMT have different and problematic impact on antibody production and response, and unrecognized immune deficiency or poor antibody response are problematic as variant COVID-19 strains continue to evolve. Protection against both MS disease activity and infections from variants remain a complex issue. Establishing and maintaining protection are important. Identifying PWMS who are at high risk for poor or sustained antibody response is important in addition to the ongoing effective treatment of MS. The landscape of available DMT choice, treatment paradigms, and COVID-19 variants and COVID-19 family protection continues to evolve.

Key clinical point: High sugar-sweetened beverage (SSB) and total fructose intake was associated with increased incidence of and mortality from proximal colon cancer, especially during the later stages of colorectal tumorigenesis.

Major finding: SSB and total fructose consumption was associated with a significant increase in the incidence of (hazard ratio [HR] per 1-serving/d increment 1.18 and HR per 25-g/d increment 1.18, respectively; both P_trend = .02) and mortality from (HR 1.39; P_trend = .002 and HR 1.42; P_trend = .003, respectively) proximal colon cancer.

Study details: This large-scale study included 121,111 adult health professionals from two US prospective cohorts, the Nurses’ Health Study and Health Professionals Follow-Up Study.

Disclosures: The study was sponsored by grants from the US National Institutes of Health, American Cancer Society, and American Institute for Cancer Research. Some authors declared consulting and advisory board participation for and receiving research funds from various sources.

Source: Yuan C et al. Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite. Am J Clin Nutr. 2022 (Apr 25). Doi: 10.1093/ajcn/nqac040

Key clinical point: High sugar-sweetened beverage (SSB) and total fructose intake was associated with increased incidence of and mortality from proximal colon cancer, especially during the later stages of colorectal tumorigenesis.

Major finding: SSB and total fructose consumption was associated with a significant increase in the incidence of (hazard ratio [HR] per 1-serving/d increment 1.18 and HR per 25-g/d increment 1.18, respectively; both P_trend = .02) and mortality from (HR 1.39; P_trend = .002 and HR 1.42; P_trend = .003, respectively) proximal colon cancer.

Study details: This large-scale study included 121,111 adult health professionals from two US prospective cohorts, the Nurses’ Health Study and Health Professionals Follow-Up Study.

Disclosures: The study was sponsored by grants from the US National Institutes of Health, American Cancer Society, and American Institute for Cancer Research. Some authors declared consulting and advisory board participation for and receiving research funds from various sources.

Source: Yuan C et al. Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite. Am J Clin Nutr. 2022 (Apr 25). Doi: 10.1093/ajcn/nqac040

Key clinical point: High sugar-sweetened beverage (SSB) and total fructose intake was associated with increased incidence of and mortality from proximal colon cancer, especially during the later stages of colorectal tumorigenesis.

Major finding: SSB and total fructose consumption was associated with a significant increase in the incidence of (hazard ratio [HR] per 1-serving/d increment 1.18 and HR per 25-g/d increment 1.18, respectively; both P_trend = .02) and mortality from (HR 1.39; P_trend = .002 and HR 1.42; P_trend = .003, respectively) proximal colon cancer.

Study details: This large-scale study included 121,111 adult health professionals from two US prospective cohorts, the Nurses’ Health Study and Health Professionals Follow-Up Study.

Disclosures: The study was sponsored by grants from the US National Institutes of Health, American Cancer Society, and American Institute for Cancer Research. Some authors declared consulting and advisory board participation for and receiving research funds from various sources.

Source: Yuan C et al. Sugar-sweetened beverage and sugar consumption and colorectal cancer incidence and mortality according to anatomic subsite. Am J Clin Nutr. 2022 (Apr 25). Doi: 10.1093/ajcn/nqac040