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Best definition of malnutrition varies by cancer type
For patients undergoing major oncologic surgery, the best definition of malnutrition used to assess postoperative risk varies by cancer type, results of a retrospective study suggest.
The current, one-size-fits-all approach to nutritional status leads to both undertreatment and overtreatment of malnutrition, as well as inaccurate estimations of postoperative risk, reported lead study author Nicholas P. McKenna, MD, of the Mayo Clinic in Rochester, Minn., and colleagues.
“Assessing nutritional status is important because it impacts preoperative planning, particularly with respect to the use of prehabilitation,” the investigators wrote. Their report is in the Journal of the American College of Surgeons. They noted that while prehabilitation has been shown to reduce postoperative risk among those who need it, identification of these patients is an area that needs improvement.
With this in mind, Dr. McKenna and colleagues analyzed 205,840 major oncologic operations, with data drawn from the American College of Surgeons National Surgical Quality Improvement (NSQIP) database.
The researchers evaluated patients’ nutritional status using three techniques: the NSQIP method, the European Society for Clinical Nutrition and Metabolism (ESPEN) definitions, and the World Health Organization body mass index (BMI) classification system.
Combining these three assessments led to seven hierarchical nutritional status categories:
- Severe malnutrition – BMI less than 18.5 kg/m2 and greater than 10% weight loss
- ESPEN 1 – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- ESPEN 2 – BMI less than 18.5 kg/m2
- NSQIP – BMI greater than 20 kg/m2 (if younger than 70 years) or 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- Mild malnutrition – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older)
- Obese – BMI at least 30 kg/m2
- No malnutrition.
The study’s primary outcomes were 30-day mortality and 30-day morbidity. The latter included a variety of complications, such as deep incisional surgical site infection, septic shock, and acute renal failure. Demographic and clinical factors were included in multivariate analyses.
Results
Most of the operations involved patients with colorectal cancer (74%), followed by pancreatic (10%), lung (9%), gastric (3%), esophageal (3%), and liver (2%) cancer.
Across all patients, 16% fell into one of five malnutrition categories: mild malnutrition (6%), NSQIP (6%), ESPEN 2 (2%), ESPEN 1 (1%), or severe malnutrition (0.6%). The remainder of patients were either obese (31%) or had normal nutritional status (54%).
Malnutrition was most common among patients with pancreatic cancer (28%) and least common among those with colorectal cancer (14%).
Aligning with previous research, this study showed that nutritional status was associated with postoperative risk. Mortality risk was highest among patients with severe malnutrition, and morbidity was most common in the severe and ESPEN 1 groups (P less than .0001 for both).
While the spectrum of classifications appeared accurate across the population, multivariable models for mortality and morbidity revealed an interaction between cancer type and malnutrition definition (P less than .0001 for both), which suggested the most accurate definition of malnutrition differed from one type of cancer to another.
Specifically, a classification of severe malnutrition was most predictive of mortality among patients with esophageal or colorectal cancer. ESPEN 1 was most predictive of mortality for patients with gastric or lung cancer, and NSQIP was most predictive for those with liver cancer.
For predicting morbidity, severe malnutrition was most accurate among patients with colorectal cancer, whereas ESPEN 1 was better suited for gastric and lung cancer.
Interpreting and applying the results
“The biggest takeaway is that the optimal definition of malnutrition varies by cancer type,” Dr. McKenna said in an interview.
He went on to explain that weight loss is a particularly important indicator of malnutrition for patients with esophageal or gastric cancer. “These are the cancers that more commonly undergo neoadjuvant chemotherapy,” he noted.
The other major finding, Dr. McKenna said, offers some perspective on short-term versus long-term risk.
“Most people consider obesity a negative prognostic factor,” he said. “But in terms of operative risk, it’s kind of a neutral effect. It doesn’t really affect the short-term outcomes of an operation.”
Still, Dr. McKenna warned that a visual assessment of patient body condition is not enough to predict postoperative risk. Instead, he recommended accurate height and weight measurements during annual and preoperative exams. He also noted that more patients are at risk than clinicians may suspect.
“Even definitions that didn’t previously exist, such as mild malnutrition, had a somewhat negative effect within colorectal cancer and esophageal cancer,” Dr. McKenna said. “So these are patients who previously probably would be considered pretty healthy, but there is probably some room to improve their nutritional status.”
While the study revealed that different types of cancer should have unique tools for measuring nutritional status, development of these systems will require more research concerning prehabilitation outcomes, according to Dr. McKenna. In the meantime, he highlighted a point of action in the clinic.
“We think, overall, especially with the rise of neoadjuvant chemotherapy upfront, before surgery, that identifying patients at risk before they start neoadjuvant chemotherapy is going to be important,” he said. “They are the ones who really need to be targeted.”
There was no external funding for this study, and the investigators reported no conflicts of interest.
SOURCE: McKenna NP et al. J Am Coll Surg. 2020 Feb 26. doi: 10.1016/j.jamcollsurg.2019.12.034.
For patients undergoing major oncologic surgery, the best definition of malnutrition used to assess postoperative risk varies by cancer type, results of a retrospective study suggest.
The current, one-size-fits-all approach to nutritional status leads to both undertreatment and overtreatment of malnutrition, as well as inaccurate estimations of postoperative risk, reported lead study author Nicholas P. McKenna, MD, of the Mayo Clinic in Rochester, Minn., and colleagues.
“Assessing nutritional status is important because it impacts preoperative planning, particularly with respect to the use of prehabilitation,” the investigators wrote. Their report is in the Journal of the American College of Surgeons. They noted that while prehabilitation has been shown to reduce postoperative risk among those who need it, identification of these patients is an area that needs improvement.
With this in mind, Dr. McKenna and colleagues analyzed 205,840 major oncologic operations, with data drawn from the American College of Surgeons National Surgical Quality Improvement (NSQIP) database.
The researchers evaluated patients’ nutritional status using three techniques: the NSQIP method, the European Society for Clinical Nutrition and Metabolism (ESPEN) definitions, and the World Health Organization body mass index (BMI) classification system.
Combining these three assessments led to seven hierarchical nutritional status categories:
- Severe malnutrition – BMI less than 18.5 kg/m2 and greater than 10% weight loss
- ESPEN 1 – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- ESPEN 2 – BMI less than 18.5 kg/m2
- NSQIP – BMI greater than 20 kg/m2 (if younger than 70 years) or 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- Mild malnutrition – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older)
- Obese – BMI at least 30 kg/m2
- No malnutrition.
The study’s primary outcomes were 30-day mortality and 30-day morbidity. The latter included a variety of complications, such as deep incisional surgical site infection, septic shock, and acute renal failure. Demographic and clinical factors were included in multivariate analyses.
Results
Most of the operations involved patients with colorectal cancer (74%), followed by pancreatic (10%), lung (9%), gastric (3%), esophageal (3%), and liver (2%) cancer.
Across all patients, 16% fell into one of five malnutrition categories: mild malnutrition (6%), NSQIP (6%), ESPEN 2 (2%), ESPEN 1 (1%), or severe malnutrition (0.6%). The remainder of patients were either obese (31%) or had normal nutritional status (54%).
Malnutrition was most common among patients with pancreatic cancer (28%) and least common among those with colorectal cancer (14%).
Aligning with previous research, this study showed that nutritional status was associated with postoperative risk. Mortality risk was highest among patients with severe malnutrition, and morbidity was most common in the severe and ESPEN 1 groups (P less than .0001 for both).
While the spectrum of classifications appeared accurate across the population, multivariable models for mortality and morbidity revealed an interaction between cancer type and malnutrition definition (P less than .0001 for both), which suggested the most accurate definition of malnutrition differed from one type of cancer to another.
Specifically, a classification of severe malnutrition was most predictive of mortality among patients with esophageal or colorectal cancer. ESPEN 1 was most predictive of mortality for patients with gastric or lung cancer, and NSQIP was most predictive for those with liver cancer.
For predicting morbidity, severe malnutrition was most accurate among patients with colorectal cancer, whereas ESPEN 1 was better suited for gastric and lung cancer.
Interpreting and applying the results
“The biggest takeaway is that the optimal definition of malnutrition varies by cancer type,” Dr. McKenna said in an interview.
He went on to explain that weight loss is a particularly important indicator of malnutrition for patients with esophageal or gastric cancer. “These are the cancers that more commonly undergo neoadjuvant chemotherapy,” he noted.
The other major finding, Dr. McKenna said, offers some perspective on short-term versus long-term risk.
“Most people consider obesity a negative prognostic factor,” he said. “But in terms of operative risk, it’s kind of a neutral effect. It doesn’t really affect the short-term outcomes of an operation.”
Still, Dr. McKenna warned that a visual assessment of patient body condition is not enough to predict postoperative risk. Instead, he recommended accurate height and weight measurements during annual and preoperative exams. He also noted that more patients are at risk than clinicians may suspect.
“Even definitions that didn’t previously exist, such as mild malnutrition, had a somewhat negative effect within colorectal cancer and esophageal cancer,” Dr. McKenna said. “So these are patients who previously probably would be considered pretty healthy, but there is probably some room to improve their nutritional status.”
While the study revealed that different types of cancer should have unique tools for measuring nutritional status, development of these systems will require more research concerning prehabilitation outcomes, according to Dr. McKenna. In the meantime, he highlighted a point of action in the clinic.
“We think, overall, especially with the rise of neoadjuvant chemotherapy upfront, before surgery, that identifying patients at risk before they start neoadjuvant chemotherapy is going to be important,” he said. “They are the ones who really need to be targeted.”
There was no external funding for this study, and the investigators reported no conflicts of interest.
SOURCE: McKenna NP et al. J Am Coll Surg. 2020 Feb 26. doi: 10.1016/j.jamcollsurg.2019.12.034.
For patients undergoing major oncologic surgery, the best definition of malnutrition used to assess postoperative risk varies by cancer type, results of a retrospective study suggest.
The current, one-size-fits-all approach to nutritional status leads to both undertreatment and overtreatment of malnutrition, as well as inaccurate estimations of postoperative risk, reported lead study author Nicholas P. McKenna, MD, of the Mayo Clinic in Rochester, Minn., and colleagues.
“Assessing nutritional status is important because it impacts preoperative planning, particularly with respect to the use of prehabilitation,” the investigators wrote. Their report is in the Journal of the American College of Surgeons. They noted that while prehabilitation has been shown to reduce postoperative risk among those who need it, identification of these patients is an area that needs improvement.
With this in mind, Dr. McKenna and colleagues analyzed 205,840 major oncologic operations, with data drawn from the American College of Surgeons National Surgical Quality Improvement (NSQIP) database.
The researchers evaluated patients’ nutritional status using three techniques: the NSQIP method, the European Society for Clinical Nutrition and Metabolism (ESPEN) definitions, and the World Health Organization body mass index (BMI) classification system.
Combining these three assessments led to seven hierarchical nutritional status categories:
- Severe malnutrition – BMI less than 18.5 kg/m2 and greater than 10% weight loss
- ESPEN 1 – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- ESPEN 2 – BMI less than 18.5 kg/m2
- NSQIP – BMI greater than 20 kg/m2 (if younger than 70 years) or 22 kg/m2 (if 70 years or older) plus greater than 10% weight loss
- Mild malnutrition – BMI 18.5-20 kg/m2 (if younger than 70 years) or less than 22 kg/m2 (if 70 years or older)
- Obese – BMI at least 30 kg/m2
- No malnutrition.
The study’s primary outcomes were 30-day mortality and 30-day morbidity. The latter included a variety of complications, such as deep incisional surgical site infection, septic shock, and acute renal failure. Demographic and clinical factors were included in multivariate analyses.
Results
Most of the operations involved patients with colorectal cancer (74%), followed by pancreatic (10%), lung (9%), gastric (3%), esophageal (3%), and liver (2%) cancer.
Across all patients, 16% fell into one of five malnutrition categories: mild malnutrition (6%), NSQIP (6%), ESPEN 2 (2%), ESPEN 1 (1%), or severe malnutrition (0.6%). The remainder of patients were either obese (31%) or had normal nutritional status (54%).
Malnutrition was most common among patients with pancreatic cancer (28%) and least common among those with colorectal cancer (14%).
Aligning with previous research, this study showed that nutritional status was associated with postoperative risk. Mortality risk was highest among patients with severe malnutrition, and morbidity was most common in the severe and ESPEN 1 groups (P less than .0001 for both).
While the spectrum of classifications appeared accurate across the population, multivariable models for mortality and morbidity revealed an interaction between cancer type and malnutrition definition (P less than .0001 for both), which suggested the most accurate definition of malnutrition differed from one type of cancer to another.
Specifically, a classification of severe malnutrition was most predictive of mortality among patients with esophageal or colorectal cancer. ESPEN 1 was most predictive of mortality for patients with gastric or lung cancer, and NSQIP was most predictive for those with liver cancer.
For predicting morbidity, severe malnutrition was most accurate among patients with colorectal cancer, whereas ESPEN 1 was better suited for gastric and lung cancer.
Interpreting and applying the results
“The biggest takeaway is that the optimal definition of malnutrition varies by cancer type,” Dr. McKenna said in an interview.
He went on to explain that weight loss is a particularly important indicator of malnutrition for patients with esophageal or gastric cancer. “These are the cancers that more commonly undergo neoadjuvant chemotherapy,” he noted.
The other major finding, Dr. McKenna said, offers some perspective on short-term versus long-term risk.
“Most people consider obesity a negative prognostic factor,” he said. “But in terms of operative risk, it’s kind of a neutral effect. It doesn’t really affect the short-term outcomes of an operation.”
Still, Dr. McKenna warned that a visual assessment of patient body condition is not enough to predict postoperative risk. Instead, he recommended accurate height and weight measurements during annual and preoperative exams. He also noted that more patients are at risk than clinicians may suspect.
“Even definitions that didn’t previously exist, such as mild malnutrition, had a somewhat negative effect within colorectal cancer and esophageal cancer,” Dr. McKenna said. “So these are patients who previously probably would be considered pretty healthy, but there is probably some room to improve their nutritional status.”
While the study revealed that different types of cancer should have unique tools for measuring nutritional status, development of these systems will require more research concerning prehabilitation outcomes, according to Dr. McKenna. In the meantime, he highlighted a point of action in the clinic.
“We think, overall, especially with the rise of neoadjuvant chemotherapy upfront, before surgery, that identifying patients at risk before they start neoadjuvant chemotherapy is going to be important,” he said. “They are the ones who really need to be targeted.”
There was no external funding for this study, and the investigators reported no conflicts of interest.
SOURCE: McKenna NP et al. J Am Coll Surg. 2020 Feb 26. doi: 10.1016/j.jamcollsurg.2019.12.034.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
Pembro ups survival in NSCLC: ‘Really extraordinary’ results
More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.
The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.
“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.
These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.
The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.
Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.
This compares with 3-year overall survival of 11-13% with docetaxel.
These results are “really extraordinary,” Herbst commented to Medscape Medical News.
The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”
Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”
“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.
“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.
Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”
However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»
She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”
The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.
This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”
Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”
“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
Responses on Re-introduction of Therapy
The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.
The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.
Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.
He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.
“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.
Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.
She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”
Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”
Study Details
KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.
They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks.
Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.
Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.
Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.
For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.
Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).
In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.
Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.
PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.
In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.
The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.
Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.
Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.
Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.
A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.
Pembro Approved at Fixed Dose
One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.
Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.
“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”
“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.
The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
This article first appeared on Medscape.com.
More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.
The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.
“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.
These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.
The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.
Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.
This compares with 3-year overall survival of 11-13% with docetaxel.
These results are “really extraordinary,” Herbst commented to Medscape Medical News.
The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”
Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”
“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.
“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.
Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”
However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»
She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”
The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.
This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”
Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”
“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
Responses on Re-introduction of Therapy
The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.
The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.
Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.
He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.
“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.
Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.
She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”
Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”
Study Details
KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.
They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks.
Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.
Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.
Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.
For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.
Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).
In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.
Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.
PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.
In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.
The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.
Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.
Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.
Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.
A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.
Pembro Approved at Fixed Dose
One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.
Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.
“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”
“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.
The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
This article first appeared on Medscape.com.
More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.
The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.
“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.
These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.
The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.
Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.
This compares with 3-year overall survival of 11-13% with docetaxel.
These results are “really extraordinary,” Herbst commented to Medscape Medical News.
The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”
Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”
“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.
“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.
Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”
However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»
She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”
The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.
This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”
Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”
“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
Responses on Re-introduction of Therapy
The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.
The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.
Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.
He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.
“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.
Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.
She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”
Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”
Study Details
KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.
They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks.
Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.
Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.
Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.
For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.
Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).
In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.
Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.
PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.
In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.
The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.
Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.
Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.
Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.
A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.
Pembro Approved at Fixed Dose
One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.
Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.
“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”
“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.
The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
This article first appeared on Medscape.com.
Pembrolizumab plus chemoradiotherapy shows early promise in NSCLC
Combination pembrolizumab and chemoradiotherapy appears safe and active for patients with locally advanced non–small cell lung cancer (NSCLC), results from a phase 1 trial suggest.
Nearly 90% of evaluable patients responded to the combination, and the 12-month progression-free survival rate was 69.7%. Pneumonitis was common, but most patients responded to high-dose corticosteroids.
Salma K. Jabbour, MD, of Rutgers Cancer Institute of New Jersey, in New Brunswick, and colleagues reported these results in JAMA Oncology.
The phase 1 study included 21 patients with locally advanced, unresectable, stage III NSCLC. Planned treatment consisted of pembrolizumab (Keytruda) at various dosing schedules, chemotherapy (weekly carboplatin and paclitaxel), and radiation (2 Gy/day, 60 Gy total).
The researchers used a standard 3 + 3 design to evaluate the safety and tolerability of pembrolizumab in five dosing cohorts.
In cohort 1, patients received pembrolizumab at 200 mg every 21 days within 2-6 weeks of completing chemoradiotherapy. In cohort 2, patients received pembrolizumab at 100 mg every 21 days, starting on day 29 of chemoradiotherapy. Cohort 3 received the 200 mg dose of pembrolizumab, starting on day 29.
Pembrolizumab was started on day 1 of chemoradiotherapy at the 100-mg dose in cohort 4 and at the 200-mg dose in cohort 5. An additional six-patient safety expansion cohort received the same treatment as cohort 5.
The median follow-up was 16 months. There was one dose-limiting toxicity – grade 5 pneumonitis, which occurred in the safety expansion cohort.
Grade 2 or higher immune-related toxicities were observed in 14 patients (67%), and grade 2 or higher pneumonitis occurred in 7 patients (33%).
“Although we observed an increased rate of pneumonitis, most patients had pneumonitis that responded to high-dose corticosteroid treatment,” the researchers noted.
There were 19 patients who received at least two cycles of pembrolizumab and were evaluable for response. The best response was complete response in 3 patients (16%), partial response in 14 patients (74%), and stable disease in 1 patient (5%).
The progression-free survival rate was 81.0% at 6 months and 69.7% at 12 months. The overall survival rate was 95.2% at 6 months and 85.2% at 12 months.
The researchers acknowledged that two key limitations of this study were the small sample size and short duration of follow-up.
“Pembrolizumab with concurrent chemoradiotherapy is tolerable for patients with locally advanced, unresectable NSCLC, although the risk of pneumonitis and long-term outcomes should be evaluated in additional studies,” commented Enriqueta Felip, MD, PhD, of Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in this study.
The study was funded by Merck. The authors and Dr. Felip disclosed relationships with Merck and other companies.
SOURCE: Jabbour SK et al. JAMA Oncol. 2020 Feb 20. doi: 10.1001/jamaoncol.2019.6731.
Combination pembrolizumab and chemoradiotherapy appears safe and active for patients with locally advanced non–small cell lung cancer (NSCLC), results from a phase 1 trial suggest.
Nearly 90% of evaluable patients responded to the combination, and the 12-month progression-free survival rate was 69.7%. Pneumonitis was common, but most patients responded to high-dose corticosteroids.
Salma K. Jabbour, MD, of Rutgers Cancer Institute of New Jersey, in New Brunswick, and colleagues reported these results in JAMA Oncology.
The phase 1 study included 21 patients with locally advanced, unresectable, stage III NSCLC. Planned treatment consisted of pembrolizumab (Keytruda) at various dosing schedules, chemotherapy (weekly carboplatin and paclitaxel), and radiation (2 Gy/day, 60 Gy total).
The researchers used a standard 3 + 3 design to evaluate the safety and tolerability of pembrolizumab in five dosing cohorts.
In cohort 1, patients received pembrolizumab at 200 mg every 21 days within 2-6 weeks of completing chemoradiotherapy. In cohort 2, patients received pembrolizumab at 100 mg every 21 days, starting on day 29 of chemoradiotherapy. Cohort 3 received the 200 mg dose of pembrolizumab, starting on day 29.
Pembrolizumab was started on day 1 of chemoradiotherapy at the 100-mg dose in cohort 4 and at the 200-mg dose in cohort 5. An additional six-patient safety expansion cohort received the same treatment as cohort 5.
The median follow-up was 16 months. There was one dose-limiting toxicity – grade 5 pneumonitis, which occurred in the safety expansion cohort.
Grade 2 or higher immune-related toxicities were observed in 14 patients (67%), and grade 2 or higher pneumonitis occurred in 7 patients (33%).
“Although we observed an increased rate of pneumonitis, most patients had pneumonitis that responded to high-dose corticosteroid treatment,” the researchers noted.
There were 19 patients who received at least two cycles of pembrolizumab and were evaluable for response. The best response was complete response in 3 patients (16%), partial response in 14 patients (74%), and stable disease in 1 patient (5%).
The progression-free survival rate was 81.0% at 6 months and 69.7% at 12 months. The overall survival rate was 95.2% at 6 months and 85.2% at 12 months.
The researchers acknowledged that two key limitations of this study were the small sample size and short duration of follow-up.
“Pembrolizumab with concurrent chemoradiotherapy is tolerable for patients with locally advanced, unresectable NSCLC, although the risk of pneumonitis and long-term outcomes should be evaluated in additional studies,” commented Enriqueta Felip, MD, PhD, of Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in this study.
The study was funded by Merck. The authors and Dr. Felip disclosed relationships with Merck and other companies.
SOURCE: Jabbour SK et al. JAMA Oncol. 2020 Feb 20. doi: 10.1001/jamaoncol.2019.6731.
Combination pembrolizumab and chemoradiotherapy appears safe and active for patients with locally advanced non–small cell lung cancer (NSCLC), results from a phase 1 trial suggest.
Nearly 90% of evaluable patients responded to the combination, and the 12-month progression-free survival rate was 69.7%. Pneumonitis was common, but most patients responded to high-dose corticosteroids.
Salma K. Jabbour, MD, of Rutgers Cancer Institute of New Jersey, in New Brunswick, and colleagues reported these results in JAMA Oncology.
The phase 1 study included 21 patients with locally advanced, unresectable, stage III NSCLC. Planned treatment consisted of pembrolizumab (Keytruda) at various dosing schedules, chemotherapy (weekly carboplatin and paclitaxel), and radiation (2 Gy/day, 60 Gy total).
The researchers used a standard 3 + 3 design to evaluate the safety and tolerability of pembrolizumab in five dosing cohorts.
In cohort 1, patients received pembrolizumab at 200 mg every 21 days within 2-6 weeks of completing chemoradiotherapy. In cohort 2, patients received pembrolizumab at 100 mg every 21 days, starting on day 29 of chemoradiotherapy. Cohort 3 received the 200 mg dose of pembrolizumab, starting on day 29.
Pembrolizumab was started on day 1 of chemoradiotherapy at the 100-mg dose in cohort 4 and at the 200-mg dose in cohort 5. An additional six-patient safety expansion cohort received the same treatment as cohort 5.
The median follow-up was 16 months. There was one dose-limiting toxicity – grade 5 pneumonitis, which occurred in the safety expansion cohort.
Grade 2 or higher immune-related toxicities were observed in 14 patients (67%), and grade 2 or higher pneumonitis occurred in 7 patients (33%).
“Although we observed an increased rate of pneumonitis, most patients had pneumonitis that responded to high-dose corticosteroid treatment,” the researchers noted.
There were 19 patients who received at least two cycles of pembrolizumab and were evaluable for response. The best response was complete response in 3 patients (16%), partial response in 14 patients (74%), and stable disease in 1 patient (5%).
The progression-free survival rate was 81.0% at 6 months and 69.7% at 12 months. The overall survival rate was 95.2% at 6 months and 85.2% at 12 months.
The researchers acknowledged that two key limitations of this study were the small sample size and short duration of follow-up.
“Pembrolizumab with concurrent chemoradiotherapy is tolerable for patients with locally advanced, unresectable NSCLC, although the risk of pneumonitis and long-term outcomes should be evaluated in additional studies,” commented Enriqueta Felip, MD, PhD, of Vall D’Hebron Institute of Oncology in Barcelona, who was not involved in this study.
The study was funded by Merck. The authors and Dr. Felip disclosed relationships with Merck and other companies.
SOURCE: Jabbour SK et al. JAMA Oncol. 2020 Feb 20. doi: 10.1001/jamaoncol.2019.6731.
FROM JAMA ONCOLOGY
Medicaid expansion linked to more early cancer diagnoses
Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.
Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.
The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.
The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).
Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).
Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).
The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.
In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.
Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.
Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.
This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.
SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.
Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.
Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.
The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.
The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).
Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).
Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).
The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.
In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.
Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.
Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.
This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.
SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.
Cancer patients in states that opted to expand Medicaid insurance coverage under the Affordable Care Act saw a slightly better rate of early diagnosis, compared with patients in states that refused expansion, according to a new study. However, time to treatment was similar in states that opted for expansion and states that did not.
Samuel U. Takvorian, MD, of the University of Pennsylvania, Philadelphia, and colleagues reported these results in JAMA Network Open.
The researchers used the National Cancer Database to examine the changes in health insurance coverage and cancer health outcomes in nonelderly patients following implementation of the Affordable Care Act in January 2014. The investigators identified records for 925,543 patients who had new-onset breast (59%), colon (15%), or non–small cell lung (27%) cancer between 2011 and 2016. The patients’ mean age was 55 years (range, 40-64 years), 79% were women, 14% were black, and 6% were Hispanic.
The researchers looked at insurance status, cancer stage at diagnosis, and treatment initiation within 30 and 90 days of diagnosis. The cohort was equally divided between residents of Medicaid expansion states (48%) and nonexpansion states (52%).
Using a statistical technique that mimics a controlled experiment, the investigators found the percentage of uninsured patients decreased more in the expansion states (adjusted difference-in-differences, −0.7 percentage points; 95% confidence interval, −1.2 to −0.3; P = .001), compared with nonexpansion states. Expansion states also had a greater increase in early-stage cancer diagnoses (adjusted DID, 0.8; 95% CI 0.3-1.2; P = .001) and a greater decrease in advanced-stage cancer diagnoses (adjusted DID, −0.5; 95% CI, −0.9 to −0.2; P = .003).
Among the 848,329 patients who underwent cancer treatment within a year of diagnosis, the percentage initiating treatment within 30 days declined from 52.7% before to 48% after Medicaid expansion in states opting in (unadjusted DID, −4.7; percentage points, 95% CI; −5.1 to −4.5). States that did not expand their Medicaid programs, meanwhile, saw the share decline from 56.9% to 51.5% in the same time period (adjusted DID, −5.4; 95% CI, −5.6 to −5.1). There was no statistically significant difference in timely treatment associated with Medicaid expansion (adjusted DID, 0.6; 95% CI, −0.2 to 1.4; P = .14).
The researchers speculated that the lack of significant between-group differences in time to treatment, despite an improvement in early-stage diagnoses associated with Medicaid expansion, could reflect a cancer care system strained by a surge in insured patients, overall increases in cancer prevalence and complexity of care, a shortage of workers, or a mixture of factors.
In a related editorial, Sue Fu, MD, of Stanford (Calif.) University, and colleagues wrote that, while the findings of increased early diagnosis seen in the study are promising, the time to treatment results are “puzzling” and deserve further consideration.
Time to treatment is important in cancer, as longer times are associated with increased mortality, Dr. Fu and colleagues noted. Slowing times to cancer treatment is a systemic problem in the United States that has been documented since the mid-2000s. Paradoxically, expanded insurance coverage could contribute to increasing time to treatment even after timely diagnosis by adding administrative burdens leading to longer wait times. “Newly insured and underinsured individuals may be particularly vulnerable to this,” the editorialists wrote.
Dr. Takvorian and colleagues noted as weaknesses of their study its observational design, a limited range of ages and cancers included, and an inability to adjust for state-level effects.
This study was funded by the National Cancer Institute and the Agency for Health Research and Quality. The authors of the study and the editorial disclosed no relevant conflicts of interest.
SOURCES: Takvorian SU et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921653; Fu S et al. JAMA Netw Open. 2020 Feb 5;3(2):e1921690.
FROM JAMA NETWORK OPEN
Tumor neoantigenicity metric improves prediction of response to immunotherapy
A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.
The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.
“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.
The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.
The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.
In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).
Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).
In a cohort of patients with non–small cell lung cancer treated with checkpoint inhibitors, those with sustained responses were more likely to have higher CSiN scores than were patients with short-term progression (P = .015).
The investigators also compared the predictive power of CSiN with existing neoantigenicity metrics, ultimately concluding that CSiN was superior.
“Overall, the neoantigen load and neoantigen fitness models were not as strongly predictive of treatment response as CSiN,” the investigators wrote.
Again using data from patients with immunogenic cancers, the investigators looked for an association between CSiN score and overall survival. Indeed, patients with higher-than-average CSiN scores had significantly better survival than that of those with lower scores (P less than .001). This finding was maintained in a multivariate analysis that accounted for disease type, stage, sex, and age.
In contrast with the above findings, CSiN did not predict survival among patients with nonimmunogenic cancer types.
“Overall, our work offers a rigorous methodology of predicting response to immunotherapy and prognosis from routine patient samples and should be useful for personalizing medicine in the modern era of immunotherapy,” the investigators concluded.
The study was funded by the National Institutes of Health, the Cancer Prevention Research Institute of Texas, and the American Cancer Society. The investigators reported no conflicts of interest.
SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.
A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.
The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.
“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.
The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.
The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.
In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).
Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).
In a cohort of patients with non–small cell lung cancer treated with checkpoint inhibitors, those with sustained responses were more likely to have higher CSiN scores than were patients with short-term progression (P = .015).
The investigators also compared the predictive power of CSiN with existing neoantigenicity metrics, ultimately concluding that CSiN was superior.
“Overall, the neoantigen load and neoantigen fitness models were not as strongly predictive of treatment response as CSiN,” the investigators wrote.
Again using data from patients with immunogenic cancers, the investigators looked for an association between CSiN score and overall survival. Indeed, patients with higher-than-average CSiN scores had significantly better survival than that of those with lower scores (P less than .001). This finding was maintained in a multivariate analysis that accounted for disease type, stage, sex, and age.
In contrast with the above findings, CSiN did not predict survival among patients with nonimmunogenic cancer types.
“Overall, our work offers a rigorous methodology of predicting response to immunotherapy and prognosis from routine patient samples and should be useful for personalizing medicine in the modern era of immunotherapy,” the investigators concluded.
The study was funded by the National Institutes of Health, the Cancer Prevention Research Institute of Texas, and the American Cancer Society. The investigators reported no conflicts of interest.
SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.
A new tumor neoantigenicity metric may improve prediction of response to immunotherapy in patients with melanoma, lung cancer, and kidney cancer, a retrospective analysis suggests.
The new metric, known as the Cauchy-Schwarz index of neoantigens (CSiN) score, incorporates both immunogenicity and clonality, according to lead study author Tianshi Lu, a PhD candidate at the University of Texas Southwestern Medical Center in Dallas, and colleagues.
“The major biological insight from this study is that the neoantigen clonal structure in each tumor specimen and the immunogenicity of the neoantigens (represented by the MHC-binding strength in our study) are predictive of response to checkpoint inhibitors and prognosis,” the investigators wrote in Science Immunology.
The study involved 2,479 patients with various cancers, including immunogenic types such as renal cell carcinoma (RCC), and nonimmunogenic types, such as pediatric acute lymphocytic leukemia.
The investigators first evaluated CSiN in relation to clinical outcome among patients with immunogenic cancers who received immunotherapy. Drawing data from multiple cohorts, the investigators found that patients who had better responses to therapy were significantly more likely to have above average CSiN scores than those who had worse responses.
In one cohort of patients with melanoma who received anti–CTLA-4 therapy, those with better responses were more likely to have high CSiN scores (P = .009). In another cohort of melanoma patients who received anti–CTLA-4 therapy, those with higher CSiN scores were more likely to achieve durable clinical benefit (response or stable disease for more than 6 months), compared with patients who had lower CSiN scores (P = .033).
Among patients with clear cell RCC treated with anti-PD-1/PD-L1 therapy, there was a significant positive association between higher CSiN scores and better response (P = .036). Among T effector-high patients with metastatic clear cell RCC, there was a significant association between higher CSiN scores and better response to atezolizumab (P = .028) but not sunitinib (P = .890).
In a cohort of patients with non–small cell lung cancer treated with checkpoint inhibitors, those with sustained responses were more likely to have higher CSiN scores than were patients with short-term progression (P = .015).
The investigators also compared the predictive power of CSiN with existing neoantigenicity metrics, ultimately concluding that CSiN was superior.
“Overall, the neoantigen load and neoantigen fitness models were not as strongly predictive of treatment response as CSiN,” the investigators wrote.
Again using data from patients with immunogenic cancers, the investigators looked for an association between CSiN score and overall survival. Indeed, patients with higher-than-average CSiN scores had significantly better survival than that of those with lower scores (P less than .001). This finding was maintained in a multivariate analysis that accounted for disease type, stage, sex, and age.
In contrast with the above findings, CSiN did not predict survival among patients with nonimmunogenic cancer types.
“Overall, our work offers a rigorous methodology of predicting response to immunotherapy and prognosis from routine patient samples and should be useful for personalizing medicine in the modern era of immunotherapy,” the investigators concluded.
The study was funded by the National Institutes of Health, the Cancer Prevention Research Institute of Texas, and the American Cancer Society. The investigators reported no conflicts of interest.
SOURCE: Lu et al. Sci Immunol. 2020 Feb 21. doi: 10.1126/sciimmunol.aaz3199.
FROM SCIENCE IMMUNOLOGY
Glaring gap in CV event reporting in pivotal cancer trials
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
Clinical trials supporting Food and Drug Adminstration approval of contemporary cancer therapies frequently failed to capture major adverse cardiovascular events (MACE) and, when they did, reported rates 2.6-fold lower than noncancer trials, new research shows.
Overall, 51.3% of trials did not report MACE, with that number reaching 57.6% in trials enrolling patients with baseline cardiovascular disease (CVD).
Nearly 40% of trials did not report any CVD events in follow-up, the authors reported online Feb. 10, 2020, in the Journal of the American College of Cardiology (2020;75:620-8).
“Even in drug classes where there were established or emerging associations with cardiotoxic events, often there were no reported heart events or cardiovascular events across years of follow-up in trials that examined hundreds or even thousands of patients. That was actually pretty surprising,” senior author Daniel Addison, MD, codirector of the cardio-oncology program at the Ohio State University Medical Center, Columbus, said in an interview.
The study was prompted by a series of events that crescendoed when his team was called to the ICU to determine whether a novel targeted agent played a role in the heart decline of a patient with acute myeloid leukemia. “I had a resident ask me a very important question: ‘How do we really know for sure that the trial actually reflects the true risk of heart events?’ to which I told him, ‘it’s difficult to know,’ ” he said.
“I think many of us rely heavily on what we see in the trials, particularly when they make it to the top journals, and quite frankly, we generally take it at face value,” Dr. Addison observed.
Lower Rate of Reported Events
The investigators reviewed CV events reported in 97,365 patients (median age, 61 years; 46% female) enrolled in 189 phase 2 and 3 trials supporting FDA approval of 123 anticancer drugs from 1998 to 2018. Biologic, targeted, or immune-based therapies accounted for 72.5% of drug approvals.
Over 148,138 person-years of follow-up (median trial duration, 30 months), there were 1,148 incidents of MACE (375 heart failure, 253 MIs, 180 strokes, 65 atrial fibrillation, 29 coronary revascularizations, and 246 CVD deaths). MACE rates were higher in the intervention group than in the control group (792 vs. 356; P less than .01). Among the 64 trials that excluded patients with baseline CVD, there were 269 incidents of MACE.
To put this finding in context, the researchers examined the reported incidence of MACE among some 6,000 similarly aged participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The overall weighted-average incidence rate was 1,408 per 100,000 person-years among MESA participants, compared with 542 events per 100,000 person-years among oncology trial participants (716 per 100,000 in the intervention arm). This represents a reported-to-expected ratio of 0.38 – a 2.6-fold lower rate of reported events (P less than .001) – and a risk difference of 866.
Further, MACE reporting was lower by a factor of 1.7 among all cancer trial participants irrespective of baseline CVD status (reported-to-expected ratio, 0.56; risk difference, 613; P less than .001).
There was no significant difference in MACE reporting between independent or industry-sponsored trials, the authors report.
No malicious intent
“There are likely some that might lean toward not wanting to attribute blame to a new drug when the drug is in a study, but I really think that the leading factor is lack of awareness,” Dr. Addison said. “I’ve talked with several cancer collaborators around the country who run large clinical trials, and I think often, when an event may be brought to someone’s attention, there is a tendency to just write it off as kind of a generic expected event due to age, or just something that’s not really pertinent to the study. So they don’t really focus on it as much.”
“Closer collaboration between cardiologists and cancer physicians is needed to better determine true cardiac risks among patients treated with these drugs.”
Breast cancer oncologist Marc E. Lippman, MD, of Georgetown University Medical Center and Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C., isn’t convinced a lack of awareness is the culprit.
“I don’t agree with that at all,” he said in an interview. “I think there are very, very clear rules and guidelines these days for adverse-event reporting. I think that’s not a very likely explanation – that it’s not on the radar.”
Part of the problem may be that some of the toxicities, particularly cardiovascular, may not emerge for years, he said. Participant screening for the trials also likely removed patients with high cardiovascular risk. “It’s very understandable to me – I’m not saying it’s good particularly – but I think it’s very understandable that, if you’re trying to develop a drug, the last thing you’d want to have is a lot of toxicity that you might have avoided by just being restrictive in who you let into the study,” Dr. Lippman said.
The underreported CVD events may also reflect the rapidly changing profile of cardiovascular toxicities associated with novel anticancer therapies.
“Providers, both cancer and noncancer, generally put cardiotoxicity in the box of anthracyclines and radiation, but particularly over the last decade, we’ve begun to understand it’s well beyond any one class of drugs,” Dr. Addison said.
“I agree completely,” Dr. Lippman said. For example, “the checkpoint inhibitors are so unbelievably different in terms of their toxicities that many people simply didn’t even know what they were getting into at first.”
One size does not fit all
Javid Moslehi, MD, director of the cardio-oncology program at Vanderbilt University, Nashville, Tenn., said echocardiography – recommended to detect changes in left ventricular function in patients exposed to anthracyclines or targeted agents like trastuzumab (Herceptin) – isn’t enough to address today’s cancer therapy–related CVD events.
“Initial drugs like anthracyclines or Herceptin in cardio-oncology were associated with systolic cardiac dysfunction, whereas the majority of issues we see in the cardio-oncology clinics today are vascular, metabolic, arrhythmogenic, and inflammatory,” he said in an interview. “Echocardiography misses the big and increasingly complex picture.”
His group, for example, has been studying myocarditis associated with immunotherapies, but none of the clinical trials require screening or surveillance for myocarditis with a cardiac biomarker like troponin.
The group also recently identified 303 deaths in patients exposed to ibrutinib, a drug that revolutionized the treatment of several B-cell malignancies but is associated with higher rates of atrial fibrillation, which is also associated with increased bleeding risk. “So there’s a little bit of a double whammy there, given that we often treat atrial fibrillation with anticoagulation and where we can cause complications in patients,” Dr. Moslehi noted.
Although there needs to be closer collaboration between cardiologists and oncologists on individual trials, cardiologists also have to realize that oncology care has become very personalized, he suggested.
“What’s probably relevant for the breast cancer patient may not be relevant for the prostate cancer patient and their respective treatments,” Dr. Moslehi said. “So if we were to say, ‘every person should get an echo,’ that may be less relevant to the prostate cancer patient where treatments can cause vascular and metabolic perturbations or to the patient treated with immunotherapy who may have myocarditis, where many of the echos can be normal. There’s no one-size-fits-all for these things.”
Wearable technologies like smartwatches could play a role in improving the reporting of CVD events with novel therapies but a lot more research needs to be done to validate these tools, Dr. Addison said. “But as we continue on into the 21st century, this is going to expand and may potentially help us,” he added.
In the interim, better standardization is needed of the cardiovascular events reported in oncology trials, particularly the Common Terminology Criteria for Adverse Events (CTCAE), said Dr. Moslehi, who also serves as chair of the American Heart Association’s subcommittee on cardio-oncology.
“Cardiovascular definitions are not exactly uniform and are not consistent with what we in cardiology consider to be important or relevant,” he said. “So I think there needs to be better standardization of these definitions, specifically within the CTCAE, which is what the oncologists use to identify adverse events.”
In a linked editorial (J Am Coll Cardiol. 2020;75:629-31), Dr. Lippman and cardiologist Nanette Bishopric, MD, of the Medstar Heart and Vascular Institute in Washington, D.C., suggested it may also be time to organize a consortium that can carry out “rigorous multicenter clinical investigations to evaluate the cardiotoxicity of emerging cancer treatments,” similar to the Thrombosis in Myocardial Infarction Study Group.
“The success of this consortium in pioneering and targeting multiple generations of drugs for the treatment of MI, involving tens of thousands of patients and thousands of collaborations across multiple national borders, is a model for how to move forward in providing the new hope of cancer cure without the trade-off of years lost to heart disease,” the editorialists concluded.
The study was supported in part by National Institutes of Health grants, including a K12-CA133250 grant to Dr. Addison. Dr. Bishopric reported being on the scientific board of C&C Biopharma. Dr. Lippman reports being on the board of directors of and holding stock in Seattle Genetics. Dr. Moslehi reported having served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron.
This article first appeared on Medscape.com.
FDA: Cell phones still look safe
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
according to a review by the Food and Drug Administration.
The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.
The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.
The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.
The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.
Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”
The full review is available on the FDA website.
Stopping smoking allows healthy lung cells to proliferate
New research results reinforce the benefits of quitting smoking.
Not only does it stop further damage to the lungs, it appears that it also allows new, , say researchers.
The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).
The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.
The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.
However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.
“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.
“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.
This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.
“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
‘Important public health message’
Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.
“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.
“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.
In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”
He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.
“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”
Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
Tobacco and mutagenesis
In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.
However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”
They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.
To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.
All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.
The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
Cells show different mutational burdens
The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.
Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.
The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”
They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10–16 for within-subject heterogeneity).
Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10–8 for heterogeneity).
Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.
It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).
In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).
However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.
Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.
Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.
“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.
They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.
“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.
“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.
However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.
In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”
The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
New research results reinforce the benefits of quitting smoking.
Not only does it stop further damage to the lungs, it appears that it also allows new, , say researchers.
The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).
The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.
The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.
However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.
“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.
“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.
This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.
“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
‘Important public health message’
Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.
“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.
“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.
In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”
He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.
“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”
Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
Tobacco and mutagenesis
In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.
However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”
They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.
To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.
All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.
The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
Cells show different mutational burdens
The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.
Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.
The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”
They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10–16 for within-subject heterogeneity).
Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10–8 for heterogeneity).
Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.
It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).
In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).
However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.
Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.
Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.
“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.
They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.
“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.
“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.
However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.
In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”
The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
New research results reinforce the benefits of quitting smoking.
Not only does it stop further damage to the lungs, it appears that it also allows new, , say researchers.
The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).
The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.
The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.
However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.
“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.
“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.
This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.
“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
‘Important public health message’
Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.
“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.
“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.
In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”
He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.
“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”
Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
Tobacco and mutagenesis
In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.
However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”
They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.
To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.
All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.
The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
Cells show different mutational burdens
The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.
Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.
The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”
They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10–16 for within-subject heterogeneity).
Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10–8 for heterogeneity).
Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.
It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).
In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).
However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.
Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.
Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.
“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.
They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.
“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.
“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.
However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.
In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”
The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
FROM NATURE
Funding failures: Tobacco prevention and cessation
When it comes to state funding for tobacco prevention and cessation, the American Lung Association grades on a curve. It did not help.
Each state’s annual funding for tobacco prevention and cessation was calculated and then compared with the Centers for Disease Control and Prevention’s recommended spending level. That percentage became the grade, with any level of funding at 80% or more of the CDC’s recommendation getting an A and anything below 50% getting an F, the ALA explained.
The three A’s went to Alaska – which spent $10.14 million, or 99.4% of the CDC-recommended $10.2 million – California (96.0%), and Maine (83.5%). The lowest levels of spending came from Georgia, which spend just 2.8% of the CDC’s recommendation of $106 million, and Missouri, which spent 3.0%, the ALA reported.
States’ grades were generally better in the four other areas of tobacco-control policy: There were 24 A’s and 9 F’s for smoke-free air laws, 1 A and 35 F’s for tobacco excise taxes, 3 A’s and 17 F’s for access to cessation treatment, and 10 A’s and 30 F’s for laws to raise the tobacco sales age to 21 years, the ALA said in the report.
Despite an overall grade of F, the federal government managed to earn some praise in that last area: “In what could only be described as unimaginable even 2 years ago, in December 2019, Congress passed bipartisan legislation to raise the minimum age of sale for tobacco products to 21,” the ALA said.
The federal government was strongly criticized on the subject of e-cigarettes. “The Trump Administration failed to prioritize public health over the tobacco industry with its Jan. 2, 2020, announcement that will leave thousands of flavored e-cigarettes on the market,” the ALA said, while concluding that the rising use of e-cigarettes in recent years “is a real-world demonstration of the failure of the U.S. Food and Drug Administration to properly oversee all tobacco products. … This failure places the lung health and lives of Americans at risk.”
When it comes to state funding for tobacco prevention and cessation, the American Lung Association grades on a curve. It did not help.
Each state’s annual funding for tobacco prevention and cessation was calculated and then compared with the Centers for Disease Control and Prevention’s recommended spending level. That percentage became the grade, with any level of funding at 80% or more of the CDC’s recommendation getting an A and anything below 50% getting an F, the ALA explained.
The three A’s went to Alaska – which spent $10.14 million, or 99.4% of the CDC-recommended $10.2 million – California (96.0%), and Maine (83.5%). The lowest levels of spending came from Georgia, which spend just 2.8% of the CDC’s recommendation of $106 million, and Missouri, which spent 3.0%, the ALA reported.
States’ grades were generally better in the four other areas of tobacco-control policy: There were 24 A’s and 9 F’s for smoke-free air laws, 1 A and 35 F’s for tobacco excise taxes, 3 A’s and 17 F’s for access to cessation treatment, and 10 A’s and 30 F’s for laws to raise the tobacco sales age to 21 years, the ALA said in the report.
Despite an overall grade of F, the federal government managed to earn some praise in that last area: “In what could only be described as unimaginable even 2 years ago, in December 2019, Congress passed bipartisan legislation to raise the minimum age of sale for tobacco products to 21,” the ALA said.
The federal government was strongly criticized on the subject of e-cigarettes. “The Trump Administration failed to prioritize public health over the tobacco industry with its Jan. 2, 2020, announcement that will leave thousands of flavored e-cigarettes on the market,” the ALA said, while concluding that the rising use of e-cigarettes in recent years “is a real-world demonstration of the failure of the U.S. Food and Drug Administration to properly oversee all tobacco products. … This failure places the lung health and lives of Americans at risk.”
When it comes to state funding for tobacco prevention and cessation, the American Lung Association grades on a curve. It did not help.
Each state’s annual funding for tobacco prevention and cessation was calculated and then compared with the Centers for Disease Control and Prevention’s recommended spending level. That percentage became the grade, with any level of funding at 80% or more of the CDC’s recommendation getting an A and anything below 50% getting an F, the ALA explained.
The three A’s went to Alaska – which spent $10.14 million, or 99.4% of the CDC-recommended $10.2 million – California (96.0%), and Maine (83.5%). The lowest levels of spending came from Georgia, which spend just 2.8% of the CDC’s recommendation of $106 million, and Missouri, which spent 3.0%, the ALA reported.
States’ grades were generally better in the four other areas of tobacco-control policy: There were 24 A’s and 9 F’s for smoke-free air laws, 1 A and 35 F’s for tobacco excise taxes, 3 A’s and 17 F’s for access to cessation treatment, and 10 A’s and 30 F’s for laws to raise the tobacco sales age to 21 years, the ALA said in the report.
Despite an overall grade of F, the federal government managed to earn some praise in that last area: “In what could only be described as unimaginable even 2 years ago, in December 2019, Congress passed bipartisan legislation to raise the minimum age of sale for tobacco products to 21,” the ALA said.
The federal government was strongly criticized on the subject of e-cigarettes. “The Trump Administration failed to prioritize public health over the tobacco industry with its Jan. 2, 2020, announcement that will leave thousands of flavored e-cigarettes on the market,” the ALA said, while concluding that the rising use of e-cigarettes in recent years “is a real-world demonstration of the failure of the U.S. Food and Drug Administration to properly oversee all tobacco products. … This failure places the lung health and lives of Americans at risk.”
Uptick in lung cancer in younger women, not related to smoking
A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.
The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.
Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.
They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.
The research was published online Feb. 5 in the International Journal of Cancer.
These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”
Historically, lung cancer higher in men
Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.
However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.
To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.
These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.
In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.
The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:
- A significant crossover from male to female dominance, seen in six countries.
- An insignificant crossover from male to female dominance, found in 23 countries.
- A continued male dominance, observed in 11 countries.
Higher incidence in women in six countries
The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.
Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.
Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.
In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.
Overall, female-to-male IRRs increased notably among the following groups:
- Individuals aged 30-34 years in Canada, Denmark, and Germany.
- Those aged 40-44 years in Germany, the Netherlands, and the United States.
- Those aged 44-50 years in the Netherlands and the United States.
- Those aged 50-54 years in Canada, Denmark, and New Zealand.
Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.
Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.
The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.
“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”
They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”
No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.
The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.
Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.
They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.
The research was published online Feb. 5 in the International Journal of Cancer.
These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”
Historically, lung cancer higher in men
Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.
However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.
To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.
These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.
In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.
The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:
- A significant crossover from male to female dominance, seen in six countries.
- An insignificant crossover from male to female dominance, found in 23 countries.
- A continued male dominance, observed in 11 countries.
Higher incidence in women in six countries
The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.
Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.
Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.
In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.
Overall, female-to-male IRRs increased notably among the following groups:
- Individuals aged 30-34 years in Canada, Denmark, and Germany.
- Those aged 40-44 years in Germany, the Netherlands, and the United States.
- Those aged 44-50 years in the Netherlands and the United States.
- Those aged 50-54 years in Canada, Denmark, and New Zealand.
Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.
Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.
The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.
“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”
They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”
No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.
The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.
Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.
They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.
The research was published online Feb. 5 in the International Journal of Cancer.
These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”
Historically, lung cancer higher in men
Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.
However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.
To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.
These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.
In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.
The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:
- A significant crossover from male to female dominance, seen in six countries.
- An insignificant crossover from male to female dominance, found in 23 countries.
- A continued male dominance, observed in 11 countries.
Higher incidence in women in six countries
The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.
Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.
Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.
In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.
Overall, female-to-male IRRs increased notably among the following groups:
- Individuals aged 30-34 years in Canada, Denmark, and Germany.
- Those aged 40-44 years in Germany, the Netherlands, and the United States.
- Those aged 44-50 years in the Netherlands and the United States.
- Those aged 50-54 years in Canada, Denmark, and New Zealand.
Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.
Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.
The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.
“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”
They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”
No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.