A newly published study that compared the accuracy of two commonly used lung cancer screening algorithms found that the American College of Radiology Lung-RADs screening tool is more accurate in detecting cancerous nodules in patients with a history of lung cancer than NELSON, a Dutch clinical trial that measures nodule volume and growth rate instead of linear measurement of nodule size as done in Lung-RADs.

The study, published in the American Journal of Roentgenology on Nov. 10, 2021,was a retrospective study of 185 patients (100 women, 85 men; mean age, 66 years) who underwent lung cancer screening at a single health care system between July 2015 and August 2018. Using Lung-RADS, seven cancers were downgraded to category 2. The weighted cancer risk was 5% for new nodules, 1% for stable existing nodules, and 44% for growing existing nodules.

“Lung-RADS scores exhibited excellent sensitivity and specificity for cancer in existing nodules and excellent sensitivity in new nodules, though low specificity in new nodules,” wrote the authors, led by Mark M. Hammer, MD, a radiologist with Brigham and Women’s Hospital in Boston.

CT scans are increasingly used for lung cancer screening, so accuracy is essential in devising an appropriate treatment plan for patients. Nearly all centers in the United States use the American College of Radiology’s Lung-RADS for lung cancer screening. In Europe, many centers use the volumetric-based approach of NELSON.

Several studies have compared the performance of nodule risk assessment algorithms, but the findings are inconsistent. Lung-RADS was found to be inferior to the Vancouver risk calculator in predicting malignancy in the National Lung Screening Trial for total nodules. Dr. Hammer previously reported that subsolid nodules classified as Lung-RADS categories 2 and 3 have a higher risk of malignancy than reported. Meanwhile, a study that followed 13,195 men and 2,594 women at high risk of lung cancer found that lung cancer mortality was lower among participants who underwent volume CT screening than among those who underwent no screening.

The authors cited the retrospective design and the small sample size as study limitations. They added that pathological proof was not obtained from benign nodules, which may represent undiagnosed cancer.

The authors declared no conflict of interest.

A newly published study that compared the accuracy of two commonly used lung cancer screening algorithms found that the American College of Radiology Lung-RADs screening tool is more accurate in detecting cancerous nodules in patients with a history of lung cancer than NELSON, a Dutch clinical trial that measures nodule volume and growth rate instead of linear measurement of nodule size as done in Lung-RADs.

The study, published in the American Journal of Roentgenology on Nov. 10, 2021,was a retrospective study of 185 patients (100 women, 85 men; mean age, 66 years) who underwent lung cancer screening at a single health care system between July 2015 and August 2018. Using Lung-RADS, seven cancers were downgraded to category 2. The weighted cancer risk was 5% for new nodules, 1% for stable existing nodules, and 44% for growing existing nodules.

“Lung-RADS scores exhibited excellent sensitivity and specificity for cancer in existing nodules and excellent sensitivity in new nodules, though low specificity in new nodules,” wrote the authors, led by Mark M. Hammer, MD, a radiologist with Brigham and Women’s Hospital in Boston.

CT scans are increasingly used for lung cancer screening, so accuracy is essential in devising an appropriate treatment plan for patients. Nearly all centers in the United States use the American College of Radiology’s Lung-RADS for lung cancer screening. In Europe, many centers use the volumetric-based approach of NELSON.

Several studies have compared the performance of nodule risk assessment algorithms, but the findings are inconsistent. Lung-RADS was found to be inferior to the Vancouver risk calculator in predicting malignancy in the National Lung Screening Trial for total nodules. Dr. Hammer previously reported that subsolid nodules classified as Lung-RADS categories 2 and 3 have a higher risk of malignancy than reported. Meanwhile, a study that followed 13,195 men and 2,594 women at high risk of lung cancer found that lung cancer mortality was lower among participants who underwent volume CT screening than among those who underwent no screening.

The authors cited the retrospective design and the small sample size as study limitations. They added that pathological proof was not obtained from benign nodules, which may represent undiagnosed cancer.

The authors declared no conflict of interest.

A newly published study that compared the accuracy of two commonly used lung cancer screening algorithms found that the American College of Radiology Lung-RADs screening tool is more accurate in detecting cancerous nodules in patients with a history of lung cancer than NELSON, a Dutch clinical trial that measures nodule volume and growth rate instead of linear measurement of nodule size as done in Lung-RADs.

The study, published in the American Journal of Roentgenology on Nov. 10, 2021,was a retrospective study of 185 patients (100 women, 85 men; mean age, 66 years) who underwent lung cancer screening at a single health care system between July 2015 and August 2018. Using Lung-RADS, seven cancers were downgraded to category 2. The weighted cancer risk was 5% for new nodules, 1% for stable existing nodules, and 44% for growing existing nodules.

“Lung-RADS scores exhibited excellent sensitivity and specificity for cancer in existing nodules and excellent sensitivity in new nodules, though low specificity in new nodules,” wrote the authors, led by Mark M. Hammer, MD, a radiologist with Brigham and Women’s Hospital in Boston.

CT scans are increasingly used for lung cancer screening, so accuracy is essential in devising an appropriate treatment plan for patients. Nearly all centers in the United States use the American College of Radiology’s Lung-RADS for lung cancer screening. In Europe, many centers use the volumetric-based approach of NELSON.

Several studies have compared the performance of nodule risk assessment algorithms, but the findings are inconsistent. Lung-RADS was found to be inferior to the Vancouver risk calculator in predicting malignancy in the National Lung Screening Trial for total nodules. Dr. Hammer previously reported that subsolid nodules classified as Lung-RADS categories 2 and 3 have a higher risk of malignancy than reported. Meanwhile, a study that followed 13,195 men and 2,594 women at high risk of lung cancer found that lung cancer mortality was lower among participants who underwent volume CT screening than among those who underwent no screening.

The authors cited the retrospective design and the small sample size as study limitations. They added that pathological proof was not obtained from benign nodules, which may represent undiagnosed cancer.

The authors declared no conflict of interest.

In recent years, the survival rate for patients with lung cancer has increased to the point where now, almost one-quarter of patients with lung cancer are alive 5 years after being diagnosed.

This new statistic is highlighted in the State of Lung Cancer report from the American Lung Association (ALA), published online on Nov. 16.

“If you look back, the 5-year survival rate has been very slowly eking up at about 1% over the years,” Andrea McKee, MD, volunteer spokesperson at the ALA, told this news organization. The report shows that the 5-year survival rate increased by 14.5% over the past 5 years. “To see this big jump is truly remarkable, so that is something we are all celebrating,” she added.

“But we have to change the fatalistic thinking that both patients and primary care physicians still have about lung cancer. Most people say, ‘Everybody I know who had lung cancer died,’ and that was the way it used to be,” she commented, “but that has now changed. Lung cancer is highly curable in its early stages, and even if not early-stage, there are treatments that are making an impact now.”

“So we’ve got to change that perception, as it does exist, even on the part of primary care providers, too,” Dr. McKee emphasized.
 

Lung cancer decreasing but still being diagnosed late

The report notes that the risk of being diagnosed with lung cancer varies considerably across the United States. For example, rates of lung cancer diagnoses are almost 2.5 times higher in Kentucky than in Utah.

Overall, the incidence is decreasing. “Over the last 5 years, the rate of new cases decreased 10% nationally,” the authors point out.

However, in almost half of the cases, the disease is diagnosed in late stages.

When diagnosed at a late stage, the 5-year survival rate for lung cancer drops to only 6%, whereas when the disease is diagnosed early, the 5-year survival rate is 60%.

At present, around 24% of cases of lung cancer are diagnosed at early stages, the report notes, but again, this varies across the United States. The highest rate (30%) is in Massachusetts, and the lowest rate (19%) is in Hawaii.

The percentage of lung cancer cases diagnosed early has been steadily increasing, presumably in part because of the introduction of low-dose CT screening for individuals at highest risk (such as smokers).

However, across the nation, only 5.7% of individuals at high risk for lung cancer underwent annual low-dose CT screening, the report notes.

“CT screening is so powerful at saving lives that even with only 5.7% of people that we’ve been able to screen, I believe it’s making a difference,” Dr. McKee commented. That small national percentage still represents a considerable number of patients, she noted, “so even with what we’ve done so far, I believe that screening is making a difference, at least within my own practice, where I’m definitely seeing it,” Dr. McKee emphasized.

Recent changes to the recommendations as to who should undergo lung cancer screening “have almost doubled the size of the screening population in the U.S.,” Dr. McKee commented. “So there are now about 15 million people who need to get screened, and it again helps that primary care physicians know that screening is very powerful at detecting early-stage lung cancer,” she said.

In her hospital’s own screening program, among the individuals who regularly undergo screening, the majority (88%) of lung cancer cases are detected at stage I or II, for which the cure rate is approximately 90%, she noted.

Another misconception of primary care physicians is that lung cancer screening has an unacceptably high false positive rate. Previous reports in the medical literature suggested the rate could be as high as 96%. “This is absolutely, positively wrong. That is not the false positive rate; the false positive rate for lung cancer screening is less than 10%,” Dr. McKee emphasized.

“So we have to change that in the minds of primary care providers as well,” she underscored.
 

Report highlights racial disparities

The report also highlights the racial disparities that persist in all aspects of lung cancer management – early diagnosis, surgical treatment, lack of treatment, and survival.

For example, Black Americans are 18% less likely to be diagnosed with early-stage disease and are 23% less likely to receive surgical treatment than their White counterparts. They are also 9% more likely to receive no treatment at all, and mortality from lung cancer among Black patients is 21% worse than it is for White patients.

The same trend is seen among Latinx persons, although they are just as likely as White patients to undergo surgical treatment.

First and foremost, “we have to make sure that the [Black and Latinx persons] are screened in an equal fashion,” Dr. McKee said. Providing screening for communities of color is one strategy that might improve screening rates, she suggested.

So, too, can outreach programs in which lung cancer experts work with leaders within these communities, because people are more likely to listen to their leaders regarding the importance of screening for early detection of lung cancer.

Physicians also need to emphasize that even for people who quit smoking decades ago, once those persons are in their 70s, “there is a spike again in lung cancer diagnoses, and that is true for both Black and White patients,” Dr. McKee stressed.

“Again, this is something that many doctors are not aware of,” she emphasized.

Dr. McKee has disclosed no relevant financial relationships.

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

In recent years, the survival rate for patients with lung cancer has increased to the point where now, almost one-quarter of patients with lung cancer are alive 5 years after being diagnosed.

This new statistic is highlighted in the State of Lung Cancer report from the American Lung Association (ALA), published online on Nov. 16.

“If you look back, the 5-year survival rate has been very slowly eking up at about 1% over the years,” Andrea McKee, MD, volunteer spokesperson at the ALA, told this news organization. The report shows that the 5-year survival rate increased by 14.5% over the past 5 years. “To see this big jump is truly remarkable, so that is something we are all celebrating,” she added.

“But we have to change the fatalistic thinking that both patients and primary care physicians still have about lung cancer. Most people say, ‘Everybody I know who had lung cancer died,’ and that was the way it used to be,” she commented, “but that has now changed. Lung cancer is highly curable in its early stages, and even if not early-stage, there are treatments that are making an impact now.”

“So we’ve got to change that perception, as it does exist, even on the part of primary care providers, too,” Dr. McKee emphasized.
 

Lung cancer decreasing but still being diagnosed late

The report notes that the risk of being diagnosed with lung cancer varies considerably across the United States. For example, rates of lung cancer diagnoses are almost 2.5 times higher in Kentucky than in Utah.

Overall, the incidence is decreasing. “Over the last 5 years, the rate of new cases decreased 10% nationally,” the authors point out.

However, in almost half of the cases, the disease is diagnosed in late stages.

When diagnosed at a late stage, the 5-year survival rate for lung cancer drops to only 6%, whereas when the disease is diagnosed early, the 5-year survival rate is 60%.

At present, around 24% of cases of lung cancer are diagnosed at early stages, the report notes, but again, this varies across the United States. The highest rate (30%) is in Massachusetts, and the lowest rate (19%) is in Hawaii.

The percentage of lung cancer cases diagnosed early has been steadily increasing, presumably in part because of the introduction of low-dose CT screening for individuals at highest risk (such as smokers).

However, across the nation, only 5.7% of individuals at high risk for lung cancer underwent annual low-dose CT screening, the report notes.

“CT screening is so powerful at saving lives that even with only 5.7% of people that we’ve been able to screen, I believe it’s making a difference,” Dr. McKee commented. That small national percentage still represents a considerable number of patients, she noted, “so even with what we’ve done so far, I believe that screening is making a difference, at least within my own practice, where I’m definitely seeing it,” Dr. McKee emphasized.

Recent changes to the recommendations as to who should undergo lung cancer screening “have almost doubled the size of the screening population in the U.S.,” Dr. McKee commented. “So there are now about 15 million people who need to get screened, and it again helps that primary care physicians know that screening is very powerful at detecting early-stage lung cancer,” she said.

In her hospital’s own screening program, among the individuals who regularly undergo screening, the majority (88%) of lung cancer cases are detected at stage I or II, for which the cure rate is approximately 90%, she noted.

Another misconception of primary care physicians is that lung cancer screening has an unacceptably high false positive rate. Previous reports in the medical literature suggested the rate could be as high as 96%. “This is absolutely, positively wrong. That is not the false positive rate; the false positive rate for lung cancer screening is less than 10%,” Dr. McKee emphasized.

“So we have to change that in the minds of primary care providers as well,” she underscored.
 

Report highlights racial disparities

The report also highlights the racial disparities that persist in all aspects of lung cancer management – early diagnosis, surgical treatment, lack of treatment, and survival.

For example, Black Americans are 18% less likely to be diagnosed with early-stage disease and are 23% less likely to receive surgical treatment than their White counterparts. They are also 9% more likely to receive no treatment at all, and mortality from lung cancer among Black patients is 21% worse than it is for White patients.

The same trend is seen among Latinx persons, although they are just as likely as White patients to undergo surgical treatment.

First and foremost, “we have to make sure that the [Black and Latinx persons] are screened in an equal fashion,” Dr. McKee said. Providing screening for communities of color is one strategy that might improve screening rates, she suggested.

So, too, can outreach programs in which lung cancer experts work with leaders within these communities, because people are more likely to listen to their leaders regarding the importance of screening for early detection of lung cancer.

Physicians also need to emphasize that even for people who quit smoking decades ago, once those persons are in their 70s, “there is a spike again in lung cancer diagnoses, and that is true for both Black and White patients,” Dr. McKee stressed.

“Again, this is something that many doctors are not aware of,” she emphasized.

Dr. McKee has disclosed no relevant financial relationships.

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

In recent years, the survival rate for patients with lung cancer has increased to the point where now, almost one-quarter of patients with lung cancer are alive 5 years after being diagnosed.

This new statistic is highlighted in the State of Lung Cancer report from the American Lung Association (ALA), published online on Nov. 16.

“If you look back, the 5-year survival rate has been very slowly eking up at about 1% over the years,” Andrea McKee, MD, volunteer spokesperson at the ALA, told this news organization. The report shows that the 5-year survival rate increased by 14.5% over the past 5 years. “To see this big jump is truly remarkable, so that is something we are all celebrating,” she added.

“But we have to change the fatalistic thinking that both patients and primary care physicians still have about lung cancer. Most people say, ‘Everybody I know who had lung cancer died,’ and that was the way it used to be,” she commented, “but that has now changed. Lung cancer is highly curable in its early stages, and even if not early-stage, there are treatments that are making an impact now.”

“So we’ve got to change that perception, as it does exist, even on the part of primary care providers, too,” Dr. McKee emphasized.
 

Lung cancer decreasing but still being diagnosed late

The report notes that the risk of being diagnosed with lung cancer varies considerably across the United States. For example, rates of lung cancer diagnoses are almost 2.5 times higher in Kentucky than in Utah.

Overall, the incidence is decreasing. “Over the last 5 years, the rate of new cases decreased 10% nationally,” the authors point out.

However, in almost half of the cases, the disease is diagnosed in late stages.

When diagnosed at a late stage, the 5-year survival rate for lung cancer drops to only 6%, whereas when the disease is diagnosed early, the 5-year survival rate is 60%.

At present, around 24% of cases of lung cancer are diagnosed at early stages, the report notes, but again, this varies across the United States. The highest rate (30%) is in Massachusetts, and the lowest rate (19%) is in Hawaii.

The percentage of lung cancer cases diagnosed early has been steadily increasing, presumably in part because of the introduction of low-dose CT screening for individuals at highest risk (such as smokers).

However, across the nation, only 5.7% of individuals at high risk for lung cancer underwent annual low-dose CT screening, the report notes.

“CT screening is so powerful at saving lives that even with only 5.7% of people that we’ve been able to screen, I believe it’s making a difference,” Dr. McKee commented. That small national percentage still represents a considerable number of patients, she noted, “so even with what we’ve done so far, I believe that screening is making a difference, at least within my own practice, where I’m definitely seeing it,” Dr. McKee emphasized.

Recent changes to the recommendations as to who should undergo lung cancer screening “have almost doubled the size of the screening population in the U.S.,” Dr. McKee commented. “So there are now about 15 million people who need to get screened, and it again helps that primary care physicians know that screening is very powerful at detecting early-stage lung cancer,” she said.

In her hospital’s own screening program, among the individuals who regularly undergo screening, the majority (88%) of lung cancer cases are detected at stage I or II, for which the cure rate is approximately 90%, she noted.

Another misconception of primary care physicians is that lung cancer screening has an unacceptably high false positive rate. Previous reports in the medical literature suggested the rate could be as high as 96%. “This is absolutely, positively wrong. That is not the false positive rate; the false positive rate for lung cancer screening is less than 10%,” Dr. McKee emphasized.

“So we have to change that in the minds of primary care providers as well,” she underscored.
 

Report highlights racial disparities

The report also highlights the racial disparities that persist in all aspects of lung cancer management – early diagnosis, surgical treatment, lack of treatment, and survival.

For example, Black Americans are 18% less likely to be diagnosed with early-stage disease and are 23% less likely to receive surgical treatment than their White counterparts. They are also 9% more likely to receive no treatment at all, and mortality from lung cancer among Black patients is 21% worse than it is for White patients.

The same trend is seen among Latinx persons, although they are just as likely as White patients to undergo surgical treatment.

First and foremost, “we have to make sure that the [Black and Latinx persons] are screened in an equal fashion,” Dr. McKee said. Providing screening for communities of color is one strategy that might improve screening rates, she suggested.

So, too, can outreach programs in which lung cancer experts work with leaders within these communities, because people are more likely to listen to their leaders regarding the importance of screening for early detection of lung cancer.

Physicians also need to emphasize that even for people who quit smoking decades ago, once those persons are in their 70s, “there is a spike again in lung cancer diagnoses, and that is true for both Black and White patients,” Dr. McKee stressed.

“Again, this is something that many doctors are not aware of,” she emphasized.

Dr. McKee has disclosed no relevant financial relationships.

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

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

Surgery offers the best chance of a cure for patients with early cancer and is fundamental to cancer management, but it does not receive enough political and financial recognition, warns a European expert.

In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.

Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.

These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.

The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.

The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.

However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.

The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
 

Best chance of cure

“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.

In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.

There is thus a substantial and steadily growing demand for surgical oncology.

It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.

Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.

It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.

The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.

At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.

Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.

Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”

At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.

Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.

Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.

D’Ugo has disclosed no relevant financial relationships.

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

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

Dr. Shailja Shah is a gastroenterologist and clinical researcher at VA San Diego and the University of California, San Diego. Dr. Shah leads a multidisciplinary research program anchored in defining non-genetic, genetic, and systems-level determinants of H. pylori treatment- and disease-related clinical outcomes, including gastric cancer, among high-risk populations. She is also actively involved in research and public policy initiatives to promote gastric cancer prevention and early detection efforts. Dr. Shah’s current and prior sources of funding include the US Dept of Veterans Affairs, AHRQ, NIH, and the American Gastroenterological Association (AGA).

As a gastroenterologist and physician scientist at UCSD/VA San Diego and Moores Cancer Center, when you think about early detection and surveillance of gastric cancer, what are some of the signs and symptoms you look for and how would you factor in risk-based screenings?

Dr. Shah: In the United States, gastric cancer is overlooked because it is thought of as a rare cancer when, in fact, it's more common than esophageal cancer and in certain groups even approaches rates of colorectal cancer. This is important because we have clear guidelines on who to screen for esophageal and colorectal cancer, but we don't have these guidelines for gastric cancer.

The majority of gastric cancer cases in the United States is non-cardia gastric cancer, which refers to the location in the stomach that this type of cancer occurs. This is in comparison to gastric cancer of the cardia which makes up a much smaller percentage. I mention this up front because the risk factor profiles for these two cancers based on anatomic location are different. Cardia gastric cancer mostly tracks with risk factors for esophageal adenocarcinoma while non-cardia gastric cancer is more common in non-white groups who share a disproportionate burden—with some groups as much as 13.5-fold higher than non-Hispanic whites.

The key to the discussion of risk-based screening for non-cardia gastric cancer is that gastric cancer is typically asymptomatic or presents with only non-specific symptoms until it's in the more advanced stages. There's no cure for gastric cancer once it is in this advanced stage, which is really when symptoms prompt the diagnostic workup. When gastric cancer is caught in the early stage where it is asymptomatic or associated with non-specific symptoms that might not prompt an immediate diagnostic workup—this is the stage that resection would be curative.

There are countries such as Japan and South Korea where endoscopic screening for gastric cancer routinely occurs. This has translated into significant reductions in gastric cancer mortality, although notably has not substantially decreased the actual incidence of cancer. This again suggests that the benefit is early detection and the opportunity for curative resection—which can be accomplished either endoscopically or surgically. The United States population overall is not universally high risk for gastric cancer; however, there are certain identifiable high-risk groups who might benefit from endoscopy for early detection. These include non-white groups and immigrants from high risk countries for gastric cancer, people with a family history of gastric cancer, as well as people with gastric precancerous changes such as atrophic gastritis and intestinal metaplasia. These precancerous changes most often are the result of chronic H. pylori infection.

We don't have very precise risk stratification models, and this is a much-needed area of research. We do, however, have evidence from cost-effectiveness analyses that upper endoscopy for gastric cancer screening at the time of colonoscopy for colorectal cancer screening might be cost effective for non-white race and ethnic groups. At the very least, data from these modeling studies can form a starting point when we think of risk-based screening; ideally, we will have data from prospective studies to guide our approach to gastric cancer screening.

Since H. pylori is one of the strongest risk factors for non-cardia gastric cancer, what is your detailed approach to diagnosis and management?

Dr. Shah: H. pylori is a gram-negative bacterium and, globally, it is the most common chronic bacterial infection. Some studies estimate that over half the world's population is infected with H. pylori. It is difficult to get a precise estimate of the global burden of H. pylori, since many times this infection is asymptomatic and it is not one that is routinely screened for in most parts of the world, including the United States. Generally, testing for H. pylori is triggered by GI symptoms such as dyspepsia, abdominal discomfort, or in patients who don't have symptoms, the things that might trigger testing would be a family history of gastric cancer, unexplained iron deficiency, long term NSAID use, and a few other situations.

It is important to diagnose H. pylori because chronic untreated infection is associated with gastric inflammation, which in some cases can progress to loss of the normal gastric glands, a condition known as atrophic gastritis, and, if replaced by intestinal-type tissue, intestinal metaplasia. Such conditions are associated with significantly higher risk of gastric dysplasia and cancer, particularly if there is ongoing H. pylori infection. This stepwise cascade from chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric adenocarcinoma is known as the correa cascade, for which H. pylori is the most common trigger.

We know that H. pylori eradication with antibiotics and high dose acid suppression does improve that inflammation and reduces the risk of gastric cancer. But the key here is that the biggest benefit of H. pylori eradication is eradicating H. pylori prior to the development severe atrophic gastritis and intestinal metaplasia. Therefore, simply testing and treating for H. pylori is not enough for gastric cancer prevention since some people might already have these advanced changes, since these typically don't cause symptoms. This forms the basis for endoscopic surveillance of these precancerous conditions, which is detailed in the most recent AGA guidelines and clinical practice update on intestinal metaplasia and atrophic gastritis, respectively.

H. pylori eradication still a cornerstone of gastric cancer prevention and risk reduction. Careful treatment selection and ensuring that eradication is confirmed warrants emphasis, particularly in the face of rising rates of H. pylori eradication failure. My key takeaway points for H. pylori eradication therapy is that prior to prescribing treatment, it's very important to review patients prior antibiotic exposures specifically macrolides and fluoroquinolones, since patients who have had treatment with these antibiotics for any condition are more likely to be colonized with resistant H. pylori strains. Clarithromycin-triple therapy should not be used unless patients are confirmed to be colonized with clarithromycin susceptible H. pylori. Bismuth-based quadruple therapy is really the preferred first line treatment instead of clarithromycin-based triple therapy given the high rates of clarithromycin resistance. It's also important to provide patients with anticipatory guidance regarding both the importance of completing the full course, as well as some expected possible side effects of antibiotics such as GI upset, nausea. The other tenant therapy is ensuring appropriate gastric acid suppression, which is a point emphasized in the recently published AGA clinical practice update on H. pylori management. All patients should have repeat non-serological H. pylori testing to ensure that eradication was successful. To reduce false positive or false negative results, this repeat testing should be done at least 2-4 weeks after completion of therapy and with patients off PPI therapy for at least 1-2 weeks.

What have you found to be some of the key disparities in gastric cancer particularly as it pertains to the racial and ethnic groups in the United States?

Dr. Shah: Racial and ethnic differences in gastric cancer incidence is a defining factor for gastric cancer in the United States. Our team recently conducted a population-based analysis of the California Cancer Registry, which is one of, if not the largest and most diverse of the SEER cancer registries. The results of this study highlighted the disparity in risk of gastric cancer based on race/ethnicity. All non-white groups in the US had a significantly higher risk of non-cardia gastric cancer compared to non-Hispanic whites. This was particularly striking in the age group that we generally consider for cancer screening, where there was anywhere from 2-fold up to 13.5-fold higher risk of non-cardia gastric cancer compared to the reference non-Hispanic whites. In some of these groups for example, Korean American men above the age of 50, these rates were on par with colorectal cancer rates. Even more concerning, it is possible that these estimates are actually underestimating the true burden of disease, since early cancer is asymptomatic most of the time and might go undiagnosed in the absence of screening.

We also know that immigrants from countries where gastric cancer incidence is high, also retain that increased risk and mortality even when they immigrate to countries gastric cancer incidence is low overall. Admittedly, this risk varies depending on immigrant generation and level of acculturation, including dietary practices, and other factors. The risk is observed to decrease over subsequent generations and depending on acculturation, which underscores opportunities for research into interventions and initiatives to address modifiable risk factors.

Given that immigrants from countries of high gastric cancer, including Asian Americans and Hispanics, comprise the vast majority of population growth in the United States, the public health implications are enormous if we continue to be complacent on gastric cancer prevention and early detection efforts.

As the fifth most common cancer and the third most common cause of cancer related deaths, based on recent studies and your personal experiences as a medical practitioner, also considering the gastric cancer does not cause symptoms until it is in the advanced stage, what are your recommendations as it relates to early detection and improving gastric cancer related outcomes?

Dr. Shah: The first step in my opinion, is recognizing that gastric cancer disproportionately affects certain populations in the US like I mentioned, especially racial and ethnic minorities and other under-represented populations, including US veterans. As a VA clinician and a VA investigator, we see that risk factors for gastric cancer, including H. pylori, disproportionately affect our veterans. The reasons are not fully understood but might relate to differential risk factors and exposures among veterans compared to civilian populations.

Gastric cancer is potentially preventable but is almost certainly curable if detected at an early stage, which really provides the rationale for risk-based screening. Unfortunately, gastric cancer has not been a research priority and there are currently no prospective trials investigating patient outcomes associated with screening versus no screening, nor studies investigating surveillance versus no surveillance of conditions like atrophic gastritis and intestinal metaplasia or  defining appropriate surveillance and screening intervals.  The AGA recently published guidelines and clinical practice updates for intestinal metaplasia and atrophic gastritis management. But one common thread that these documents specifically called attention to, was the lack of high-quality data informing practice, especially practice in the United States. Other research priority areas include risk factors and risk stratification algorithms both for incident and fatal gastric cancer, as well as progression of atrophic gastritis and intestinal metaplasia. Having a better understanding of these factors would really help to fine tune our algorithms, and potentially identify factors that can even be intervened on to halt progression.

The last point that I'll highlight actually relates to non-H. pylori associated gastric cancer. We spend a lot of time focused on H. pylori associated gastric cancer, but an increasing number of gastric cancers are being diagnosed in people without evidence of H. pylori infection. Better understanding the interaction between genetic and environmental triggers and how this differs from H. pylori associated gastric cancer is critical to our approach to control and prevention since there certainly could be important nuances.

A potential new urine biomarker for prostate cancer not only spots the presence of aggressive tumors, it also indicates the amount of these tumors, according to a recent report.

In a study of biopsy and prostatectomy samples, researchers found that the multigene Prostate Urine Risk-4 (PUR-4) signature was strongly associated with the presence and amount of Gleason pattern 4 tumors, but not tumors of less aggressive histology.

Given that increased Gleason pattern 4 tumor burden is associated with disease progression in men at intermediate risk, the results suggest that “PUR can show us which men at intermediate risk may require treatment and which may instead be managed conservatively with surveillance,” said senior author Jeremy Clark, PhD, of the University of East Anglia, Norwich, England. “PUR will also be useful for monitoring disease in men that do not currently require treatment and flag up the emergence and expansion of aggressive disease.”

The study by Dr. Clark and colleagues was published online on Nov. 3, 2021, in Life.

Tests using the traditional blood-based biomarker for prostate cancer – prostate-specific antigen (PSA) – have limited sensitivity and specificity, leading to unnecessary biopsies and overtreatment.

The PUR biomarker, one of several emerging alternatives to PSA, is a four-group classifier based on 36 genes, Dr. Clark and colleagues explained. Its categories correspond to the probabilities of the presence of normal tissue (PUR-1), and D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer.

Dr. Clark’s team found in earlier research that the PUR-4 signature was able to predict disease progression in men on active surveillance for prostate cancer up to 5 years after a single urine sample. For their latest study, they sought to understand the relationship between PUR-4 and the amount and grade of tumor.

On the basis of biopsy samples from 215 men with prostate cancer, the researchers found that PUR-4 signature values correlated significantly with increasing Gleason grade.

There was no significant difference in PSA level by tumor volume for Gleason grade 1, 2, or 3. The same was true for PUR-4 and Gleason grade 1 tumors, which only contain less clinically significant Gleason pattern 3 cancer. However, PUR-4 values in men with Gleason grade 2 tumors larger than the median were significantly greater than for smaller tumors. PUR-4 values for large Gleason grade 3 tumors were also greater than for smaller ones, although the difference did not reach statistical significance.

“Since [Gleason grade] 2 and [Gleason grade] 3 contain both Gleason pattern 3 and 4 cancer these observations suggest that Gleason Pattern 4 cancer may be contributing to PUR-4 status,” the authors wrote.

The researchers also examined radical-prostatectomy specimens from nine men – three with Gleason grade 1, four with Gleason grade 2, and two with Gleason grade 3 tumors, as determined on the basis of presurgical biopsy.

There was no significant correlation between PUR-4 and PSA levels, nor were PUR-4 values linked to total tumor area or Gleason pattern 3 tumor area. But the amount of Gleason pattern 4 tumors showed a strong correlation with PUR-4 values, which did not change after adjusting for total prostate size.

“Our study shows that the PUR test can assess the amount of Gleason pattern 4 without the need for a biopsy,” Dr. Clark said in an interview. “It could therefore be a very useful tool indeed for assessing a man’s risk of dying from prostate cancer.”

Jack Schalken, PhD, a professor of experimental urology at Radboud University Medical Center in Nijmegen, the Netherlands, called PUR “another test” for prostate cancer the performance of which is in the same range as that of existing products.

“In fact, several tests are commercially available, but the clinical use is surprisingly low,” he told this news organization. Dr. Schalken, who was not involved in the new study, has reviewed several biomarkers for prostate cancer.

The PUR test is now undergoing validation in an international study that is expected to last another 2 years, Dr. Clark said. If successful, the test would stand out for several reasons.

First, it is based on many genes, so it is able to spot malignancies that other tests, which rely on just a few genes, may not pick up. In addition, although it is sensitive to the amount of Gleason pattern 4 tumor, it does not seem to detect the clinically less significant Gleason pattern 3 cancers.

“We have an at-home collection kit – the men do not have to come to a hospital to provide a urine sample,” Dr. Clark said.

The study did not receive commercial funding. Dr. Clark and two coauthors have filed a patent application related to their research.
 

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

A potential new urine biomarker for prostate cancer not only spots the presence of aggressive tumors, it also indicates the amount of these tumors, according to a recent report.

In a study of biopsy and prostatectomy samples, researchers found that the multigene Prostate Urine Risk-4 (PUR-4) signature was strongly associated with the presence and amount of Gleason pattern 4 tumors, but not tumors of less aggressive histology.

Given that increased Gleason pattern 4 tumor burden is associated with disease progression in men at intermediate risk, the results suggest that “PUR can show us which men at intermediate risk may require treatment and which may instead be managed conservatively with surveillance,” said senior author Jeremy Clark, PhD, of the University of East Anglia, Norwich, England. “PUR will also be useful for monitoring disease in men that do not currently require treatment and flag up the emergence and expansion of aggressive disease.”

The study by Dr. Clark and colleagues was published online on Nov. 3, 2021, in Life.

Tests using the traditional blood-based biomarker for prostate cancer – prostate-specific antigen (PSA) – have limited sensitivity and specificity, leading to unnecessary biopsies and overtreatment.

The PUR biomarker, one of several emerging alternatives to PSA, is a four-group classifier based on 36 genes, Dr. Clark and colleagues explained. Its categories correspond to the probabilities of the presence of normal tissue (PUR-1), and D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer.

Dr. Clark’s team found in earlier research that the PUR-4 signature was able to predict disease progression in men on active surveillance for prostate cancer up to 5 years after a single urine sample. For their latest study, they sought to understand the relationship between PUR-4 and the amount and grade of tumor.

On the basis of biopsy samples from 215 men with prostate cancer, the researchers found that PUR-4 signature values correlated significantly with increasing Gleason grade.

There was no significant difference in PSA level by tumor volume for Gleason grade 1, 2, or 3. The same was true for PUR-4 and Gleason grade 1 tumors, which only contain less clinically significant Gleason pattern 3 cancer. However, PUR-4 values in men with Gleason grade 2 tumors larger than the median were significantly greater than for smaller tumors. PUR-4 values for large Gleason grade 3 tumors were also greater than for smaller ones, although the difference did not reach statistical significance.

“Since [Gleason grade] 2 and [Gleason grade] 3 contain both Gleason pattern 3 and 4 cancer these observations suggest that Gleason Pattern 4 cancer may be contributing to PUR-4 status,” the authors wrote.

The researchers also examined radical-prostatectomy specimens from nine men – three with Gleason grade 1, four with Gleason grade 2, and two with Gleason grade 3 tumors, as determined on the basis of presurgical biopsy.

There was no significant correlation between PUR-4 and PSA levels, nor were PUR-4 values linked to total tumor area or Gleason pattern 3 tumor area. But the amount of Gleason pattern 4 tumors showed a strong correlation with PUR-4 values, which did not change after adjusting for total prostate size.

“Our study shows that the PUR test can assess the amount of Gleason pattern 4 without the need for a biopsy,” Dr. Clark said in an interview. “It could therefore be a very useful tool indeed for assessing a man’s risk of dying from prostate cancer.”

Jack Schalken, PhD, a professor of experimental urology at Radboud University Medical Center in Nijmegen, the Netherlands, called PUR “another test” for prostate cancer the performance of which is in the same range as that of existing products.

“In fact, several tests are commercially available, but the clinical use is surprisingly low,” he told this news organization. Dr. Schalken, who was not involved in the new study, has reviewed several biomarkers for prostate cancer.

The PUR test is now undergoing validation in an international study that is expected to last another 2 years, Dr. Clark said. If successful, the test would stand out for several reasons.

First, it is based on many genes, so it is able to spot malignancies that other tests, which rely on just a few genes, may not pick up. In addition, although it is sensitive to the amount of Gleason pattern 4 tumor, it does not seem to detect the clinically less significant Gleason pattern 3 cancers.

“We have an at-home collection kit – the men do not have to come to a hospital to provide a urine sample,” Dr. Clark said.

The study did not receive commercial funding. Dr. Clark and two coauthors have filed a patent application related to their research.
 

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

A potential new urine biomarker for prostate cancer not only spots the presence of aggressive tumors, it also indicates the amount of these tumors, according to a recent report.

In a study of biopsy and prostatectomy samples, researchers found that the multigene Prostate Urine Risk-4 (PUR-4) signature was strongly associated with the presence and amount of Gleason pattern 4 tumors, but not tumors of less aggressive histology.

Given that increased Gleason pattern 4 tumor burden is associated with disease progression in men at intermediate risk, the results suggest that “PUR can show us which men at intermediate risk may require treatment and which may instead be managed conservatively with surveillance,” said senior author Jeremy Clark, PhD, of the University of East Anglia, Norwich, England. “PUR will also be useful for monitoring disease in men that do not currently require treatment and flag up the emergence and expansion of aggressive disease.”

The study by Dr. Clark and colleagues was published online on Nov. 3, 2021, in Life.

Tests using the traditional blood-based biomarker for prostate cancer – prostate-specific antigen (PSA) – have limited sensitivity and specificity, leading to unnecessary biopsies and overtreatment.

The PUR biomarker, one of several emerging alternatives to PSA, is a four-group classifier based on 36 genes, Dr. Clark and colleagues explained. Its categories correspond to the probabilities of the presence of normal tissue (PUR-1), and D’Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer.

Dr. Clark’s team found in earlier research that the PUR-4 signature was able to predict disease progression in men on active surveillance for prostate cancer up to 5 years after a single urine sample. For their latest study, they sought to understand the relationship between PUR-4 and the amount and grade of tumor.

On the basis of biopsy samples from 215 men with prostate cancer, the researchers found that PUR-4 signature values correlated significantly with increasing Gleason grade.

There was no significant difference in PSA level by tumor volume for Gleason grade 1, 2, or 3. The same was true for PUR-4 and Gleason grade 1 tumors, which only contain less clinically significant Gleason pattern 3 cancer. However, PUR-4 values in men with Gleason grade 2 tumors larger than the median were significantly greater than for smaller tumors. PUR-4 values for large Gleason grade 3 tumors were also greater than for smaller ones, although the difference did not reach statistical significance.

“Since [Gleason grade] 2 and [Gleason grade] 3 contain both Gleason pattern 3 and 4 cancer these observations suggest that Gleason Pattern 4 cancer may be contributing to PUR-4 status,” the authors wrote.

The researchers also examined radical-prostatectomy specimens from nine men – three with Gleason grade 1, four with Gleason grade 2, and two with Gleason grade 3 tumors, as determined on the basis of presurgical biopsy.

There was no significant correlation between PUR-4 and PSA levels, nor were PUR-4 values linked to total tumor area or Gleason pattern 3 tumor area. But the amount of Gleason pattern 4 tumors showed a strong correlation with PUR-4 values, which did not change after adjusting for total prostate size.

“Our study shows that the PUR test can assess the amount of Gleason pattern 4 without the need for a biopsy,” Dr. Clark said in an interview. “It could therefore be a very useful tool indeed for assessing a man’s risk of dying from prostate cancer.”

Jack Schalken, PhD, a professor of experimental urology at Radboud University Medical Center in Nijmegen, the Netherlands, called PUR “another test” for prostate cancer the performance of which is in the same range as that of existing products.

“In fact, several tests are commercially available, but the clinical use is surprisingly low,” he told this news organization. Dr. Schalken, who was not involved in the new study, has reviewed several biomarkers for prostate cancer.

The PUR test is now undergoing validation in an international study that is expected to last another 2 years, Dr. Clark said. If successful, the test would stand out for several reasons.

First, it is based on many genes, so it is able to spot malignancies that other tests, which rely on just a few genes, may not pick up. In addition, although it is sensitive to the amount of Gleason pattern 4 tumor, it does not seem to detect the clinically less significant Gleason pattern 3 cancers.

“We have an at-home collection kit – the men do not have to come to a hospital to provide a urine sample,” Dr. Clark said.

The study did not receive commercial funding. Dr. Clark and two coauthors have filed a patent application related to their research.
 

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

The risk of occult gastric adenocarcinoma is highly prevalent in hereditary lobular breast cancer (HLBC) families who harbor any type of CDH1 variant and this risk remains high in patients with no family history of gastric cancer, a prospective cohort study has shown.

“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.

“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.

The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.

“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.

Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.

The median age at the time of endoscopic carcinoma detection was only 33 years.

“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.

The median age at the time patients elected to undergo total gastrectomy was 50 years.

The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.

Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.

“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”

Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.

Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.

Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.

The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.

The risk of occult gastric adenocarcinoma is highly prevalent in hereditary lobular breast cancer (HLBC) families who harbor any type of CDH1 variant and this risk remains high in patients with no family history of gastric cancer, a prospective cohort study has shown.

“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.

“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.

The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.

“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.

Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.

The median age at the time of endoscopic carcinoma detection was only 33 years.

“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.

The median age at the time patients elected to undergo total gastrectomy was 50 years.

The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.

Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.

“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”

Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.

Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.

Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.

The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.

The risk of occult gastric adenocarcinoma is highly prevalent in hereditary lobular breast cancer (HLBC) families who harbor any type of CDH1 variant and this risk remains high in patients with no family history of gastric cancer, a prospective cohort study has shown.

“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.

“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.

The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.

“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.

Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.

The median age at the time of endoscopic carcinoma detection was only 33 years.

“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.

The median age at the time patients elected to undergo total gastrectomy was 50 years.

The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.

Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.

“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”

Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.

Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.

Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.

The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.

In Australia, where they know a thing or two about skin cancer, authors of a large prospective population-based cohort study found that melanomas detected through routine skin checks were associated with lower all-cause mortality, but not melanoma-specific mortality.

Among patients in New South Wales diagnosed with melanoma in 2006 or 2007 and followed for nearly 12 years, there was no significant difference in the rate of melanoma-specific death associated with either patient-detected or clinician-detected melanomas in an analysis adjusted for prognostic factors.

Although melanomas found through routine clinician-performed skin checks were associated with a 25% reduction in all-cause mortality compared with patient-detected lesions (P = .006), this difference may have been due to the tendency of health-oriented patients to participate in screening programs.

The study – one of the largest to date and performed in an area of the world where there is a high incidence of skin cancer and high degree of public awareness of the risks of too much sun exposure – could not fully answer its central question: Can routine skin checks, a proxy for skin cancer screening, significantly decrease the incidence of melanoma-related deaths?

“A large randomized clinical trial is needed to provide definitive evidence that screening for skin cancer reduces melanoma-specific and all-cause mortality among people invited (vs. not invited) to screen, but there are concerns about feasibility. Our findings could be used to estimate the sample size for a future trial,” wrote Caroline G. Watts, PhD, of the University of Sydney, Australia, and colleagues. Their study was published online Nov. 3 in JAMA Dermatology.

In an editorial accompanying the study, dermatologists Allan C. Halpern, MD, and Michael A. Marchetti, MD, of Memorial Sloan-Kettering Cancer Center in New York, point out that “there has never been a randomized clinical trial of melanoma screening, nor is there one currently ongoing or planned. Even if one were to be initiated immediately, such a trial would take well over a decade to conduct.

“Thus, for the foreseeable future, our approaches to melanoma secondary prevention need to be based on indirect evidence and our understanding of biology and epidemiology,” they wrote.

A dermatology researcher who was not involved in the study said that while it doesn’t solve the screening conundrum, it does highlight the value of public health campaigns.

“The way that I interpret the data, especially the fact that it’s coming out of Australia, is that if education about self-examination is done properly, that can also be effective in terms of detecting these skin cancers,” said Shawn Demehri, MD, PhD, principal investigator at the Cutaneous Biology Research Center at Massachusetts General Hospital, Boston. Dr. Demehri was asked to comment on the study.

“I would argue that the results would probably have been different if the study had been conducted in the U.S. rather than Australia, because the education in terms of self-examination is much more advanced and organized in Australia,” he said in an interview.

Study details

To assess melanoma-specific and all-cause mortality associated with melanoma identified through routine skin checks, Dr. Watts and colleagues followed patients diagnosed with melanoma from October 2006 through October 2007 who were enrolled in the Melanoma Patterns of Care Study. The patients were followed until 2018 (mean follow-up 11.9 years).

Of the 2,452 patients for whom data were available, 291 had an initial diagnosis of primary melanoma in situ (MIS), and 2,161 were diagnosed with invasive cutaneous melanoma.

The median age at diagnosis was 65 years, ranging from 16 to 98 years. Nearly two-thirds of the patients (61%) were men.

Among all patients, 858 (35%) had melanoma detected during a routine skin check, 1,148 (47%) detected the lesions themselves, 293 (12%) had incidentally-detected melanomas, and 153 (6%) had lesions detected by other, unspecified means.

In analyses adjusted for age and sex, the investigators found that compared with patient-detected lesions, melanomas detected during routine skin checks were associated with a 59% lower risk for melanoma-specific mortality (subhazard ratio, 0.41, P < .001) and 36% lower risk for all-cause mortality (hazard ratio, 0.64, P < .001).

But after adjustment for melanoma prognostic factors such as ulceration and mitotic rate, the association of skin check–detected lesions with melanoma-specific mortality was no longer statistically significant. The association with lower all-cause mortality was somewhat attenuated, but remained significant (HR, 0.75, P = .006).

Factors associated with a higher likelihood of melanoma detection during routine skin checks included males vs. females, a history of melanoma, having multiple moles, age 50 or older, and residence in a urban vs. rural areas.
 

Screen with care

In their editorial, Dr. Halpern and Dr. Marchetti propose methods for screening that find a balance between detection of significant disease and potential harm to patients from unnecessary biopsy or invasive procedures.

“For many lesions, we could use serial photography and dermoscopy in lieu of tissue biopsy to identify those that are truly dynamic outliers and likely to be of greater risk to the patient. An analogous approach is already used for the management of small lung nodules detected incidentally and through screening,” they wrote.

They also raise the issue of potential overdiagnosis and overtreatment of MIS, and recommend an approach similar to that used for some older patients with prostate cancer, for example.

“The consequences of MIS treatment differ greatly based on the type, anatomic location, and size of the tumor; these factors should be considered in shared decision-making with patients. Options such as active surveillance and topical therapy should be discussed, particularly in those with significant comorbidities or advanced age,” they wrote.

The study was supported by grants from the Australian National Health and Medical Research Council, Cancer Institute New South Wales, and the New South Wales State Government. Dr. Watts, Dr. Halpern, Dr. Marchetti, and Dr. Demehri reported having no conflicts of interest.

In Australia, where they know a thing or two about skin cancer, authors of a large prospective population-based cohort study found that melanomas detected through routine skin checks were associated with lower all-cause mortality, but not melanoma-specific mortality.

Among patients in New South Wales diagnosed with melanoma in 2006 or 2007 and followed for nearly 12 years, there was no significant difference in the rate of melanoma-specific death associated with either patient-detected or clinician-detected melanomas in an analysis adjusted for prognostic factors.

Although melanomas found through routine clinician-performed skin checks were associated with a 25% reduction in all-cause mortality compared with patient-detected lesions (P = .006), this difference may have been due to the tendency of health-oriented patients to participate in screening programs.

The study – one of the largest to date and performed in an area of the world where there is a high incidence of skin cancer and high degree of public awareness of the risks of too much sun exposure – could not fully answer its central question: Can routine skin checks, a proxy for skin cancer screening, significantly decrease the incidence of melanoma-related deaths?

“A large randomized clinical trial is needed to provide definitive evidence that screening for skin cancer reduces melanoma-specific and all-cause mortality among people invited (vs. not invited) to screen, but there are concerns about feasibility. Our findings could be used to estimate the sample size for a future trial,” wrote Caroline G. Watts, PhD, of the University of Sydney, Australia, and colleagues. Their study was published online Nov. 3 in JAMA Dermatology.

In an editorial accompanying the study, dermatologists Allan C. Halpern, MD, and Michael A. Marchetti, MD, of Memorial Sloan-Kettering Cancer Center in New York, point out that “there has never been a randomized clinical trial of melanoma screening, nor is there one currently ongoing or planned. Even if one were to be initiated immediately, such a trial would take well over a decade to conduct.

“Thus, for the foreseeable future, our approaches to melanoma secondary prevention need to be based on indirect evidence and our understanding of biology and epidemiology,” they wrote.

A dermatology researcher who was not involved in the study said that while it doesn’t solve the screening conundrum, it does highlight the value of public health campaigns.

“The way that I interpret the data, especially the fact that it’s coming out of Australia, is that if education about self-examination is done properly, that can also be effective in terms of detecting these skin cancers,” said Shawn Demehri, MD, PhD, principal investigator at the Cutaneous Biology Research Center at Massachusetts General Hospital, Boston. Dr. Demehri was asked to comment on the study.

“I would argue that the results would probably have been different if the study had been conducted in the U.S. rather than Australia, because the education in terms of self-examination is much more advanced and organized in Australia,” he said in an interview.

Study details

To assess melanoma-specific and all-cause mortality associated with melanoma identified through routine skin checks, Dr. Watts and colleagues followed patients diagnosed with melanoma from October 2006 through October 2007 who were enrolled in the Melanoma Patterns of Care Study. The patients were followed until 2018 (mean follow-up 11.9 years).

Of the 2,452 patients for whom data were available, 291 had an initial diagnosis of primary melanoma in situ (MIS), and 2,161 were diagnosed with invasive cutaneous melanoma.

The median age at diagnosis was 65 years, ranging from 16 to 98 years. Nearly two-thirds of the patients (61%) were men.

Among all patients, 858 (35%) had melanoma detected during a routine skin check, 1,148 (47%) detected the lesions themselves, 293 (12%) had incidentally-detected melanomas, and 153 (6%) had lesions detected by other, unspecified means.

In analyses adjusted for age and sex, the investigators found that compared with patient-detected lesions, melanomas detected during routine skin checks were associated with a 59% lower risk for melanoma-specific mortality (subhazard ratio, 0.41, P < .001) and 36% lower risk for all-cause mortality (hazard ratio, 0.64, P < .001).

But after adjustment for melanoma prognostic factors such as ulceration and mitotic rate, the association of skin check–detected lesions with melanoma-specific mortality was no longer statistically significant. The association with lower all-cause mortality was somewhat attenuated, but remained significant (HR, 0.75, P = .006).

Factors associated with a higher likelihood of melanoma detection during routine skin checks included males vs. females, a history of melanoma, having multiple moles, age 50 or older, and residence in a urban vs. rural areas.
 

Screen with care

In their editorial, Dr. Halpern and Dr. Marchetti propose methods for screening that find a balance between detection of significant disease and potential harm to patients from unnecessary biopsy or invasive procedures.

“For many lesions, we could use serial photography and dermoscopy in lieu of tissue biopsy to identify those that are truly dynamic outliers and likely to be of greater risk to the patient. An analogous approach is already used for the management of small lung nodules detected incidentally and through screening,” they wrote.

They also raise the issue of potential overdiagnosis and overtreatment of MIS, and recommend an approach similar to that used for some older patients with prostate cancer, for example.

“The consequences of MIS treatment differ greatly based on the type, anatomic location, and size of the tumor; these factors should be considered in shared decision-making with patients. Options such as active surveillance and topical therapy should be discussed, particularly in those with significant comorbidities or advanced age,” they wrote.

The study was supported by grants from the Australian National Health and Medical Research Council, Cancer Institute New South Wales, and the New South Wales State Government. Dr. Watts, Dr. Halpern, Dr. Marchetti, and Dr. Demehri reported having no conflicts of interest.

In Australia, where they know a thing or two about skin cancer, authors of a large prospective population-based cohort study found that melanomas detected through routine skin checks were associated with lower all-cause mortality, but not melanoma-specific mortality.

Among patients in New South Wales diagnosed with melanoma in 2006 or 2007 and followed for nearly 12 years, there was no significant difference in the rate of melanoma-specific death associated with either patient-detected or clinician-detected melanomas in an analysis adjusted for prognostic factors.

Although melanomas found through routine clinician-performed skin checks were associated with a 25% reduction in all-cause mortality compared with patient-detected lesions (P = .006), this difference may have been due to the tendency of health-oriented patients to participate in screening programs.

The study – one of the largest to date and performed in an area of the world where there is a high incidence of skin cancer and high degree of public awareness of the risks of too much sun exposure – could not fully answer its central question: Can routine skin checks, a proxy for skin cancer screening, significantly decrease the incidence of melanoma-related deaths?

“A large randomized clinical trial is needed to provide definitive evidence that screening for skin cancer reduces melanoma-specific and all-cause mortality among people invited (vs. not invited) to screen, but there are concerns about feasibility. Our findings could be used to estimate the sample size for a future trial,” wrote Caroline G. Watts, PhD, of the University of Sydney, Australia, and colleagues. Their study was published online Nov. 3 in JAMA Dermatology.

In an editorial accompanying the study, dermatologists Allan C. Halpern, MD, and Michael A. Marchetti, MD, of Memorial Sloan-Kettering Cancer Center in New York, point out that “there has never been a randomized clinical trial of melanoma screening, nor is there one currently ongoing or planned. Even if one were to be initiated immediately, such a trial would take well over a decade to conduct.

“Thus, for the foreseeable future, our approaches to melanoma secondary prevention need to be based on indirect evidence and our understanding of biology and epidemiology,” they wrote.

A dermatology researcher who was not involved in the study said that while it doesn’t solve the screening conundrum, it does highlight the value of public health campaigns.

“The way that I interpret the data, especially the fact that it’s coming out of Australia, is that if education about self-examination is done properly, that can also be effective in terms of detecting these skin cancers,” said Shawn Demehri, MD, PhD, principal investigator at the Cutaneous Biology Research Center at Massachusetts General Hospital, Boston. Dr. Demehri was asked to comment on the study.

“I would argue that the results would probably have been different if the study had been conducted in the U.S. rather than Australia, because the education in terms of self-examination is much more advanced and organized in Australia,” he said in an interview.

Study details

To assess melanoma-specific and all-cause mortality associated with melanoma identified through routine skin checks, Dr. Watts and colleagues followed patients diagnosed with melanoma from October 2006 through October 2007 who were enrolled in the Melanoma Patterns of Care Study. The patients were followed until 2018 (mean follow-up 11.9 years).

Of the 2,452 patients for whom data were available, 291 had an initial diagnosis of primary melanoma in situ (MIS), and 2,161 were diagnosed with invasive cutaneous melanoma.

The median age at diagnosis was 65 years, ranging from 16 to 98 years. Nearly two-thirds of the patients (61%) were men.

Among all patients, 858 (35%) had melanoma detected during a routine skin check, 1,148 (47%) detected the lesions themselves, 293 (12%) had incidentally-detected melanomas, and 153 (6%) had lesions detected by other, unspecified means.

In analyses adjusted for age and sex, the investigators found that compared with patient-detected lesions, melanomas detected during routine skin checks were associated with a 59% lower risk for melanoma-specific mortality (subhazard ratio, 0.41, P < .001) and 36% lower risk for all-cause mortality (hazard ratio, 0.64, P < .001).

But after adjustment for melanoma prognostic factors such as ulceration and mitotic rate, the association of skin check–detected lesions with melanoma-specific mortality was no longer statistically significant. The association with lower all-cause mortality was somewhat attenuated, but remained significant (HR, 0.75, P = .006).

Factors associated with a higher likelihood of melanoma detection during routine skin checks included males vs. females, a history of melanoma, having multiple moles, age 50 or older, and residence in a urban vs. rural areas.
 

Screen with care

In their editorial, Dr. Halpern and Dr. Marchetti propose methods for screening that find a balance between detection of significant disease and potential harm to patients from unnecessary biopsy or invasive procedures.

“For many lesions, we could use serial photography and dermoscopy in lieu of tissue biopsy to identify those that are truly dynamic outliers and likely to be of greater risk to the patient. An analogous approach is already used for the management of small lung nodules detected incidentally and through screening,” they wrote.

They also raise the issue of potential overdiagnosis and overtreatment of MIS, and recommend an approach similar to that used for some older patients with prostate cancer, for example.

“The consequences of MIS treatment differ greatly based on the type, anatomic location, and size of the tumor; these factors should be considered in shared decision-making with patients. Options such as active surveillance and topical therapy should be discussed, particularly in those with significant comorbidities or advanced age,” they wrote.

The study was supported by grants from the Australian National Health and Medical Research Council, Cancer Institute New South Wales, and the New South Wales State Government. Dr. Watts, Dr. Halpern, Dr. Marchetti, and Dr. Demehri reported having no conflicts of interest.

In patients with metastatic urothelial carcinoma, immunotherapy, antibody drug conjugates and targeted agents are being added to the potential treatment options for this incurable condition, which has a limited life expectancy. This is according to a review of the recent therapeutic advances and ongoing clinical trials in metastatic urothelial carcinoma.

“Survival in the metastatic setting is 12-15 months with cisplatin-based combination chemotherapy, but only 3-6 months if left untreated,” wrote Srikala S. Sridhar, MD, of the University of Toronto, and colleagues. Their report is in Therapeutic Advances in Medical Oncology. “More recently, with the advent of immunotherapy, antibody-drug conjugates, and targeted agents, the treatment landscape has changed significantly, with overall survival now approaching two years.”

Both the incidence and mortality from bladder cancer have risen over the past few decades. Around 5% of patients are metastatic at presentation, but nearly half of patients with muscle-invasive bladder cancer will eventually relapse and develop metastatic disease.

For first-line treatment in metastatic urothelial carcinoma, cisplatin-based chemotherapy remains the preferred option with response rates up to 72%, but durability is an issue with most patients experiencing disease progression. In patients with locally advanced or metastatic disease, who are not eligible for cisplatin-based chemotherapy and whose tumors express PD-L1, or patients who are not eligible for any platinum-based regimen regardless of PD-L1 status, the immune checkpoint inhibitors atezolizumab and pembrolizumab have received accelerated Food and Drug administration approval. More recently, pembrolizumab gained full FDA approval for use in patients not eligible to receive platinum-based chemotherapy.

While phase 3 studies are evaluating chemotherapy combined with atezolizumab or pembrolizumab, the results have not been promising. Moreover, the decreased survival observed in the immunotherapy-alone arms of these trials led the FDA to issue a warning that single agent immunotherapy should be used only in patients who are not eligible for cisplatin-based therapy and have PD-L1 expression, or in those not eligible for any platinum-based regimens regardless of PD-L1 expression.

“More intensive treatment in metastatic urothelial carcinoma is not always better,” the authors wrote. “Some of the reasons for this could be that chemotherapy and immunotherapy are targeting a similar population of cells, or that chemotherapy and immunotherapy are antagonistic on some level.”

Maintenance strategies are considered standard of care for other advanced solid tumors. In patients with bladder cancer without disease progression after a first line platinum-based chemotherapy, maintenance avelumab, an anti PD-L1, has shown an overall survival of 21.4 months versus 14.3 months with best supportive care, a finding that the authors described as “practice changing.” Meanwhile, a separate trial showed increased progression-free survival with maintenance pembrolizumab, but no increased overall survival.

For second-line treatment, immunotherapy is currently the standard of care in patients with disease progression during or after platinum-based chemotherapy. While the efficiency of five anti PD-1 and PD-L1 antibodies has been reported in the second-line setting, pembrolizumab is the only immune checkpoint inhibitor to receive full FDA approval. Atezolizumab, nivolumab, avelumab, and durvalumab have received accelerated approval.

“In urothelial carcinomas, PD-1 appears to have an advantage over anti PD-L1 in the second-line setting, but in the maintenance setting, it seems to be the opposite,” the authors wrote.

Erdafitinib is the only fibroblast growth factor receptor (FGFR) inhibitor approved for locally advanced or metastatic urothelial carcinoma, progressing on platinum-based chemotherapy. The oral potent tyrosine kinase inhibitor of FGFR 1-4 is approved for use only in patients with susceptible FGFR3 gene mutations or FGFR2/3 gene fusions. Despite being approved for second-line treatment, erdafitinib is used mainly in third-line treatment after progression on immunotherapy. 

The antibody drug conjugates sacituzumab govitecan and enfortumab vedotin, which have gained accelerated FDA approval, provide other options for patients with metastatic urothelial carcinoma resistant to chemotherapy and checkpoint inhibitors. As these antibody drug conjugates have different mechanisms of action and toxicity profiles, they could be used in the same patient throughout the disease course, but further research is needed. Meanwhile, many chemotherapy options, including docetaxel, gemcitabine, ifosfamide, and pemetrexed, have been tested in metastatic urothelial carcinoma with some response after platinum-based treatment.

“A number of studies evaluating promising therapeutic strategies are still ongoing and will hopefully provide information for some important unanswered questions and further guide treatment sequencing in advanced urothelial carcinoma,” the authors wrote.

They declared that there are no conflicts of interest.

In patients with metastatic urothelial carcinoma, immunotherapy, antibody drug conjugates and targeted agents are being added to the potential treatment options for this incurable condition, which has a limited life expectancy. This is according to a review of the recent therapeutic advances and ongoing clinical trials in metastatic urothelial carcinoma.

“Survival in the metastatic setting is 12-15 months with cisplatin-based combination chemotherapy, but only 3-6 months if left untreated,” wrote Srikala S. Sridhar, MD, of the University of Toronto, and colleagues. Their report is in Therapeutic Advances in Medical Oncology. “More recently, with the advent of immunotherapy, antibody-drug conjugates, and targeted agents, the treatment landscape has changed significantly, with overall survival now approaching two years.”

Both the incidence and mortality from bladder cancer have risen over the past few decades. Around 5% of patients are metastatic at presentation, but nearly half of patients with muscle-invasive bladder cancer will eventually relapse and develop metastatic disease.

For first-line treatment in metastatic urothelial carcinoma, cisplatin-based chemotherapy remains the preferred option with response rates up to 72%, but durability is an issue with most patients experiencing disease progression. In patients with locally advanced or metastatic disease, who are not eligible for cisplatin-based chemotherapy and whose tumors express PD-L1, or patients who are not eligible for any platinum-based regimen regardless of PD-L1 status, the immune checkpoint inhibitors atezolizumab and pembrolizumab have received accelerated Food and Drug administration approval. More recently, pembrolizumab gained full FDA approval for use in patients not eligible to receive platinum-based chemotherapy.

While phase 3 studies are evaluating chemotherapy combined with atezolizumab or pembrolizumab, the results have not been promising. Moreover, the decreased survival observed in the immunotherapy-alone arms of these trials led the FDA to issue a warning that single agent immunotherapy should be used only in patients who are not eligible for cisplatin-based therapy and have PD-L1 expression, or in those not eligible for any platinum-based regimens regardless of PD-L1 expression.

“More intensive treatment in metastatic urothelial carcinoma is not always better,” the authors wrote. “Some of the reasons for this could be that chemotherapy and immunotherapy are targeting a similar population of cells, or that chemotherapy and immunotherapy are antagonistic on some level.”

Maintenance strategies are considered standard of care for other advanced solid tumors. In patients with bladder cancer without disease progression after a first line platinum-based chemotherapy, maintenance avelumab, an anti PD-L1, has shown an overall survival of 21.4 months versus 14.3 months with best supportive care, a finding that the authors described as “practice changing.” Meanwhile, a separate trial showed increased progression-free survival with maintenance pembrolizumab, but no increased overall survival.

For second-line treatment, immunotherapy is currently the standard of care in patients with disease progression during or after platinum-based chemotherapy. While the efficiency of five anti PD-1 and PD-L1 antibodies has been reported in the second-line setting, pembrolizumab is the only immune checkpoint inhibitor to receive full FDA approval. Atezolizumab, nivolumab, avelumab, and durvalumab have received accelerated approval.

“In urothelial carcinomas, PD-1 appears to have an advantage over anti PD-L1 in the second-line setting, but in the maintenance setting, it seems to be the opposite,” the authors wrote.

Erdafitinib is the only fibroblast growth factor receptor (FGFR) inhibitor approved for locally advanced or metastatic urothelial carcinoma, progressing on platinum-based chemotherapy. The oral potent tyrosine kinase inhibitor of FGFR 1-4 is approved for use only in patients with susceptible FGFR3 gene mutations or FGFR2/3 gene fusions. Despite being approved for second-line treatment, erdafitinib is used mainly in third-line treatment after progression on immunotherapy. 

The antibody drug conjugates sacituzumab govitecan and enfortumab vedotin, which have gained accelerated FDA approval, provide other options for patients with metastatic urothelial carcinoma resistant to chemotherapy and checkpoint inhibitors. As these antibody drug conjugates have different mechanisms of action and toxicity profiles, they could be used in the same patient throughout the disease course, but further research is needed. Meanwhile, many chemotherapy options, including docetaxel, gemcitabine, ifosfamide, and pemetrexed, have been tested in metastatic urothelial carcinoma with some response after platinum-based treatment.

“A number of studies evaluating promising therapeutic strategies are still ongoing and will hopefully provide information for some important unanswered questions and further guide treatment sequencing in advanced urothelial carcinoma,” the authors wrote.

They declared that there are no conflicts of interest.

In patients with metastatic urothelial carcinoma, immunotherapy, antibody drug conjugates and targeted agents are being added to the potential treatment options for this incurable condition, which has a limited life expectancy. This is according to a review of the recent therapeutic advances and ongoing clinical trials in metastatic urothelial carcinoma.

“Survival in the metastatic setting is 12-15 months with cisplatin-based combination chemotherapy, but only 3-6 months if left untreated,” wrote Srikala S. Sridhar, MD, of the University of Toronto, and colleagues. Their report is in Therapeutic Advances in Medical Oncology. “More recently, with the advent of immunotherapy, antibody-drug conjugates, and targeted agents, the treatment landscape has changed significantly, with overall survival now approaching two years.”

Both the incidence and mortality from bladder cancer have risen over the past few decades. Around 5% of patients are metastatic at presentation, but nearly half of patients with muscle-invasive bladder cancer will eventually relapse and develop metastatic disease.

For first-line treatment in metastatic urothelial carcinoma, cisplatin-based chemotherapy remains the preferred option with response rates up to 72%, but durability is an issue with most patients experiencing disease progression. In patients with locally advanced or metastatic disease, who are not eligible for cisplatin-based chemotherapy and whose tumors express PD-L1, or patients who are not eligible for any platinum-based regimen regardless of PD-L1 status, the immune checkpoint inhibitors atezolizumab and pembrolizumab have received accelerated Food and Drug administration approval. More recently, pembrolizumab gained full FDA approval for use in patients not eligible to receive platinum-based chemotherapy.

While phase 3 studies are evaluating chemotherapy combined with atezolizumab or pembrolizumab, the results have not been promising. Moreover, the decreased survival observed in the immunotherapy-alone arms of these trials led the FDA to issue a warning that single agent immunotherapy should be used only in patients who are not eligible for cisplatin-based therapy and have PD-L1 expression, or in those not eligible for any platinum-based regimens regardless of PD-L1 expression.

“More intensive treatment in metastatic urothelial carcinoma is not always better,” the authors wrote. “Some of the reasons for this could be that chemotherapy and immunotherapy are targeting a similar population of cells, or that chemotherapy and immunotherapy are antagonistic on some level.”

Maintenance strategies are considered standard of care for other advanced solid tumors. In patients with bladder cancer without disease progression after a first line platinum-based chemotherapy, maintenance avelumab, an anti PD-L1, has shown an overall survival of 21.4 months versus 14.3 months with best supportive care, a finding that the authors described as “practice changing.” Meanwhile, a separate trial showed increased progression-free survival with maintenance pembrolizumab, but no increased overall survival.

For second-line treatment, immunotherapy is currently the standard of care in patients with disease progression during or after platinum-based chemotherapy. While the efficiency of five anti PD-1 and PD-L1 antibodies has been reported in the second-line setting, pembrolizumab is the only immune checkpoint inhibitor to receive full FDA approval. Atezolizumab, nivolumab, avelumab, and durvalumab have received accelerated approval.

“In urothelial carcinomas, PD-1 appears to have an advantage over anti PD-L1 in the second-line setting, but in the maintenance setting, it seems to be the opposite,” the authors wrote.

Erdafitinib is the only fibroblast growth factor receptor (FGFR) inhibitor approved for locally advanced or metastatic urothelial carcinoma, progressing on platinum-based chemotherapy. The oral potent tyrosine kinase inhibitor of FGFR 1-4 is approved for use only in patients with susceptible FGFR3 gene mutations or FGFR2/3 gene fusions. Despite being approved for second-line treatment, erdafitinib is used mainly in third-line treatment after progression on immunotherapy. 

The antibody drug conjugates sacituzumab govitecan and enfortumab vedotin, which have gained accelerated FDA approval, provide other options for patients with metastatic urothelial carcinoma resistant to chemotherapy and checkpoint inhibitors. As these antibody drug conjugates have different mechanisms of action and toxicity profiles, they could be used in the same patient throughout the disease course, but further research is needed. Meanwhile, many chemotherapy options, including docetaxel, gemcitabine, ifosfamide, and pemetrexed, have been tested in metastatic urothelial carcinoma with some response after platinum-based treatment.

“A number of studies evaluating promising therapeutic strategies are still ongoing and will hopefully provide information for some important unanswered questions and further guide treatment sequencing in advanced urothelial carcinoma,” the authors wrote.

They declared that there are no conflicts of interest.

U.S. regulators have made it easier for physicians, patients, and researchers to determine the status of cancer medicines cleared for sale based on limited evidence, including a public list detailing cases where accelerated approvals have been rescinded for lack of evidence.

On Oct. 29, the Food and Drug Administration posted new websites detailing the status of oncology medicines given these special clearances:

• Ongoing | Cancer Accelerated Approvals 
• Verified Clinical Benefit | Cancer Accelerated Approvals
• Withdrawn | Cancer Accelerated Approvals

The FDA’s cancer center also has created a web page called Project Confirm to provide more information on the way it uses accelerated approvals.

There has been increased concern about medicines cleared by accelerated approvals in recent years, culminating in an uproar over the controversial June approval of aducanumab (Aduhelm) for Alzheimer’s disease. This drew more attention to a debate already underway about how much data supports some of the indications for some cancer drugs.

Federal and state officials and advisers are putting more pressure on pharmaceutical companies to prove that medicines that are put on the market through accelerated approval do deliver meaningful benefits for patients.

In addition, earlier this month two of the top health advisers in Barack Obama’s administration proposed a new model through which Medicare could reduce payments for certain cancer drugs cleared through accelerated approvals – and even cut off reimbursements in cases where companies fail to deliver confirmatory evidence for expected benefits.

This “Pay for Drugs That Work Model” was proposed by Richard Frank, PhD, and Ezekiel Emanuel, MD, PhD, in a recent JAMA article. In their view, the FDA’s accelerated drug approval process allows for too many delays in obtaining answers as to whether medicines cleared this way provide expected benefits.

“The proposed Pay for Drugs That Work model could test a modified approach for incentivizing rapid completion of confirmatory trials to inform clinicians and patients about the true risks and benefits of new drugs and improve the value for money of cancer drugs that receive accelerated approval,” they wrote.
 

Excel files, regular updates

For the FDA, accelerated approvals require balancing an estimated potential benefit for people facing serious diseases (for example, cancer) against serious risks, including potentially exposing patients to costly, toxic drugs that will later be shown not to work for their conditions.

For many years, there has been significant pressure on the FDA to lean toward speedier approvals, with members of Congress, advocacy groups, and drugmakers advocating for broad use of surrogate data in deciding on clearances. The FDA posts biannual reports on its website that highlight how quickly approvals have been granted. But these biannual reports don’t provide much information on the status of accelerated-approval drugs, other than to say if they have been given full approval or withdrawn.

The newly created websites from the FDA’s oncology division appear to reflect growing public interest in knowing what standards the agency sets for confirmatory trials and what deadlines companies face to deliver evidence of significant benefit for their drugs.

The new sortable websites also include details on trials and have links to Excel files which will help researchers and others seeking to track patterns with accelerated approvals. The FDA said in an interview that it intends to update these sites when there are developments with accelerated approvals for cancer drugs, such as new clearances of this type, conversions to regular approvals, and withdrawn approvals.

Julia Beaver, MD, chief of medical oncology at the FDA’s Oncology Center of Excellence, and acting deputy director of the Office of Oncologic Diseases of the FDA’s Center for Drug Evaluation and Research, described the new websites as part of a “commitment to preserve the integrity” of the accelerated approval program.

“These new web pages will make information on our accelerated approvals more transparent,” Dr. Beaver said in an email to this news organization.

The FDA has been able to speed many medicines to market and clear additional uses for drugs already sold through the program, giving people earlier access in many cases to critical medicines, Dr. Beaver said.

More than 165 oncology indications have received accelerated approval, with almost half converted to regular approval in a median of 3 years. Less than 10% of these indications were withdrawn, Dr. Beaver said.

“Of those accelerated approvals that were converted to regular approval, many demonstrated survival advantages to patients with several types of cancer or provided meaningful therapeutic options where none previously existed,” she said.

However, Dr. Beaver also has made public the FDA’s concerns with what she and Richard Pazdur, MD, director of the Oncology Center of Excellence, have described as “dangling” accelerated approvals. 

These are cases where the required trials did not end up confirming benefit for a medicine, yet the manufacturer did not move to withdraw an accelerated approval. The FDA’s cancer center has already announced that it is doing an “industry-wide evaluation of accelerated approvals in oncology in which confirmatory trials did not confirm clinical benefit.”

This stems in part from what can be called the FDA’s “growing pains” in its efforts to manage the rapidly changing landscape for these immunotherapy checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials for an Oncologic Drugs Advisory Committee (ODAC) meeting last April on dangling accelerated approvals.

A newly posted chart on withdrawn oncology accelerated approvals, posted by the FDA’s cancer division, makes it clear that the pace of these rescinded clearances has picked up. The chart lists a total 14 withdrawn indications of oncology accelerated approvals.

Six of these withdrawals happened this year.

There were two withdrawals in 2020, including the December withdrawal of nivolumab, (Opdivo) for a form of metastatic lung cancer.

Then there was a significant gap, with no withdrawals going back to 2013 (when there was one). There were two withdrawals in 2012 and three in 2011.

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

U.S. regulators have made it easier for physicians, patients, and researchers to determine the status of cancer medicines cleared for sale based on limited evidence, including a public list detailing cases where accelerated approvals have been rescinded for lack of evidence.

On Oct. 29, the Food and Drug Administration posted new websites detailing the status of oncology medicines given these special clearances:

• Ongoing | Cancer Accelerated Approvals 
• Verified Clinical Benefit | Cancer Accelerated Approvals
• Withdrawn | Cancer Accelerated Approvals

The FDA’s cancer center also has created a web page called Project Confirm to provide more information on the way it uses accelerated approvals.

There has been increased concern about medicines cleared by accelerated approvals in recent years, culminating in an uproar over the controversial June approval of aducanumab (Aduhelm) for Alzheimer’s disease. This drew more attention to a debate already underway about how much data supports some of the indications for some cancer drugs.

Federal and state officials and advisers are putting more pressure on pharmaceutical companies to prove that medicines that are put on the market through accelerated approval do deliver meaningful benefits for patients.

In addition, earlier this month two of the top health advisers in Barack Obama’s administration proposed a new model through which Medicare could reduce payments for certain cancer drugs cleared through accelerated approvals – and even cut off reimbursements in cases where companies fail to deliver confirmatory evidence for expected benefits.

This “Pay for Drugs That Work Model” was proposed by Richard Frank, PhD, and Ezekiel Emanuel, MD, PhD, in a recent JAMA article. In their view, the FDA’s accelerated drug approval process allows for too many delays in obtaining answers as to whether medicines cleared this way provide expected benefits.

“The proposed Pay for Drugs That Work model could test a modified approach for incentivizing rapid completion of confirmatory trials to inform clinicians and patients about the true risks and benefits of new drugs and improve the value for money of cancer drugs that receive accelerated approval,” they wrote.
 

Excel files, regular updates

For the FDA, accelerated approvals require balancing an estimated potential benefit for people facing serious diseases (for example, cancer) against serious risks, including potentially exposing patients to costly, toxic drugs that will later be shown not to work for their conditions.

For many years, there has been significant pressure on the FDA to lean toward speedier approvals, with members of Congress, advocacy groups, and drugmakers advocating for broad use of surrogate data in deciding on clearances. The FDA posts biannual reports on its website that highlight how quickly approvals have been granted. But these biannual reports don’t provide much information on the status of accelerated-approval drugs, other than to say if they have been given full approval or withdrawn.

The newly created websites from the FDA’s oncology division appear to reflect growing public interest in knowing what standards the agency sets for confirmatory trials and what deadlines companies face to deliver evidence of significant benefit for their drugs.

The new sortable websites also include details on trials and have links to Excel files which will help researchers and others seeking to track patterns with accelerated approvals. The FDA said in an interview that it intends to update these sites when there are developments with accelerated approvals for cancer drugs, such as new clearances of this type, conversions to regular approvals, and withdrawn approvals.

Julia Beaver, MD, chief of medical oncology at the FDA’s Oncology Center of Excellence, and acting deputy director of the Office of Oncologic Diseases of the FDA’s Center for Drug Evaluation and Research, described the new websites as part of a “commitment to preserve the integrity” of the accelerated approval program.

“These new web pages will make information on our accelerated approvals more transparent,” Dr. Beaver said in an email to this news organization.

The FDA has been able to speed many medicines to market and clear additional uses for drugs already sold through the program, giving people earlier access in many cases to critical medicines, Dr. Beaver said.

More than 165 oncology indications have received accelerated approval, with almost half converted to regular approval in a median of 3 years. Less than 10% of these indications were withdrawn, Dr. Beaver said.

“Of those accelerated approvals that were converted to regular approval, many demonstrated survival advantages to patients with several types of cancer or provided meaningful therapeutic options where none previously existed,” she said.

However, Dr. Beaver also has made public the FDA’s concerns with what she and Richard Pazdur, MD, director of the Oncology Center of Excellence, have described as “dangling” accelerated approvals. 

These are cases where the required trials did not end up confirming benefit for a medicine, yet the manufacturer did not move to withdraw an accelerated approval. The FDA’s cancer center has already announced that it is doing an “industry-wide evaluation of accelerated approvals in oncology in which confirmatory trials did not confirm clinical benefit.”

This stems in part from what can be called the FDA’s “growing pains” in its efforts to manage the rapidly changing landscape for these immunotherapy checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials for an Oncologic Drugs Advisory Committee (ODAC) meeting last April on dangling accelerated approvals.

A newly posted chart on withdrawn oncology accelerated approvals, posted by the FDA’s cancer division, makes it clear that the pace of these rescinded clearances has picked up. The chart lists a total 14 withdrawn indications of oncology accelerated approvals.

Six of these withdrawals happened this year.

There were two withdrawals in 2020, including the December withdrawal of nivolumab, (Opdivo) for a form of metastatic lung cancer.

Then there was a significant gap, with no withdrawals going back to 2013 (when there was one). There were two withdrawals in 2012 and three in 2011.

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

U.S. regulators have made it easier for physicians, patients, and researchers to determine the status of cancer medicines cleared for sale based on limited evidence, including a public list detailing cases where accelerated approvals have been rescinded for lack of evidence.

On Oct. 29, the Food and Drug Administration posted new websites detailing the status of oncology medicines given these special clearances:

• Ongoing | Cancer Accelerated Approvals 
• Verified Clinical Benefit | Cancer Accelerated Approvals
• Withdrawn | Cancer Accelerated Approvals

The FDA’s cancer center also has created a web page called Project Confirm to provide more information on the way it uses accelerated approvals.

There has been increased concern about medicines cleared by accelerated approvals in recent years, culminating in an uproar over the controversial June approval of aducanumab (Aduhelm) for Alzheimer’s disease. This drew more attention to a debate already underway about how much data supports some of the indications for some cancer drugs.

Federal and state officials and advisers are putting more pressure on pharmaceutical companies to prove that medicines that are put on the market through accelerated approval do deliver meaningful benefits for patients.

In addition, earlier this month two of the top health advisers in Barack Obama’s administration proposed a new model through which Medicare could reduce payments for certain cancer drugs cleared through accelerated approvals – and even cut off reimbursements in cases where companies fail to deliver confirmatory evidence for expected benefits.

This “Pay for Drugs That Work Model” was proposed by Richard Frank, PhD, and Ezekiel Emanuel, MD, PhD, in a recent JAMA article. In their view, the FDA’s accelerated drug approval process allows for too many delays in obtaining answers as to whether medicines cleared this way provide expected benefits.

“The proposed Pay for Drugs That Work model could test a modified approach for incentivizing rapid completion of confirmatory trials to inform clinicians and patients about the true risks and benefits of new drugs and improve the value for money of cancer drugs that receive accelerated approval,” they wrote.
 

Excel files, regular updates

For the FDA, accelerated approvals require balancing an estimated potential benefit for people facing serious diseases (for example, cancer) against serious risks, including potentially exposing patients to costly, toxic drugs that will later be shown not to work for their conditions.

For many years, there has been significant pressure on the FDA to lean toward speedier approvals, with members of Congress, advocacy groups, and drugmakers advocating for broad use of surrogate data in deciding on clearances. The FDA posts biannual reports on its website that highlight how quickly approvals have been granted. But these biannual reports don’t provide much information on the status of accelerated-approval drugs, other than to say if they have been given full approval or withdrawn.

The newly created websites from the FDA’s oncology division appear to reflect growing public interest in knowing what standards the agency sets for confirmatory trials and what deadlines companies face to deliver evidence of significant benefit for their drugs.

The new sortable websites also include details on trials and have links to Excel files which will help researchers and others seeking to track patterns with accelerated approvals. The FDA said in an interview that it intends to update these sites when there are developments with accelerated approvals for cancer drugs, such as new clearances of this type, conversions to regular approvals, and withdrawn approvals.

Julia Beaver, MD, chief of medical oncology at the FDA’s Oncology Center of Excellence, and acting deputy director of the Office of Oncologic Diseases of the FDA’s Center for Drug Evaluation and Research, described the new websites as part of a “commitment to preserve the integrity” of the accelerated approval program.

“These new web pages will make information on our accelerated approvals more transparent,” Dr. Beaver said in an email to this news organization.

The FDA has been able to speed many medicines to market and clear additional uses for drugs already sold through the program, giving people earlier access in many cases to critical medicines, Dr. Beaver said.

More than 165 oncology indications have received accelerated approval, with almost half converted to regular approval in a median of 3 years. Less than 10% of these indications were withdrawn, Dr. Beaver said.

“Of those accelerated approvals that were converted to regular approval, many demonstrated survival advantages to patients with several types of cancer or provided meaningful therapeutic options where none previously existed,” she said.

However, Dr. Beaver also has made public the FDA’s concerns with what she and Richard Pazdur, MD, director of the Oncology Center of Excellence, have described as “dangling” accelerated approvals. 

These are cases where the required trials did not end up confirming benefit for a medicine, yet the manufacturer did not move to withdraw an accelerated approval. The FDA’s cancer center has already announced that it is doing an “industry-wide evaluation of accelerated approvals in oncology in which confirmatory trials did not confirm clinical benefit.”

This stems in part from what can be called the FDA’s “growing pains” in its efforts to manage the rapidly changing landscape for these immunotherapy checkpoint inhibitors. This field of medicine has experienced an “unprecedented level of drug development” in recent years, FDA officials said in briefing materials for an Oncologic Drugs Advisory Committee (ODAC) meeting last April on dangling accelerated approvals.

A newly posted chart on withdrawn oncology accelerated approvals, posted by the FDA’s cancer division, makes it clear that the pace of these rescinded clearances has picked up. The chart lists a total 14 withdrawn indications of oncology accelerated approvals.

Six of these withdrawals happened this year.

There were two withdrawals in 2020, including the December withdrawal of nivolumab, (Opdivo) for a form of metastatic lung cancer.

Then there was a significant gap, with no withdrawals going back to 2013 (when there was one). There were two withdrawals in 2012 and three in 2011.

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