Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

The art of yoga has been practiced for thousands of years and most recently has been incorporated into medical practice as a holistic approach to healing. Veterans return from war with a unique set of physical and mental limitations, and for them a unique healing strategy must be established.

One piece of the healing puzzle is alternative therapy, and to accommodate wounded warriors, Warriors at Ease was established. With resources available at http://warriorsatease.com, Warriors at Ease “brings the healing power of yoga and meditation to military communities around the world, especially those affected by combat stress, PTSD [posttraumatic stress disorder], and trauma.”

This website offers information on earning certification to teach yoga and meditation in military communities, including why, how, and where. Webinars and residential trainings are offered on such topics as Fundamentals, Teaching Trauma-Sensitive Meditation, and Advanced Skills for Addressing Combat-Related Issues. A certified instructor can also be found through the zip code search function.

The art of yoga has been practiced for thousands of years and most recently has been incorporated into medical practice as a holistic approach to healing. Veterans return from war with a unique set of physical and mental limitations, and for them a unique healing strategy must be established.

One piece of the healing puzzle is alternative therapy, and to accommodate wounded warriors, Warriors at Ease was established. With resources available at http://warriorsatease.com, Warriors at Ease “brings the healing power of yoga and meditation to military communities around the world, especially those affected by combat stress, PTSD [posttraumatic stress disorder], and trauma.”

This website offers information on earning certification to teach yoga and meditation in military communities, including why, how, and where. Webinars and residential trainings are offered on such topics as Fundamentals, Teaching Trauma-Sensitive Meditation, and Advanced Skills for Addressing Combat-Related Issues. A certified instructor can also be found through the zip code search function.

The art of yoga has been practiced for thousands of years and most recently has been incorporated into medical practice as a holistic approach to healing. Veterans return from war with a unique set of physical and mental limitations, and for them a unique healing strategy must be established.

One piece of the healing puzzle is alternative therapy, and to accommodate wounded warriors, Warriors at Ease was established. With resources available at http://warriorsatease.com, Warriors at Ease “brings the healing power of yoga and meditation to military communities around the world, especially those affected by combat stress, PTSD [posttraumatic stress disorder], and trauma.”

This website offers information on earning certification to teach yoga and meditation in military communities, including why, how, and where. Webinars and residential trainings are offered on such topics as Fundamentals, Teaching Trauma-Sensitive Meditation, and Advanced Skills for Addressing Combat-Related Issues. A certified instructor can also be found through the zip code search function.

Prescription medications

Credit: CDC

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) as prophylaxis for deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.

Apixaban is already FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The latest approval is supported by data from 3 trials comprising the ADVANCE clinical trial program.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

The prescribing information for apixaban includes a boxed warning detailing the increased risk of stroke in patients with nonvalvular atrial fibrillation who discontinue the drug without adequate continuous anticoagulation.

The boxed warning also states that, in patients undergoing spinal epidural anesthesia or spinal puncture, apixaban poses an increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis.

The risk of these events may be increased by the use of indwelling epidural catheters for the administration of analgesia or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Healthcare professionals should monitor patients for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.

For more information on adverse events and contraindications, see the full prescribing information for apixaban. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

Prescription medications

Credit: CDC

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) as prophylaxis for deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.

Apixaban is already FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The latest approval is supported by data from 3 trials comprising the ADVANCE clinical trial program.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

The prescribing information for apixaban includes a boxed warning detailing the increased risk of stroke in patients with nonvalvular atrial fibrillation who discontinue the drug without adequate continuous anticoagulation.

The boxed warning also states that, in patients undergoing spinal epidural anesthesia or spinal puncture, apixaban poses an increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis.

The risk of these events may be increased by the use of indwelling epidural catheters for the administration of analgesia or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Healthcare professionals should monitor patients for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.

For more information on adverse events and contraindications, see the full prescribing information for apixaban. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

Prescription medications

Credit: CDC

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) as prophylaxis for deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.

Apixaban is already FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The latest approval is supported by data from 3 trials comprising the ADVANCE clinical trial program.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

The prescribing information for apixaban includes a boxed warning detailing the increased risk of stroke in patients with nonvalvular atrial fibrillation who discontinue the drug without adequate continuous anticoagulation.

The boxed warning also states that, in patients undergoing spinal epidural anesthesia or spinal puncture, apixaban poses an increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis.

The risk of these events may be increased by the use of indwelling epidural catheters for the administration of analgesia or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs, platelet aggregation inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Healthcare professionals should monitor patients for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.

For more information on adverse events and contraindications, see the full prescribing information for apixaban. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”

A sickled red blood cell

(right) and a normal one

Credit: Betty Pace

The American Thoracic Society has developed clinical practice guidelines to help clinicians identify and manage patients with sickle cell disease who are at an increased risk for mortality from pulmonary hypertension.

“With the development of new treatments, many patients with sickle cell disease are now surviving long enough to develop pulmonary hypertension, with an estimated prevalence of 6% to 11%,” said guideline author Elizabeth S. Klings, MD, of the Boston University School of Medicine in Massachusetts.

“Although pulmonary hypertension and elevated tricuspid jet velocity [TRV, an indicator of pulmonary hypertension measured by echocardiography] are both associated with an increased mortality risk, there is currently no standardized approach for identifying and managing these patients.”

So Dr Klings and her colleagues decided to offer some guidance. Their recommendations for managing these patients appear in the American Journal of Respiratory and Critical Care Medicine.

The guideline authors point out that clinicians can evaluate patient mortality noninvasively by measuring the TRV with Doppler echocardiography or by measuring serum N-terminal pro–brain natriuretic peptide (NT-pro-BNP) levels.

An invasive method is taking direct hemodynamic measurements via right heart catheterization (RHC).

An increased risk for mortality is defined as a TRV ≥ 2.5 m/second, an NT-pro-BNP level ≥ 160 pg/mL, or RHC-confirmed pulmonary hypertension.

Patients who meet these criteria should receive hydroxyurea. Patients who do not respond to or are not candidates for hydroxyurea treatment can be considered for chronic transfusion therapy.

For patients with RHC-confirmed pulmonary hypertension, venous thromboembolism, and no additional risk factors for hemorrhage, the guidelines recommend indefinite anticoagulant therapy rather than a limited duration of therapy.

Patients with elevated TRV alone or elevated NT-pro-BNP alone should not be treated with targeted pulmonary arterial hypertension therapies, including prostanoid, endothelin receptor antagonist, and phosphodiesterase-5 inhibitor therapy.

Most patients with RHC-confirmed pulmonary hypertension should not receive targeted therapy.

For select patents with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms, the guidelines suggest a trial of either a prostanoid or an endothelin receptor antagonist.

Patients with RHC-confirmed marked elevation of pulmonary vascular resistance, normal pulmonary capillary wedge pressure, and related symptoms should not receive phosphodiesterase-5 inhibitor therapy as first-line treatment.

“Most of our current recommendations are limited by a lack of large-scale clinical trials in this population,” Dr Klings noted. “We need to continue our research efforts into this disease and its management to understand what the optimal treatment regimen for these patients is.”

“Management of patients with sickle cell disease with an increased risk for mortality and pulmonary hypertension will ultimately be a collaborative effort, including adult and pediatric pulmonologists, cardiologists, and hematologists.”

Study Overview

Objective. To compare weight loss among patients using self-directed methods vs. those participating in a multi-component Weight Watchers (WW) program where participants could access content in person, online, or using mobile applications.

Study design. Randomized trial funded by Weight Watchers International.

Setting and participants. A market research firm was used to identify potentially eligible persons in a Northeastern U.S. metro area. Of those who responded to emails describing the project (n = 336), 292 were deemed eligible based on having a body mass index (BMI) between 27 and 40 kg/m2, not currently being on a diet or taking weight-loss medications, and not reporting any medical conditions that could interfere with their participation in a weight loss program (eg, thyroid disease, cardiac disease, pregnancy, cancer).

Eligible participants who consented were computer randomized to 1 of 2 arms. The intervention arm participants were provided with free access to the WW program, and those in the control group received only informational materials. The WW program consisted of putting participants on a food and physical activity plan and providing them with group support, as well as teaching them skills to help promote behavior change in a series of 24 weekly in-person meetings. In addition to in-person meetings, information and support could be accessed online and using mobile devices that allowed the formation of an online community with message board capabilities. Participants were followed for a 24-week period with weigh-ins at baseline and 3 and 6 months.

Main outcome measures. The primary outcomes in this study were the difference between the groups in BMI or weight at 3 and 6 months. BMI was measured at in-person study visits. Repeated-measures ANOVA was used to compare the groups, both on persons who completed the trial and also with an intention-to-treat sub-analysis where the last available measure was carried forward to the 6-month mark for those who were lost to follow-up.

Secondary outcomes included evaluation of the impact of mode (in person, online, or mobile device) and frequency of access of the WW program on BMI change. Participants were categorized as having high attendance if they came to more than 50% of the in-person sessions, or low attendance if they came to fewer. They were categorized as frequent or infrequent users of the web or mobile interfaces dichotomized around self-reported use of at least 2 times per week. One-way ANOVA was used to compare weight losses according to the type and frequency of access amongst WW participants. Logistic regression was used to evaluate the impact of the exposure of high vs. low attendance on dichotomized weight loss outcomes at the 5% and 10% level.

Results. There were no significant differences between the WW (n = 147) and self-help (n = 145) arms with respect to baseline characteristics. The sample was predominantly female (89.8%), middle aged (mean (SD) 46.5 (10.5) yr), and white (90.7%). The mean BMI at baseline was in the class I (BMI ≥ 30 but < 35) obesity category (mean (SD) 33.0 (3.6) kg/m²). Of the total sample of 292 initial participants, 257 (88%) completed the 6-month trial.

Both primary and intention-to-treat analyses revealed a greater degree of weight loss (or BMI reduction) among WW versus self-help participants. Specifically, the WW participants lost a mean of 4.6 kg at 6 months, and the self-help participants lost a mean of 0.6 kg. When the outcome was dichotomized around probability of achieving at least a 5% or 10% weight loss, WW participants were far more likely to achieve both outcomes (5% loss: odds ratio [OR] 8.0, 95% CI 3.9-16.2; 10% loss: OR 8.8, 95% CI 3.0-25.9). The most rapid weight loss period for WW participants was clearly in the first 3 months of the trial, after which weight loss slowed considerably.

Among the WW participants, when individuals were compared according to how many modes of access they used (0, 1, 2 or 3), participants using all 3 modes had significantly greater weight loss (P < 0.01) than all others. Mean weight loss was approximately equal between persons who used 1 or 2 modes of access. Overall weight loss at 6 months varied from a mean of 2 kg in the “0 components group” to approximately 4.5 kg in the 1 or 2 components group, to almost 10 kg in the 3 components group. Frequency of contact (in person or electronically) also corresponded to the amount of weight lost.

On average, the WW group attended fewer than 50% of the available 24 weekly sessions (mean (sd) 9.1 (7.3) sessions attended). However, those who came to at least 12 sessions were far more likely to achieve 5% and/or 10% weight losses than those who attended fewer sessions (5% loss: OR 11.2, 95% CI 4.6-26.9; 10% loss: OR 15.5, 95% CI 5.6-43.2). Frequent (vs. less frequent) use of the online website and mobile devices were also associated with statistically significant improvements in weight loss; however, the magnitude of effect for these modalities was much smaller than for the frequency of in person visits. Frequent website users, for example, had an OR of 3.1 (95% CI 1.5-6.5) for achieving a 5% weight loss compared with less frequent users, and frequent mobile app users had an OR of 2.0 (95% CI 1.0-4.1) for achieving that 5% loss compared with nonfrequent users. Stepwise regression models supported this pattern, indicating that the greatest predictor of weight loss was attendance at in-person meetings, accounting for 29.4% of the variance in 6-month weight losses.

Conclusion. Participants randomized to participate in a commercially available weight loss program with access to in-person, online, and mobile support lost significantly more weight than those who attempted to lose weight via self-help.

Commentary

With the prevalence of obesity in the United States now exceeding 30% [1], primary care physicians are routinely asked to counsel patients on the dangers of excess weight or to provide advice on how best to lose weight. In light of time demands, lack of expertise in weight loss management, and, historically, lack of reimbursement for obesity-specific care, primary care practices have not traditionally been ideal locations for provision of weight management services [2]. Behavioral approaches to weight loss require relatively high-frequency contact for a period of at least several months in order to provide the greatest chance of patients successfully losing weight [3]. In fact, many behavior change programs are modeled after the Diabetes Prevention Program, which relied on 24 weekly face-to-face visits (followed by every other week visits) in order for participants to achieve even modest weight losses (5%-10% of starting weight) [4]. To integrate such a program into most primary care practices has not been widely feasible, however. For physicians practicing in large academic centers, there may be specialized weight clinics where patients can be referred to receive such care, but for most community physicians and those practicing in smaller organizations, finding the right place to refer patients interested in weight loss via diet and exercise can be difficult. As a result of this and other factors, many patients elect to self-manage their own weight loss attempts with limited success.

One option for primary care physicians who do not feel comfortable or able to oversee the behavioral weight loss attempts of their patients is to consider referral to a commercial weight loss program, such as the one examined in this study. There are several such programs throughout the United States, and, as pointed out by these authors, the WW program itself has funded previous research studies, including one randomized trial that showed modestly superior weight loss outcomes amongst its participants, as compared to self-directed therapy [5]. A 2005 systematic review of commercially available weight loss programs concluded that there was limited evidence to support the use of such programs, particularly those that were internet-based [6]. The current study builds upon existing work by evaluating the impact of the newer, 3-modality (in-person, online, and mobile) WW intervention. Such an evaluation is important given the present-day near ubiquity of smartphone and internet access for most middle-aged US adults.

This randomized controlled trial tested this newer-modality WW program against self-directed behavioral weight loss therapy and found that participants achieved greater weight loss with the WW program. The randomized design was a strength of the study, as was the use of intention-to-treat analysis (although loss to follow-up was relatively minimal). The findings of improved weight loss amongst WW participants are not novel, however, they underscore that this program is a viable option for patients who are financially able (and motivated) to commit to such an endeavor. In terms of evaluating the added value of internet-based and mobile applications to the traditional in-person visit, although the authors note that participants who used all 3 modalities lost the most weight, it was in-person visit attendance that accounted for the greatest share of weight loss success. Thus, the internet and mobile app access methods ought not be considered as replacements for the in-person visits but rather as supplements, which does not support their use as an alternative for busy people who don’t have time to participate in person. Additionally, as noted by the authors in their discussion section, the number of components accessed by participants could merely be a marker for level of motivation—thus it was higher motivation levels perhaps driving the weight loss, rather than an additive effect of the 3 modalities. Because motivation to change was not assessed in this study, it is difficult to know what role this factor played in weight loss for the WW participants.

Unfortunately, the trial did not follow participants past the end of the intervention period to determine whether the weight changes were maintained once WW participation was complete. At least 1 prior study evaluating this program, however, showed that despite some weight regain, participants in this commercial program do maintain a larger degree of weight loss than their self-management counterparts at up to 2 years after randomization [6].

The generalizability of these study findings may be somewhat limited based on the demographics of trial participants. Nearly all of them were non-Hispanic white women, which is not too surprising given the nature of the intervention. It does raise an important question, however, about whether similar programs are available for (or of interest to) male and/or non-white patients. While it is possible that the geographic area they sampled from for the study was simply predominated by non-Hispanic white residents, no data were provided about the sampling pool, so one can only assume a somewhat biased response based on the nature of the intervention. Additionally, the patients in this study were, on average, class I obesity patients and lost only a moderate amount of weight. Furthermore, medically complex persons were excluded from participating. Providers caring for patients with more severe degrees of obesity and/or those who have multiple poorly controlled medical conditions should carefully consider whether such patients are appropriate for commercial programs before referring them, and should calibrate their patients’ expectations of the degree and durability of weight loss that will be obtained through such programs.

The participants in this trial received the WW intervention free of charge, which would obviously not be the case for real-world patients enrolling in commercial weight loss programs. Cost, therefore, might be an important barrier to assess prior to referring any patients to such programs. However, the idea of paying for the intervention might paradoxically improve outcomes—the concept of having “skin in the game,” or feeling more compelled to participate in something you have paid for, a popular concept in behavioral economics, could come into play in this context. Paying for WW might “frame” the service as desirable, making people more likely to attend, as opposed to essentially being paid to do it (as in this study), which might have framed it more as a chore, or something undesirable [7].

Finally, given the possible upcoming shift in provider reimbursement for obesity-related counseling heralded by 2012 Centers for Medicare and Medicaid coverage changes [8], providers may become increasingly comfortable managing their patients’ weight loss attempts in the primary care setting, decreasing the need for outsourcing to commercial programs in the near future.

Applications for Clinical Practice

Commercial weight loss programs with combined modalities of in-person, online, and mobile support can provide an alternative to self-directed weight loss, particularly for patients in the demographic groups targeted by such programs. Clinicians who do not feel able to provide such care in the clinical context, or who do not have referral access to clinical weight loss programs might consider referral to commercial programs for some patients. Appropriate selection of patients is important, however, and physicians should consider factors such as financial means, desired amount of weight loss, and medical complexity before recommending such a program. Furthermore, the evidence surrounding long-term maintenance of weight loss after participation in such programs is weak.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To compare weight loss among patients using self-directed methods vs. those participating in a multi-component Weight Watchers (WW) program where participants could access content in person, online, or using mobile applications.

Study design. Randomized trial funded by Weight Watchers International.

Setting and participants. A market research firm was used to identify potentially eligible persons in a Northeastern U.S. metro area. Of those who responded to emails describing the project (n = 336), 292 were deemed eligible based on having a body mass index (BMI) between 27 and 40 kg/m2, not currently being on a diet or taking weight-loss medications, and not reporting any medical conditions that could interfere with their participation in a weight loss program (eg, thyroid disease, cardiac disease, pregnancy, cancer).

Eligible participants who consented were computer randomized to 1 of 2 arms. The intervention arm participants were provided with free access to the WW program, and those in the control group received only informational materials. The WW program consisted of putting participants on a food and physical activity plan and providing them with group support, as well as teaching them skills to help promote behavior change in a series of 24 weekly in-person meetings. In addition to in-person meetings, information and support could be accessed online and using mobile devices that allowed the formation of an online community with message board capabilities. Participants were followed for a 24-week period with weigh-ins at baseline and 3 and 6 months.

Main outcome measures. The primary outcomes in this study were the difference between the groups in BMI or weight at 3 and 6 months. BMI was measured at in-person study visits. Repeated-measures ANOVA was used to compare the groups, both on persons who completed the trial and also with an intention-to-treat sub-analysis where the last available measure was carried forward to the 6-month mark for those who were lost to follow-up.

Secondary outcomes included evaluation of the impact of mode (in person, online, or mobile device) and frequency of access of the WW program on BMI change. Participants were categorized as having high attendance if they came to more than 50% of the in-person sessions, or low attendance if they came to fewer. They were categorized as frequent or infrequent users of the web or mobile interfaces dichotomized around self-reported use of at least 2 times per week. One-way ANOVA was used to compare weight losses according to the type and frequency of access amongst WW participants. Logistic regression was used to evaluate the impact of the exposure of high vs. low attendance on dichotomized weight loss outcomes at the 5% and 10% level.

Results. There were no significant differences between the WW (n = 147) and self-help (n = 145) arms with respect to baseline characteristics. The sample was predominantly female (89.8%), middle aged (mean (SD) 46.5 (10.5) yr), and white (90.7%). The mean BMI at baseline was in the class I (BMI ≥ 30 but < 35) obesity category (mean (SD) 33.0 (3.6) kg/m²). Of the total sample of 292 initial participants, 257 (88%) completed the 6-month trial.

Both primary and intention-to-treat analyses revealed a greater degree of weight loss (or BMI reduction) among WW versus self-help participants. Specifically, the WW participants lost a mean of 4.6 kg at 6 months, and the self-help participants lost a mean of 0.6 kg. When the outcome was dichotomized around probability of achieving at least a 5% or 10% weight loss, WW participants were far more likely to achieve both outcomes (5% loss: odds ratio [OR] 8.0, 95% CI 3.9-16.2; 10% loss: OR 8.8, 95% CI 3.0-25.9). The most rapid weight loss period for WW participants was clearly in the first 3 months of the trial, after which weight loss slowed considerably.

Among the WW participants, when individuals were compared according to how many modes of access they used (0, 1, 2 or 3), participants using all 3 modes had significantly greater weight loss (P < 0.01) than all others. Mean weight loss was approximately equal between persons who used 1 or 2 modes of access. Overall weight loss at 6 months varied from a mean of 2 kg in the “0 components group” to approximately 4.5 kg in the 1 or 2 components group, to almost 10 kg in the 3 components group. Frequency of contact (in person or electronically) also corresponded to the amount of weight lost.

On average, the WW group attended fewer than 50% of the available 24 weekly sessions (mean (sd) 9.1 (7.3) sessions attended). However, those who came to at least 12 sessions were far more likely to achieve 5% and/or 10% weight losses than those who attended fewer sessions (5% loss: OR 11.2, 95% CI 4.6-26.9; 10% loss: OR 15.5, 95% CI 5.6-43.2). Frequent (vs. less frequent) use of the online website and mobile devices were also associated with statistically significant improvements in weight loss; however, the magnitude of effect for these modalities was much smaller than for the frequency of in person visits. Frequent website users, for example, had an OR of 3.1 (95% CI 1.5-6.5) for achieving a 5% weight loss compared with less frequent users, and frequent mobile app users had an OR of 2.0 (95% CI 1.0-4.1) for achieving that 5% loss compared with nonfrequent users. Stepwise regression models supported this pattern, indicating that the greatest predictor of weight loss was attendance at in-person meetings, accounting for 29.4% of the variance in 6-month weight losses.

Conclusion. Participants randomized to participate in a commercially available weight loss program with access to in-person, online, and mobile support lost significantly more weight than those who attempted to lose weight via self-help.

Commentary

With the prevalence of obesity in the United States now exceeding 30% [1], primary care physicians are routinely asked to counsel patients on the dangers of excess weight or to provide advice on how best to lose weight. In light of time demands, lack of expertise in weight loss management, and, historically, lack of reimbursement for obesity-specific care, primary care practices have not traditionally been ideal locations for provision of weight management services [2]. Behavioral approaches to weight loss require relatively high-frequency contact for a period of at least several months in order to provide the greatest chance of patients successfully losing weight [3]. In fact, many behavior change programs are modeled after the Diabetes Prevention Program, which relied on 24 weekly face-to-face visits (followed by every other week visits) in order for participants to achieve even modest weight losses (5%-10% of starting weight) [4]. To integrate such a program into most primary care practices has not been widely feasible, however. For physicians practicing in large academic centers, there may be specialized weight clinics where patients can be referred to receive such care, but for most community physicians and those practicing in smaller organizations, finding the right place to refer patients interested in weight loss via diet and exercise can be difficult. As a result of this and other factors, many patients elect to self-manage their own weight loss attempts with limited success.

One option for primary care physicians who do not feel comfortable or able to oversee the behavioral weight loss attempts of their patients is to consider referral to a commercial weight loss program, such as the one examined in this study. There are several such programs throughout the United States, and, as pointed out by these authors, the WW program itself has funded previous research studies, including one randomized trial that showed modestly superior weight loss outcomes amongst its participants, as compared to self-directed therapy [5]. A 2005 systematic review of commercially available weight loss programs concluded that there was limited evidence to support the use of such programs, particularly those that were internet-based [6]. The current study builds upon existing work by evaluating the impact of the newer, 3-modality (in-person, online, and mobile) WW intervention. Such an evaluation is important given the present-day near ubiquity of smartphone and internet access for most middle-aged US adults.

This randomized controlled trial tested this newer-modality WW program against self-directed behavioral weight loss therapy and found that participants achieved greater weight loss with the WW program. The randomized design was a strength of the study, as was the use of intention-to-treat analysis (although loss to follow-up was relatively minimal). The findings of improved weight loss amongst WW participants are not novel, however, they underscore that this program is a viable option for patients who are financially able (and motivated) to commit to such an endeavor. In terms of evaluating the added value of internet-based and mobile applications to the traditional in-person visit, although the authors note that participants who used all 3 modalities lost the most weight, it was in-person visit attendance that accounted for the greatest share of weight loss success. Thus, the internet and mobile app access methods ought not be considered as replacements for the in-person visits but rather as supplements, which does not support their use as an alternative for busy people who don’t have time to participate in person. Additionally, as noted by the authors in their discussion section, the number of components accessed by participants could merely be a marker for level of motivation—thus it was higher motivation levels perhaps driving the weight loss, rather than an additive effect of the 3 modalities. Because motivation to change was not assessed in this study, it is difficult to know what role this factor played in weight loss for the WW participants.

Unfortunately, the trial did not follow participants past the end of the intervention period to determine whether the weight changes were maintained once WW participation was complete. At least 1 prior study evaluating this program, however, showed that despite some weight regain, participants in this commercial program do maintain a larger degree of weight loss than their self-management counterparts at up to 2 years after randomization [6].

The generalizability of these study findings may be somewhat limited based on the demographics of trial participants. Nearly all of them were non-Hispanic white women, which is not too surprising given the nature of the intervention. It does raise an important question, however, about whether similar programs are available for (or of interest to) male and/or non-white patients. While it is possible that the geographic area they sampled from for the study was simply predominated by non-Hispanic white residents, no data were provided about the sampling pool, so one can only assume a somewhat biased response based on the nature of the intervention. Additionally, the patients in this study were, on average, class I obesity patients and lost only a moderate amount of weight. Furthermore, medically complex persons were excluded from participating. Providers caring for patients with more severe degrees of obesity and/or those who have multiple poorly controlled medical conditions should carefully consider whether such patients are appropriate for commercial programs before referring them, and should calibrate their patients’ expectations of the degree and durability of weight loss that will be obtained through such programs.

The participants in this trial received the WW intervention free of charge, which would obviously not be the case for real-world patients enrolling in commercial weight loss programs. Cost, therefore, might be an important barrier to assess prior to referring any patients to such programs. However, the idea of paying for the intervention might paradoxically improve outcomes—the concept of having “skin in the game,” or feeling more compelled to participate in something you have paid for, a popular concept in behavioral economics, could come into play in this context. Paying for WW might “frame” the service as desirable, making people more likely to attend, as opposed to essentially being paid to do it (as in this study), which might have framed it more as a chore, or something undesirable [7].

Finally, given the possible upcoming shift in provider reimbursement for obesity-related counseling heralded by 2012 Centers for Medicare and Medicaid coverage changes [8], providers may become increasingly comfortable managing their patients’ weight loss attempts in the primary care setting, decreasing the need for outsourcing to commercial programs in the near future.

Applications for Clinical Practice

Commercial weight loss programs with combined modalities of in-person, online, and mobile support can provide an alternative to self-directed weight loss, particularly for patients in the demographic groups targeted by such programs. Clinicians who do not feel able to provide such care in the clinical context, or who do not have referral access to clinical weight loss programs might consider referral to commercial programs for some patients. Appropriate selection of patients is important, however, and physicians should consider factors such as financial means, desired amount of weight loss, and medical complexity before recommending such a program. Furthermore, the evidence surrounding long-term maintenance of weight loss after participation in such programs is weak.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To compare weight loss among patients using self-directed methods vs. those participating in a multi-component Weight Watchers (WW) program where participants could access content in person, online, or using mobile applications.

Study design. Randomized trial funded by Weight Watchers International.

Setting and participants. A market research firm was used to identify potentially eligible persons in a Northeastern U.S. metro area. Of those who responded to emails describing the project (n = 336), 292 were deemed eligible based on having a body mass index (BMI) between 27 and 40 kg/m2, not currently being on a diet or taking weight-loss medications, and not reporting any medical conditions that could interfere with their participation in a weight loss program (eg, thyroid disease, cardiac disease, pregnancy, cancer).

Eligible participants who consented were computer randomized to 1 of 2 arms. The intervention arm participants were provided with free access to the WW program, and those in the control group received only informational materials. The WW program consisted of putting participants on a food and physical activity plan and providing them with group support, as well as teaching them skills to help promote behavior change in a series of 24 weekly in-person meetings. In addition to in-person meetings, information and support could be accessed online and using mobile devices that allowed the formation of an online community with message board capabilities. Participants were followed for a 24-week period with weigh-ins at baseline and 3 and 6 months.

Main outcome measures. The primary outcomes in this study were the difference between the groups in BMI or weight at 3 and 6 months. BMI was measured at in-person study visits. Repeated-measures ANOVA was used to compare the groups, both on persons who completed the trial and also with an intention-to-treat sub-analysis where the last available measure was carried forward to the 6-month mark for those who were lost to follow-up.

Secondary outcomes included evaluation of the impact of mode (in person, online, or mobile device) and frequency of access of the WW program on BMI change. Participants were categorized as having high attendance if they came to more than 50% of the in-person sessions, or low attendance if they came to fewer. They were categorized as frequent or infrequent users of the web or mobile interfaces dichotomized around self-reported use of at least 2 times per week. One-way ANOVA was used to compare weight losses according to the type and frequency of access amongst WW participants. Logistic regression was used to evaluate the impact of the exposure of high vs. low attendance on dichotomized weight loss outcomes at the 5% and 10% level.

Results. There were no significant differences between the WW (n = 147) and self-help (n = 145) arms with respect to baseline characteristics. The sample was predominantly female (89.8%), middle aged (mean (SD) 46.5 (10.5) yr), and white (90.7%). The mean BMI at baseline was in the class I (BMI ≥ 30 but < 35) obesity category (mean (SD) 33.0 (3.6) kg/m²). Of the total sample of 292 initial participants, 257 (88%) completed the 6-month trial.

Both primary and intention-to-treat analyses revealed a greater degree of weight loss (or BMI reduction) among WW versus self-help participants. Specifically, the WW participants lost a mean of 4.6 kg at 6 months, and the self-help participants lost a mean of 0.6 kg. When the outcome was dichotomized around probability of achieving at least a 5% or 10% weight loss, WW participants were far more likely to achieve both outcomes (5% loss: odds ratio [OR] 8.0, 95% CI 3.9-16.2; 10% loss: OR 8.8, 95% CI 3.0-25.9). The most rapid weight loss period for WW participants was clearly in the first 3 months of the trial, after which weight loss slowed considerably.

Among the WW participants, when individuals were compared according to how many modes of access they used (0, 1, 2 or 3), participants using all 3 modes had significantly greater weight loss (P < 0.01) than all others. Mean weight loss was approximately equal between persons who used 1 or 2 modes of access. Overall weight loss at 6 months varied from a mean of 2 kg in the “0 components group” to approximately 4.5 kg in the 1 or 2 components group, to almost 10 kg in the 3 components group. Frequency of contact (in person or electronically) also corresponded to the amount of weight lost.

On average, the WW group attended fewer than 50% of the available 24 weekly sessions (mean (sd) 9.1 (7.3) sessions attended). However, those who came to at least 12 sessions were far more likely to achieve 5% and/or 10% weight losses than those who attended fewer sessions (5% loss: OR 11.2, 95% CI 4.6-26.9; 10% loss: OR 15.5, 95% CI 5.6-43.2). Frequent (vs. less frequent) use of the online website and mobile devices were also associated with statistically significant improvements in weight loss; however, the magnitude of effect for these modalities was much smaller than for the frequency of in person visits. Frequent website users, for example, had an OR of 3.1 (95% CI 1.5-6.5) for achieving a 5% weight loss compared with less frequent users, and frequent mobile app users had an OR of 2.0 (95% CI 1.0-4.1) for achieving that 5% loss compared with nonfrequent users. Stepwise regression models supported this pattern, indicating that the greatest predictor of weight loss was attendance at in-person meetings, accounting for 29.4% of the variance in 6-month weight losses.

Conclusion. Participants randomized to participate in a commercially available weight loss program with access to in-person, online, and mobile support lost significantly more weight than those who attempted to lose weight via self-help.

Commentary

With the prevalence of obesity in the United States now exceeding 30% [1], primary care physicians are routinely asked to counsel patients on the dangers of excess weight or to provide advice on how best to lose weight. In light of time demands, lack of expertise in weight loss management, and, historically, lack of reimbursement for obesity-specific care, primary care practices have not traditionally been ideal locations for provision of weight management services [2]. Behavioral approaches to weight loss require relatively high-frequency contact for a period of at least several months in order to provide the greatest chance of patients successfully losing weight [3]. In fact, many behavior change programs are modeled after the Diabetes Prevention Program, which relied on 24 weekly face-to-face visits (followed by every other week visits) in order for participants to achieve even modest weight losses (5%-10% of starting weight) [4]. To integrate such a program into most primary care practices has not been widely feasible, however. For physicians practicing in large academic centers, there may be specialized weight clinics where patients can be referred to receive such care, but for most community physicians and those practicing in smaller organizations, finding the right place to refer patients interested in weight loss via diet and exercise can be difficult. As a result of this and other factors, many patients elect to self-manage their own weight loss attempts with limited success.

One option for primary care physicians who do not feel comfortable or able to oversee the behavioral weight loss attempts of their patients is to consider referral to a commercial weight loss program, such as the one examined in this study. There are several such programs throughout the United States, and, as pointed out by these authors, the WW program itself has funded previous research studies, including one randomized trial that showed modestly superior weight loss outcomes amongst its participants, as compared to self-directed therapy [5]. A 2005 systematic review of commercially available weight loss programs concluded that there was limited evidence to support the use of such programs, particularly those that were internet-based [6]. The current study builds upon existing work by evaluating the impact of the newer, 3-modality (in-person, online, and mobile) WW intervention. Such an evaluation is important given the present-day near ubiquity of smartphone and internet access for most middle-aged US adults.

This randomized controlled trial tested this newer-modality WW program against self-directed behavioral weight loss therapy and found that participants achieved greater weight loss with the WW program. The randomized design was a strength of the study, as was the use of intention-to-treat analysis (although loss to follow-up was relatively minimal). The findings of improved weight loss amongst WW participants are not novel, however, they underscore that this program is a viable option for patients who are financially able (and motivated) to commit to such an endeavor. In terms of evaluating the added value of internet-based and mobile applications to the traditional in-person visit, although the authors note that participants who used all 3 modalities lost the most weight, it was in-person visit attendance that accounted for the greatest share of weight loss success. Thus, the internet and mobile app access methods ought not be considered as replacements for the in-person visits but rather as supplements, which does not support their use as an alternative for busy people who don’t have time to participate in person. Additionally, as noted by the authors in their discussion section, the number of components accessed by participants could merely be a marker for level of motivation—thus it was higher motivation levels perhaps driving the weight loss, rather than an additive effect of the 3 modalities. Because motivation to change was not assessed in this study, it is difficult to know what role this factor played in weight loss for the WW participants.

Unfortunately, the trial did not follow participants past the end of the intervention period to determine whether the weight changes were maintained once WW participation was complete. At least 1 prior study evaluating this program, however, showed that despite some weight regain, participants in this commercial program do maintain a larger degree of weight loss than their self-management counterparts at up to 2 years after randomization [6].

The generalizability of these study findings may be somewhat limited based on the demographics of trial participants. Nearly all of them were non-Hispanic white women, which is not too surprising given the nature of the intervention. It does raise an important question, however, about whether similar programs are available for (or of interest to) male and/or non-white patients. While it is possible that the geographic area they sampled from for the study was simply predominated by non-Hispanic white residents, no data were provided about the sampling pool, so one can only assume a somewhat biased response based on the nature of the intervention. Additionally, the patients in this study were, on average, class I obesity patients and lost only a moderate amount of weight. Furthermore, medically complex persons were excluded from participating. Providers caring for patients with more severe degrees of obesity and/or those who have multiple poorly controlled medical conditions should carefully consider whether such patients are appropriate for commercial programs before referring them, and should calibrate their patients’ expectations of the degree and durability of weight loss that will be obtained through such programs.

The participants in this trial received the WW intervention free of charge, which would obviously not be the case for real-world patients enrolling in commercial weight loss programs. Cost, therefore, might be an important barrier to assess prior to referring any patients to such programs. However, the idea of paying for the intervention might paradoxically improve outcomes—the concept of having “skin in the game,” or feeling more compelled to participate in something you have paid for, a popular concept in behavioral economics, could come into play in this context. Paying for WW might “frame” the service as desirable, making people more likely to attend, as opposed to essentially being paid to do it (as in this study), which might have framed it more as a chore, or something undesirable [7].

Finally, given the possible upcoming shift in provider reimbursement for obesity-related counseling heralded by 2012 Centers for Medicare and Medicaid coverage changes [8], providers may become increasingly comfortable managing their patients’ weight loss attempts in the primary care setting, decreasing the need for outsourcing to commercial programs in the near future.

Applications for Clinical Practice

Commercial weight loss programs with combined modalities of in-person, online, and mobile support can provide an alternative to self-directed weight loss, particularly for patients in the demographic groups targeted by such programs. Clinicians who do not feel able to provide such care in the clinical context, or who do not have referral access to clinical weight loss programs might consider referral to commercial programs for some patients. Appropriate selection of patients is important, however, and physicians should consider factors such as financial means, desired amount of weight loss, and medical complexity before recommending such a program. Furthermore, the evidence surrounding long-term maintenance of weight loss after participation in such programs is weak.

—Kristina Lewis, MD, MPH