Sharon Worcester

TAMPA – The ability to perform daily activities was not associated with the completion of chemotherapy without dose reduction or delay in elderly women with ovarian, primary peritoneal, or fallopian tube cancer.

However, reporting limited social activities was significantly associated with decreased chemotherapy tolerance, reported Dr. Vivian E. von Gruenigen at the annual meeting of the Society of Gynecologic Oncology.

In the study, 149 women with a mean age of 77 years received carboplatin and paclitaxel (regimen 1) and 59 women with a mean age of 83 years received carboplatin alone (regimen 2), either after primary surgery or as neoadjuvant therapy. Among the study participants, 82% in regimen 1 and 54% in regimen 2 completed four cycles of the chemotherapy without dose reduction or delay of more than 7 days, and 92% in regimen 1 and 75% in regimen 2 eventually completed all cycles. Treatment delays of 7 days or longer were required by 18% of women in regimen 1 and 46% of women in regimen 2.

After adjusting for chemotherapy received, age, and performance status at baseline, instrumental activities of daily living (IADL) scores were not significantly associated with the ability to complete all four cycles (P = .2); only the report of limited social activities was significantly associated with the ability to complete all four cycles (P = .034), Dr. von Gruenigen of Northeastern Ohio Universities, Rootstown, reported during a late-breaking abstract session.

Women in the study were aged 70 years or older with newly diagnosed, pathology-confirmed adenocarcinoma of the ovary, peritoneum, or fallopian tube. The treatment regimen used was decided upon by the treating physician and patient. Those in regimen 1 received carboplatin (AUC 5) and paclitaxel (135 mg/m² plus granulocyte colony-stimulating factor), every 3 weeks. Those in regimen 2 received carboplatin (AUC 5) every 3 weeks.

Geriatric assessment at baseline, before the third cycle, and after the fourth cycle included assessments of activities of daily living, quality of life, social activity, and social support. Since elderly women with primary ovarian cancer are less likely to be offered standard cancer treatments, develop higher levels of toxicity, and have lower survival rates, Dr. von Gruenigen and her colleagues aimed to determine whether the geriatric assessment was associated with the ability of elderly patients to complete platinum-based chemotherapy.

The study is the first large prospective U.S. study of elderly women with ovarian cancer, she said, noting that in addition to not being provided with appropriate care, few elderly women with ovarian cancer are included in clinical trials.

This is particularly concerning given that with the aging population, ovarian cancer rates will increase among the elderly, including among the "oldest of old."

"Chronological age does not automatically equal functional age. For healthcare professionals to apply study results to patients seen in clinical practice, we need to expand beyond measuring performance status as reported by us – the healthcare provider – and become more flexible with parameters of care," she said.

In the current study, patients in the regimen 1 and 2 groups were very different populations. In addition to being younger, having higher completion rates, and requiring fewer treatment delays, the women in the regimen 1 group were also fitter (11% vs. 37% had a performance status of 2-3), but the groups did not differ with respect to race or stage.

It is possible that physicians and patients are considering geriatric score and quality of life already when selecting treatment, Dr. von Gruenigen noted.

Regardless of therapy regimen, most patients eventually completed four cycles of chemotherapy, and quality of life improved over time – even in the very elderly.

A third "dose-dense" study arm involving weekly carboplatin and paclitaxel treatment was added in Aug. 13 after the initial two arms completed accrual. The new arm continues to accrue, and an analysis of pharmacokinetics is also ongoing.

Future study design may involve incorporating single-agent carboplatin into trials with the oldest patients.

"In summary, cautious management, appropriate treatment, and prevention of toxicity through interventions are needed in this elderly population," she said.

Dr. von Gruenigen reported having no disclosures.

TAMPA – The ability to perform daily activities was not associated with the completion of chemotherapy without dose reduction or delay in elderly women with ovarian, primary peritoneal, or fallopian tube cancer.

However, reporting limited social activities was significantly associated with decreased chemotherapy tolerance, reported Dr. Vivian E. von Gruenigen at the annual meeting of the Society of Gynecologic Oncology.

In the study, 149 women with a mean age of 77 years received carboplatin and paclitaxel (regimen 1) and 59 women with a mean age of 83 years received carboplatin alone (regimen 2), either after primary surgery or as neoadjuvant therapy. Among the study participants, 82% in regimen 1 and 54% in regimen 2 completed four cycles of the chemotherapy without dose reduction or delay of more than 7 days, and 92% in regimen 1 and 75% in regimen 2 eventually completed all cycles. Treatment delays of 7 days or longer were required by 18% of women in regimen 1 and 46% of women in regimen 2.

After adjusting for chemotherapy received, age, and performance status at baseline, instrumental activities of daily living (IADL) scores were not significantly associated with the ability to complete all four cycles (P = .2); only the report of limited social activities was significantly associated with the ability to complete all four cycles (P = .034), Dr. von Gruenigen of Northeastern Ohio Universities, Rootstown, reported during a late-breaking abstract session.

Women in the study were aged 70 years or older with newly diagnosed, pathology-confirmed adenocarcinoma of the ovary, peritoneum, or fallopian tube. The treatment regimen used was decided upon by the treating physician and patient. Those in regimen 1 received carboplatin (AUC 5) and paclitaxel (135 mg/m² plus granulocyte colony-stimulating factor), every 3 weeks. Those in regimen 2 received carboplatin (AUC 5) every 3 weeks.

Geriatric assessment at baseline, before the third cycle, and after the fourth cycle included assessments of activities of daily living, quality of life, social activity, and social support. Since elderly women with primary ovarian cancer are less likely to be offered standard cancer treatments, develop higher levels of toxicity, and have lower survival rates, Dr. von Gruenigen and her colleagues aimed to determine whether the geriatric assessment was associated with the ability of elderly patients to complete platinum-based chemotherapy.

The study is the first large prospective U.S. study of elderly women with ovarian cancer, she said, noting that in addition to not being provided with appropriate care, few elderly women with ovarian cancer are included in clinical trials.

This is particularly concerning given that with the aging population, ovarian cancer rates will increase among the elderly, including among the "oldest of old."

"Chronological age does not automatically equal functional age. For healthcare professionals to apply study results to patients seen in clinical practice, we need to expand beyond measuring performance status as reported by us – the healthcare provider – and become more flexible with parameters of care," she said.

In the current study, patients in the regimen 1 and 2 groups were very different populations. In addition to being younger, having higher completion rates, and requiring fewer treatment delays, the women in the regimen 1 group were also fitter (11% vs. 37% had a performance status of 2-3), but the groups did not differ with respect to race or stage.

It is possible that physicians and patients are considering geriatric score and quality of life already when selecting treatment, Dr. von Gruenigen noted.

Regardless of therapy regimen, most patients eventually completed four cycles of chemotherapy, and quality of life improved over time – even in the very elderly.

A third "dose-dense" study arm involving weekly carboplatin and paclitaxel treatment was added in Aug. 13 after the initial two arms completed accrual. The new arm continues to accrue, and an analysis of pharmacokinetics is also ongoing.

Future study design may involve incorporating single-agent carboplatin into trials with the oldest patients.

"In summary, cautious management, appropriate treatment, and prevention of toxicity through interventions are needed in this elderly population," she said.

Dr. von Gruenigen reported having no disclosures.

TAMPA – The ability to perform daily activities was not associated with the completion of chemotherapy without dose reduction or delay in elderly women with ovarian, primary peritoneal, or fallopian tube cancer.

However, reporting limited social activities was significantly associated with decreased chemotherapy tolerance, reported Dr. Vivian E. von Gruenigen at the annual meeting of the Society of Gynecologic Oncology.

In the study, 149 women with a mean age of 77 years received carboplatin and paclitaxel (regimen 1) and 59 women with a mean age of 83 years received carboplatin alone (regimen 2), either after primary surgery or as neoadjuvant therapy. Among the study participants, 82% in regimen 1 and 54% in regimen 2 completed four cycles of the chemotherapy without dose reduction or delay of more than 7 days, and 92% in regimen 1 and 75% in regimen 2 eventually completed all cycles. Treatment delays of 7 days or longer were required by 18% of women in regimen 1 and 46% of women in regimen 2.

After adjusting for chemotherapy received, age, and performance status at baseline, instrumental activities of daily living (IADL) scores were not significantly associated with the ability to complete all four cycles (P = .2); only the report of limited social activities was significantly associated with the ability to complete all four cycles (P = .034), Dr. von Gruenigen of Northeastern Ohio Universities, Rootstown, reported during a late-breaking abstract session.

Women in the study were aged 70 years or older with newly diagnosed, pathology-confirmed adenocarcinoma of the ovary, peritoneum, or fallopian tube. The treatment regimen used was decided upon by the treating physician and patient. Those in regimen 1 received carboplatin (AUC 5) and paclitaxel (135 mg/m² plus granulocyte colony-stimulating factor), every 3 weeks. Those in regimen 2 received carboplatin (AUC 5) every 3 weeks.

Geriatric assessment at baseline, before the third cycle, and after the fourth cycle included assessments of activities of daily living, quality of life, social activity, and social support. Since elderly women with primary ovarian cancer are less likely to be offered standard cancer treatments, develop higher levels of toxicity, and have lower survival rates, Dr. von Gruenigen and her colleagues aimed to determine whether the geriatric assessment was associated with the ability of elderly patients to complete platinum-based chemotherapy.

The study is the first large prospective U.S. study of elderly women with ovarian cancer, she said, noting that in addition to not being provided with appropriate care, few elderly women with ovarian cancer are included in clinical trials.

This is particularly concerning given that with the aging population, ovarian cancer rates will increase among the elderly, including among the "oldest of old."

"Chronological age does not automatically equal functional age. For healthcare professionals to apply study results to patients seen in clinical practice, we need to expand beyond measuring performance status as reported by us – the healthcare provider – and become more flexible with parameters of care," she said.

In the current study, patients in the regimen 1 and 2 groups were very different populations. In addition to being younger, having higher completion rates, and requiring fewer treatment delays, the women in the regimen 1 group were also fitter (11% vs. 37% had a performance status of 2-3), but the groups did not differ with respect to race or stage.

It is possible that physicians and patients are considering geriatric score and quality of life already when selecting treatment, Dr. von Gruenigen noted.

Regardless of therapy regimen, most patients eventually completed four cycles of chemotherapy, and quality of life improved over time – even in the very elderly.

A third "dose-dense" study arm involving weekly carboplatin and paclitaxel treatment was added in Aug. 13 after the initial two arms completed accrual. The new arm continues to accrue, and an analysis of pharmacokinetics is also ongoing.

Future study design may involve incorporating single-agent carboplatin into trials with the oldest patients.

"In summary, cautious management, appropriate treatment, and prevention of toxicity through interventions are needed in this elderly population," she said.

Dr. von Gruenigen reported having no disclosures.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.

The results of the exploration thus far suggest that is no longer the case.

A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.

In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.

The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.

"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.

Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.

The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.

In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.

"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."

The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.

"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.

Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.

The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.

"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.

Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.

This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.

"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."

A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.

Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.

Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.

Dr. Horn reported receiving grant or research support from Astellas Pharma, and consulting fees or honoraria from Boehringer Ingelheim. She has served as a scientific adviser for Bristol-Myers Squibb, Helix BioPharma, and Puma Biotechnology.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Tremendous progress has been made in recent years in the area of immunotherapy for the treatment of melanoma, and new agents and combinations continue to emerge, with some interesting response patterns, according to Dr. John A. Thompson.

Ipilimumab, for example, was added as a category 1 first-line systemic treatment option for melanoma to the 2012 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Melanoma. The change was based largely on two trials showing prolonged survival in patients treated with the monoclonal antibody.

In one study (the MDX010-20 trial), 650 patients with previously treated metastatic melanoma were randomized to receive either ipilimumab and a gp100 vaccine, ipilimumab alone, or vaccine alone. Those who received ipilimumab had better overall survival (10 months, 10.1 months, and 6.4 months, respectively). The hazard ratios for death were 0.68 and 0.66 for ipilimumab plus gp100 vs. gp100 alone, and for ipilimumab alone vs. gp100 alone, respectively (N. Engl. J. Med. 2010;363:711-23).

A plateau on the survival curve after about 2.5 years out to about 5 years suggests that ipilimumab-treated patients may have prolonged survival, said Dr. Thompson, codirector of the Seattle Cancer Care Alliance Melanoma Clinic and a member of the NCCN Guidelines Panel on Melanoma.

The second trial (CA184-024) was a randomized controlled trial of ipilimumab as first-line therapy in about 500 patients with metastatic melanoma who were randomized to receive ipilimumab and dacarbazine or placebo and dacarbazine. The ipilimumab group had significantly better overall survival (11.2 vs. 9.1 months), and survival was higher among the ipilimumab-treated patients at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%, and 3 years (20.8% vs. 12.2%), with a hazard ratio for death of 0.72 (N. Engl. J. Med. 2011;364:2517-26).

It is important to keep in mind that ipilimumab can be associated with an "interesting" response pattern, and that response may be delayed, Dr. Thompson noted at the annual conference of the National Comprehensive Cancer Network.

He described one case involving a patient with extensive disease considered to be nonresectable. After 12 weeks, having received four doses, the patient’s disease appeared to progress with swelling and an increase in the size of tumors.

However, without further therapy, the disease began to regress by week 14, and by 2 years it was completely eliminated, Dr. Thompson said.

"So we have to be patient and wait for the generation of an immune response to ipilimumab," he said.

In a more recent study, ipilimumab was shown to be useful for the treatment of uveal melanoma. The response rate in 39 patients with metastatic uveal melanoma who were included in the multicenter, retrospective study and who were treated with either 3 mg/kg (34 patients) or 10 mg/kg (5 patients), was 2.6% at 12 weeks, and the response plus stable disease rate was 46% (Cancer 2013;119:3687).

At week 23, the response rate was 2.6% and the response plus stable disease rate was 28.2%. One patient had a complete response, and 1 had a partial response at 100 weeks, for an immune-related response rate of 5.1%. The median overall survival from first dose was 9.6 months.

Treatment in all three trials was associated with significant toxicity, Dr. Thompson said.

"We have to be very careful in managing the potential for immune-related adverse events. I think everyone using this agent or similar immune-checkpoint inhibitor drugs should educate themselves about the types of toxicities and how they should be handled," he said, noting that useful information about the risks of serious immune-mediated adverse reactions, along with algorithms for managing them, can be found at www.yervoy.com/hcp/rems.

He also said he routinely gives patients a "wallet card" that lists potential side effects, which can be helpful for identifying drug-related effects and for providing valuable information during doctor or emergency department visits.

Toxicities generally involve the skin (pruritus, rash), the gastrointestinal tract (diarrhea, abdominal pain, blood in stool, bowel perforation, peritoneal signs), the liver (elevated aspartate aminotransferase/alanine aminotransferase or bilirubin), the endocrine system (fatigue, headache, mental status changes, hypotension, abnormal thyroid function tests/serum chemistries), and the neurological system (unilateral or bilateral weakness, sensory alterations, paresthesias).

Toxicities affecting the skin typically appear around the time of the second dose, and GI effects tend to begin around the time of the third dose, he said. The GI toxicities affect up to 25% of patients, can progress rapidly, and require active intervention; patients should be advised not to ignore symptoms or write them off as a result of "something they ate."

Endocrine toxicities tend to occur toward the end of treatment, and some can be subtle in onset and difficult to diagnose without careful monitoring.

In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.

For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.

As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.

"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.

Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.

A simplified treatment algorithm can be used to help select the appropriate treatment, he added.

For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).

For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.

The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.

Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.

As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.

A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.

"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.

Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

HOLLYWOOD, FLA. – Uridine triacetate, an orally bioavailable prodrug of uridine, is a safe and highly effective antidote to 5-fluorouracil overexposure, a series of case reports suggests.

Of 126 adults and 6 children with 5-fluorouracil (5-FU) poisoning who have been treated to date with the investigational agent, 127 (97%) experienced a full recovery, and 3% died as a result of the poisoning, Michael Bamat of Wellstat Therapeutics reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Only 4 of 40 historical controls (10%) recovered after receiving supportive care following 5-FU overexposure, and 36 (90%) died, Mr. Bamat said.

Treatment, which includes 20 10-g doses every 6 hours for adults and 20 6.2-g/m² doses every 6 hours for children, was initiated as soon as possible after 5-FU administration ceased. Treated patients experienced a reduction or absence of expected gastrointestinal, hematologic, and other toxicities associated with 5-FU poisoning, and more than half resumed chemotherapy within 3 weeks of the overexposure. Any adverse events attributable to treatment were mild.

The findings are notable because 5-FU is widely used to treat solid tumors – particularly gastrointestinal tumors – but its use is hampered by concerns about life-threatening or lethal toxicity that can occur as a result of pump programming errors, dosage miscalculations, or other errors related to intravenous infusion of the drug, Mr. Bamat explained.

In fact, about 275,000 cancer patients are treated with 5-FU each year, and the National Institutes of Health estimates that 8,250 of those develop serious toxic reactions, and that more than 1,300 die each year as a result of those reactions, he noted.

5-FU is typically given at or near the maximum tolerated dose over 1 to 4 days. In addition to administration accidents and errors, several other factors can contribute to overexposure, including dihydropyrimidine dehydrogenase (DPD) deficiency and other forms of impaired 5-FU elimination or hypersensitivity.

The majority of cases in this series were overexposed to 5-FU as a result of infusion pump misprogramming or malfunction, and were treated with uridine triacetate under a Food and Drug Administration–approved Expanded Access Protocol or emergency use regulatory provision in the United States, Europe and elsewhere, Mr. Bamat explained.

The agent is being developed "to solve the clinical problem of delivering uridine into the bloodstream," according to the Wellstat website. Although uridine is a specific pharmacologic antidote for 5-FU poisoning, its direct use is precluded by poor oral bioavailability and complications during infusion, he said.

However, uridine triacetate is efficiently absorbed and rapidly converted to circulating uridine by deacetylation; uridine triacetate improves uridine delivery four- to eightfold.

The investigational drug could "open the door to important new therapies for a number of diseases and conditions," according to Wellstat. In addition to 5-FU exposure, it could be used to enhance the efficacy of 5-FU for cancer treatment (by allowing for repeated exposure of tumor to unprecedented levels of intact 5-FU, thereby potentially increasing efficacy), and it might also have a role in the treatment of mitochondrial and neurodegenerative diseases. Additional clinical trials are planned.

Uridine triacetate is being developed by Wellstat Therapeutics. Mr. Bamat is vice president of research and development at Wellstat.

TAMPA – Women who undergo bariatric surgery to lose weight are about 70% less likely to develop uterine cancer than are obese women who do not undergo such surgery, according to findings from a large retrospective cohort study.

The risk reduction was even greater (81%) among those who maintained their weight loss after surgery. The findings suggest that obesity may be a modifiable risk factor for uterine cancer, reported Dr. Kristy Kay Ward of the Moores Cancer Center at the University of California, San Diego.

Of more than 7.4 million inpatient admissions among women aged 18 years or older who were registered in the University Health System Consortium dataset from Jan. 1, 2009, to June 1, 2013, 103,797 had a history of bariatric surgery, and 44,345 had a diagnosis of uterine malignancy. The overall rate of uterine malignancy was 599/100,000 patients among those without a history of bariatric surgery, and which was 2.8 times higher among obese vs. nonobese patients within this group (1,409 vs. 496 per 100,000).

The overall rate of uterine cancer among those with a history of bariatric surgery was 408/100,000, but the rate was 2.5 times higher among those with persistent obesity after surgery, compared with those who maintained weight loss after surgery (682/100,000 vs. 270/100,000), Dr. Ward said at the annual meeting of the Society of Gynecologic Oncology.

Compared with obese women without a history of bariatric surgery, the relative risk of uterine cancer was 0.29 for women with prior bariatric surgery, 0.19 for women with normal weight after surgery, and 0.48 for women who remained obese after surgery, so the overall risk reduction with surgery was 70%, the maximum risk reduction (for those with normal weight after surgery) was 81%, and the lowest reduction in risk (for those who had surgery but remained obese) was 52%, Dr. Ward said.

Though limited by the retrospective nature of the study and the fact that the data didn’t differentiate between types of bariatric surgery, the findings are notable, because about 50,000 women were diagnosed with uterine cancer in 2013, making it the most common cancer affecting female reproductive organs. Furthermore, endometrial cancer, which accounts for 95% of uterine cancers, is associated with obesity in about 50% of cases, she explained.

In fact, obese women are two- to fourfold more likely to develop endometrial cancer than are women of normal weight, she said.

The current findings suggest that "a history of bariatric surgery is associated with substantial and clinically significantly reduced risk of uterine malignancy," she said, adding: "Our previous work, in agreement with the findings of others, had indicated that the risk of uterine malignancy increases linearly with BMI [body mass index]. Along with the findings of the current study, this supports that obesity may be a modifiable risk factor related to the development of endometrial cancer."

The mechanism for the link between bariatric surgery and reduced uterine cancer risk remains unclear, but fat loss likely plays a role, as adiposity is known to increase endogenous estrogen circulation. The bariatric surgery itself may also "somehow be influencing the immune system and decreasing inflammation," thereby contributing to decreased cancer risk, Dr. Ward noted.

The findings suggest that weight reduction measures, including bariatric surgery in appropriate candidates, are vitally important in obese women, she said.

"Screening of patients, counseling patients about the dangers of obesity, and appropriate referral for bariatric surgery may have great impact on the overall health of this population," she concluded, adding that future research should examine the benefits of bariatric surgery for the reduction of cancer, including endometrial cancer.

Dr. Ward reported having no disclosures.

TAMPA – Women who undergo bariatric surgery to lose weight are about 70% less likely to develop uterine cancer than are obese women who do not undergo such surgery, according to findings from a large retrospective cohort study.

The risk reduction was even greater (81%) among those who maintained their weight loss after surgery. The findings suggest that obesity may be a modifiable risk factor for uterine cancer, reported Dr. Kristy Kay Ward of the Moores Cancer Center at the University of California, San Diego.

Of more than 7.4 million inpatient admissions among women aged 18 years or older who were registered in the University Health System Consortium dataset from Jan. 1, 2009, to June 1, 2013, 103,797 had a history of bariatric surgery, and 44,345 had a diagnosis of uterine malignancy. The overall rate of uterine malignancy was 599/100,000 patients among those without a history of bariatric surgery, and which was 2.8 times higher among obese vs. nonobese patients within this group (1,409 vs. 496 per 100,000).

The overall rate of uterine cancer among those with a history of bariatric surgery was 408/100,000, but the rate was 2.5 times higher among those with persistent obesity after surgery, compared with those who maintained weight loss after surgery (682/100,000 vs. 270/100,000), Dr. Ward said at the annual meeting of the Society of Gynecologic Oncology.

Compared with obese women without a history of bariatric surgery, the relative risk of uterine cancer was 0.29 for women with prior bariatric surgery, 0.19 for women with normal weight after surgery, and 0.48 for women who remained obese after surgery, so the overall risk reduction with surgery was 70%, the maximum risk reduction (for those with normal weight after surgery) was 81%, and the lowest reduction in risk (for those who had surgery but remained obese) was 52%, Dr. Ward said.

Though limited by the retrospective nature of the study and the fact that the data didn’t differentiate between types of bariatric surgery, the findings are notable, because about 50,000 women were diagnosed with uterine cancer in 2013, making it the most common cancer affecting female reproductive organs. Furthermore, endometrial cancer, which accounts for 95% of uterine cancers, is associated with obesity in about 50% of cases, she explained.

In fact, obese women are two- to fourfold more likely to develop endometrial cancer than are women of normal weight, she said.

The current findings suggest that "a history of bariatric surgery is associated with substantial and clinically significantly reduced risk of uterine malignancy," she said, adding: "Our previous work, in agreement with the findings of others, had indicated that the risk of uterine malignancy increases linearly with BMI [body mass index]. Along with the findings of the current study, this supports that obesity may be a modifiable risk factor related to the development of endometrial cancer."

The mechanism for the link between bariatric surgery and reduced uterine cancer risk remains unclear, but fat loss likely plays a role, as adiposity is known to increase endogenous estrogen circulation. The bariatric surgery itself may also "somehow be influencing the immune system and decreasing inflammation," thereby contributing to decreased cancer risk, Dr. Ward noted.

The findings suggest that weight reduction measures, including bariatric surgery in appropriate candidates, are vitally important in obese women, she said.

"Screening of patients, counseling patients about the dangers of obesity, and appropriate referral for bariatric surgery may have great impact on the overall health of this population," she concluded, adding that future research should examine the benefits of bariatric surgery for the reduction of cancer, including endometrial cancer.

Dr. Ward reported having no disclosures.

TAMPA – Women who undergo bariatric surgery to lose weight are about 70% less likely to develop uterine cancer than are obese women who do not undergo such surgery, according to findings from a large retrospective cohort study.

The risk reduction was even greater (81%) among those who maintained their weight loss after surgery. The findings suggest that obesity may be a modifiable risk factor for uterine cancer, reported Dr. Kristy Kay Ward of the Moores Cancer Center at the University of California, San Diego.

Of more than 7.4 million inpatient admissions among women aged 18 years or older who were registered in the University Health System Consortium dataset from Jan. 1, 2009, to June 1, 2013, 103,797 had a history of bariatric surgery, and 44,345 had a diagnosis of uterine malignancy. The overall rate of uterine malignancy was 599/100,000 patients among those without a history of bariatric surgery, and which was 2.8 times higher among obese vs. nonobese patients within this group (1,409 vs. 496 per 100,000).

The overall rate of uterine cancer among those with a history of bariatric surgery was 408/100,000, but the rate was 2.5 times higher among those with persistent obesity after surgery, compared with those who maintained weight loss after surgery (682/100,000 vs. 270/100,000), Dr. Ward said at the annual meeting of the Society of Gynecologic Oncology.

Compared with obese women without a history of bariatric surgery, the relative risk of uterine cancer was 0.29 for women with prior bariatric surgery, 0.19 for women with normal weight after surgery, and 0.48 for women who remained obese after surgery, so the overall risk reduction with surgery was 70%, the maximum risk reduction (for those with normal weight after surgery) was 81%, and the lowest reduction in risk (for those who had surgery but remained obese) was 52%, Dr. Ward said.

Though limited by the retrospective nature of the study and the fact that the data didn’t differentiate between types of bariatric surgery, the findings are notable, because about 50,000 women were diagnosed with uterine cancer in 2013, making it the most common cancer affecting female reproductive organs. Furthermore, endometrial cancer, which accounts for 95% of uterine cancers, is associated with obesity in about 50% of cases, she explained.

In fact, obese women are two- to fourfold more likely to develop endometrial cancer than are women of normal weight, she said.

The current findings suggest that "a history of bariatric surgery is associated with substantial and clinically significantly reduced risk of uterine malignancy," she said, adding: "Our previous work, in agreement with the findings of others, had indicated that the risk of uterine malignancy increases linearly with BMI [body mass index]. Along with the findings of the current study, this supports that obesity may be a modifiable risk factor related to the development of endometrial cancer."

The mechanism for the link between bariatric surgery and reduced uterine cancer risk remains unclear, but fat loss likely plays a role, as adiposity is known to increase endogenous estrogen circulation. The bariatric surgery itself may also "somehow be influencing the immune system and decreasing inflammation," thereby contributing to decreased cancer risk, Dr. Ward noted.

The findings suggest that weight reduction measures, including bariatric surgery in appropriate candidates, are vitally important in obese women, she said.

"Screening of patients, counseling patients about the dangers of obesity, and appropriate referral for bariatric surgery may have great impact on the overall health of this population," she concluded, adding that future research should examine the benefits of bariatric surgery for the reduction of cancer, including endometrial cancer.

Dr. Ward reported having no disclosures.

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).

HOLLYWOOD, FLA. – Compliance with tamoxifen treatment regimens among hormone receptor–positive breast cancer patients is suboptimal, but use of an oral liquid formulation could help change that, findings from a large CAPTURE (Compliance and Preference for Tamoxifen Registry) Internet-based survey suggest.

Of 626 women with breast cancer who were using tamoxifen and who participated in the health care provider–administered survey, 88 (14%) reported missing between 2 and 10 doses each month, and 75 (12%) said they had stopped taking tamoxifen for periods of more than 2 weeks; 13% said they would prefer an oral liquid formulation over the tablet formulation, 22% said they would be willing to try an oral liquid formulation, and 7% said they believed an oral liquid formulation would help them improve long-term adherence, Dr. Stefan Gluck reported in a poster at the annual conference of the National Comprehensive Cancer Network.

Of those who reported missing two or more doses per month, 22% said they would prefer an oral liquid formulation, 30% said they would try a liquid formulation, and 16% said they thought an oral liquid formulation would help improve their compliance, said Dr. Gluck of the University of Miami Health System’s Sylvester Comprehensive Cancer Center, Miami.

Responses on the validated Eating Assessment Tool (EAT-10), which was administered along with the 36-item survey, suggested that swallowing difficulties contributed to the lack of compliance in 48 (8%) of respondents, Dr. Gluck said.

Those with swallowing difficulties did not differ significantly from the overall study population with respect to age, race, or education, although a higher percentage of those with swallowing difficulties had undergone a mastectomy (65% vs. 46%), and had experienced or been diagnosed with persistent or frequent symptoms of heartburn, acid reflux, or gastroesophageal reflux disease (44% vs. 26%). Of those with swallowing difficulties, 35% said they would prefer an oral liquid form, 50% said they were willing to try a liquid formulation, and 25% said a liquid formulation would help improve their compliance with long-term tamoxifen therapy.

Reasons given for stopping tamoxifen for more than 2 weeks included side effects in 27% of cases, physician recommendation in 17% of cases, "felt better" in 4% of cases, expense in 3% of cases, and "other" reasons in 49% of cases.

Respondents were women with a mean age of 55 years at a mean of 3 years since breast cancer diagnosis. Most (66%) had invasive disease, 29% had noninvasive disease, and 5% had metastatic disease. The vast majority (97%) had undergone surgery, 58% received radiation therapy, and 47% received chemotherapy. The women had been taking tamoxifen for a median of 2 years, with the vast majority (98%) taking a 20-mg dose.

The importance of adherence to 5 full years of tamoxifen for long-term positive outcomes in women with hormone receptor–positive breast cancer has been well documented, and breast cancer treatment guidelines updated by the National Comprehensive Cancer Network in March 2013 recommend consideration of up to 10 years of tamoxifen therapy, Dr. Gluck noted.

Though limited by factors inherent in survey methodology, including self-reported data, the findings of this study "provide an avenue for improving the adherence of patients to long-term tamoxifen treatment by providing them a choice between a tablet and an oral liquid," he concluded.

CAPTURE is a project of DARA BioSciences, which markets the only Food and Drug Administration–approved liquid tamoxifen formulation (Soltamox).

TAMPA – Women with BRCA1 mutations who undergo risk-reducing salpingo-oophorectomy may remain at risk for rare types of aggressive uterine cancer, according to preliminary findings from a prospective cohort study.

Of 525 women with BRCA1 or BRCA2 gene mutations who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy and who were followed for a median of 5.8 years, 4 developed a high-risk uterine corpus cancer, including 2 who developed serous disease, 1 who developed carcinosarcoma, and 1 who developed leiomyosarcoma. All occurred in the 296 women in the study who had BRCA1 mutations, for a 2.1% 10-year risk of uterine cancer following RRSO in those women, Dr. Catherine Shu reported during a late-breaking abstract session at the annual meeting of the Society of Gynecologic Oncology.

© Christian Jasiuk/Thinkstockphotos.com

The expected number of these types of high-risk cancer in this population, based on age- and race-based Surveillance, Epidemiology, and End Results (SEER) data adjusted for prevalence of hysterectomy, was 0.28, for a highly significant ratio of observed to expected cancers (O/E) of 14.48 (P less than .001), said Dr. Shu, chief fellow in medical oncology at Memorial Sloan Kettering Cancer Center, New York.

One of the cases occurred among the 169 women in the study with no prior breast cancer (O/E, 16.7; P =.06), and three occurred among 356 with prior breast cancer (O/E, 14.01; P =.001). When stratified based on tamoxifen exposure, high-risk uterine cancer was observed in 2 of 131woman with exposure (O/E, 21.68; P =.004), and in 2 of 394 with no exposure (O/E, 10.87; P =.015), Dr. Shu said.

The women included in the study represented 79% of all women at Memorial Sloan Kettering Cancer Center who underwent genetic testing followed by risk-reducing surgery without hysterectomy from June 1, 1995, to Dec. 31, 2011. They had a mean age of 46.1 years.

The "time at risk" for participants began after both receipt of genetic testing results and RRSO, and the participants were followed annually by questionnaires and medical records review. Censoring events were hysterectomy, uterine cancer diagnosis, last follow-up, or death, Dr. Shu noted.

Importantly, no increased risk was seen for more common types of uterine cancer, including endometrioid, mucinous, adenocarcinoma, and not otherwise specified cancers.

Those who developed high-risk cancer were treated with chemotherapy and/or radiation, and all four were living at the time of Dr. Shu’s presentation, although one had metastatic disease.

Although this study is one of the largest prospective studies to date to look at the likelihood of high-risk uterine cancer among BRCA-positive patients who undergo RRSO without hysterectomy, it has a number of limitations, such as possible misclassification of rare uterine cancer subtypes in the SEER database and possible confounding by tamoxifen exposure. The findings require confirmation and should thus be considered preliminary, Dr. Shu said.

Indeed, it would be premature at this point to recommend routine hysterectomy along with RRSO women with BRCA1 mutations; the decision regarding hysterectomy at the time of RRSO may depend on the patient’s age, prior cancer history, and other risk factors, senior author Noah D. Kauff of Memorial Sloan Kettering Cancer Center, said in a press statement.

Currently, based on the fact that women with a BRCA1 mutation have a 39%-46% chance of developing ovarian cancer and 50%-85% chance of developing breast cancer, the National Comprehensive Cancer Network recommends RRSO between ages 35 years and 40 years, after childbearing is complete.

Hysterectomy at the time of RRSO is not recommended because of risks associated with the procedure, including bleeding and infection risks, as well the potential for long-term problems with bladder, bowel, and sexual function, and also because uterine cancers that develop after RRSO have been thought to generally be low risk, according to the press statement.

The current findings suggest this may not be the case,

Pending confirmation of the findings, women with BRCA1 gene mutations who are considering risk-reducing surgery should be advised that "this report suggests they may be at risk for rare types of aggressive uterine cancer," and the potential advantages and disadvantages of concomitant hysterectomy should be discussed, Dr. Kauff said.

Dr. Shu and Dr. Kauff reported having no disclosures.

TAMPA – Women with BRCA1 mutations who undergo risk-reducing salpingo-oophorectomy may remain at risk for rare types of aggressive uterine cancer, according to preliminary findings from a prospective cohort study.

Of 525 women with BRCA1 or BRCA2 gene mutations who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy and who were followed for a median of 5.8 years, 4 developed a high-risk uterine corpus cancer, including 2 who developed serous disease, 1 who developed carcinosarcoma, and 1 who developed leiomyosarcoma. All occurred in the 296 women in the study who had BRCA1 mutations, for a 2.1% 10-year risk of uterine cancer following RRSO in those women, Dr. Catherine Shu reported during a late-breaking abstract session at the annual meeting of the Society of Gynecologic Oncology.

© Christian Jasiuk/Thinkstockphotos.com

The expected number of these types of high-risk cancer in this population, based on age- and race-based Surveillance, Epidemiology, and End Results (SEER) data adjusted for prevalence of hysterectomy, was 0.28, for a highly significant ratio of observed to expected cancers (O/E) of 14.48 (P less than .001), said Dr. Shu, chief fellow in medical oncology at Memorial Sloan Kettering Cancer Center, New York.

One of the cases occurred among the 169 women in the study with no prior breast cancer (O/E, 16.7; P =.06), and three occurred among 356 with prior breast cancer (O/E, 14.01; P =.001). When stratified based on tamoxifen exposure, high-risk uterine cancer was observed in 2 of 131woman with exposure (O/E, 21.68; P =.004), and in 2 of 394 with no exposure (O/E, 10.87; P =.015), Dr. Shu said.

The women included in the study represented 79% of all women at Memorial Sloan Kettering Cancer Center who underwent genetic testing followed by risk-reducing surgery without hysterectomy from June 1, 1995, to Dec. 31, 2011. They had a mean age of 46.1 years.

The "time at risk" for participants began after both receipt of genetic testing results and RRSO, and the participants were followed annually by questionnaires and medical records review. Censoring events were hysterectomy, uterine cancer diagnosis, last follow-up, or death, Dr. Shu noted.

Importantly, no increased risk was seen for more common types of uterine cancer, including endometrioid, mucinous, adenocarcinoma, and not otherwise specified cancers.

Those who developed high-risk cancer were treated with chemotherapy and/or radiation, and all four were living at the time of Dr. Shu’s presentation, although one had metastatic disease.

Although this study is one of the largest prospective studies to date to look at the likelihood of high-risk uterine cancer among BRCA-positive patients who undergo RRSO without hysterectomy, it has a number of limitations, such as possible misclassification of rare uterine cancer subtypes in the SEER database and possible confounding by tamoxifen exposure. The findings require confirmation and should thus be considered preliminary, Dr. Shu said.

Indeed, it would be premature at this point to recommend routine hysterectomy along with RRSO women with BRCA1 mutations; the decision regarding hysterectomy at the time of RRSO may depend on the patient’s age, prior cancer history, and other risk factors, senior author Noah D. Kauff of Memorial Sloan Kettering Cancer Center, said in a press statement.

Currently, based on the fact that women with a BRCA1 mutation have a 39%-46% chance of developing ovarian cancer and 50%-85% chance of developing breast cancer, the National Comprehensive Cancer Network recommends RRSO between ages 35 years and 40 years, after childbearing is complete.

Hysterectomy at the time of RRSO is not recommended because of risks associated with the procedure, including bleeding and infection risks, as well the potential for long-term problems with bladder, bowel, and sexual function, and also because uterine cancers that develop after RRSO have been thought to generally be low risk, according to the press statement.

The current findings suggest this may not be the case,

Pending confirmation of the findings, women with BRCA1 gene mutations who are considering risk-reducing surgery should be advised that "this report suggests they may be at risk for rare types of aggressive uterine cancer," and the potential advantages and disadvantages of concomitant hysterectomy should be discussed, Dr. Kauff said.

Dr. Shu and Dr. Kauff reported having no disclosures.

TAMPA – Women with BRCA1 mutations who undergo risk-reducing salpingo-oophorectomy may remain at risk for rare types of aggressive uterine cancer, according to preliminary findings from a prospective cohort study.

Of 525 women with BRCA1 or BRCA2 gene mutations who underwent risk-reducing salpingo-oophorectomy (RRSO) without hysterectomy and who were followed for a median of 5.8 years, 4 developed a high-risk uterine corpus cancer, including 2 who developed serous disease, 1 who developed carcinosarcoma, and 1 who developed leiomyosarcoma. All occurred in the 296 women in the study who had BRCA1 mutations, for a 2.1% 10-year risk of uterine cancer following RRSO in those women, Dr. Catherine Shu reported during a late-breaking abstract session at the annual meeting of the Society of Gynecologic Oncology.

© Christian Jasiuk/Thinkstockphotos.com

The expected number of these types of high-risk cancer in this population, based on age- and race-based Surveillance, Epidemiology, and End Results (SEER) data adjusted for prevalence of hysterectomy, was 0.28, for a highly significant ratio of observed to expected cancers (O/E) of 14.48 (P less than .001), said Dr. Shu, chief fellow in medical oncology at Memorial Sloan Kettering Cancer Center, New York.

One of the cases occurred among the 169 women in the study with no prior breast cancer (O/E, 16.7; P =.06), and three occurred among 356 with prior breast cancer (O/E, 14.01; P =.001). When stratified based on tamoxifen exposure, high-risk uterine cancer was observed in 2 of 131woman with exposure (O/E, 21.68; P =.004), and in 2 of 394 with no exposure (O/E, 10.87; P =.015), Dr. Shu said.

The women included in the study represented 79% of all women at Memorial Sloan Kettering Cancer Center who underwent genetic testing followed by risk-reducing surgery without hysterectomy from June 1, 1995, to Dec. 31, 2011. They had a mean age of 46.1 years.

The "time at risk" for participants began after both receipt of genetic testing results and RRSO, and the participants were followed annually by questionnaires and medical records review. Censoring events were hysterectomy, uterine cancer diagnosis, last follow-up, or death, Dr. Shu noted.

Importantly, no increased risk was seen for more common types of uterine cancer, including endometrioid, mucinous, adenocarcinoma, and not otherwise specified cancers.

Those who developed high-risk cancer were treated with chemotherapy and/or radiation, and all four were living at the time of Dr. Shu’s presentation, although one had metastatic disease.

Although this study is one of the largest prospective studies to date to look at the likelihood of high-risk uterine cancer among BRCA-positive patients who undergo RRSO without hysterectomy, it has a number of limitations, such as possible misclassification of rare uterine cancer subtypes in the SEER database and possible confounding by tamoxifen exposure. The findings require confirmation and should thus be considered preliminary, Dr. Shu said.

Indeed, it would be premature at this point to recommend routine hysterectomy along with RRSO women with BRCA1 mutations; the decision regarding hysterectomy at the time of RRSO may depend on the patient’s age, prior cancer history, and other risk factors, senior author Noah D. Kauff of Memorial Sloan Kettering Cancer Center, said in a press statement.

Currently, based on the fact that women with a BRCA1 mutation have a 39%-46% chance of developing ovarian cancer and 50%-85% chance of developing breast cancer, the National Comprehensive Cancer Network recommends RRSO between ages 35 years and 40 years, after childbearing is complete.

Hysterectomy at the time of RRSO is not recommended because of risks associated with the procedure, including bleeding and infection risks, as well the potential for long-term problems with bladder, bowel, and sexual function, and also because uterine cancers that develop after RRSO have been thought to generally be low risk, according to the press statement.

The current findings suggest this may not be the case,

Pending confirmation of the findings, women with BRCA1 gene mutations who are considering risk-reducing surgery should be advised that "this report suggests they may be at risk for rare types of aggressive uterine cancer," and the potential advantages and disadvantages of concomitant hysterectomy should be discussed, Dr. Kauff said.

Dr. Shu and Dr. Kauff reported having no disclosures.

Strict adherence to the new risk-based American College of Cardiology–American Heart Association guidelines for managing cholesterol would increase the number of adults eligible for statin therapy by nearly 13 million, a study suggests.

Most of the increase would be among older adults without cardiovascular disease, Michael J. Pencina, Ph.D., of the Duke Clinical Research Institute of Duke University, Durham, N.C., and his colleagues reported online March 19 in the New England Journal of Medicine.

The investigators used fasting data from 3,773 adults aged 40-75 years who participated in the National Health and Nutrition Examination Survey (NHANES) of 2005-2010 to estimate the number of individuals for whom statin therapy would be recommended under the new guidelines, published in November 2013, compared with the previously recommended 2007 guidelines from the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program.

After extrapolating the results to the estimated population of U.S. adults aged 40-75 years (115.4 million adults), they determined that 14.4 million adults would be newly eligible for statin therapy based on the new guidelines, and that 1.6 million previously eligible adults would become ineligible under the new guidelines, for a net increase in the number of adults receiving or eligible for statin therapy from 43.2 million (38%) to 56.0 million (49%), the investigators said (N. Engl. J. Med. 2014 March 19 [doi: 10.1056/NEJMoa1315665]).

Of the 12.8 million additional eligible adults, 10.4 million would be individuals without existing cardiovascular disease, and 8.4 million of those would be aged 60-75 years; among the 60- to 75-year-olds without cardiovascular disease, the percentage eligible would increase from 30% to 87% for men, and from 21% to 54% for women.

"The median age of adults who would be newly eligible for statin therapy under the new ACC-AHA guidelines would be 63.4 years, and 61.7% would be men. The median LDL cholesterol level for these adults is 105.2 mg per deciliter," the investigators wrote, adding that the new guidelines increase the estimated number of adults who would be eligible across all categories.

The largest increase would occur among adults who have an indication for primary prevention on the basis of their 10-year risk of cardiovascular disease (15.1 million by the new guidelines vs. 6.9 million by ATP III), they said.

"Furthermore, 2.4 million adults with prevalent cardiovascular disease and LDL cholesterol levels of less than 100 mg per deciliter who would not be eligible for statin therapy according to the ATP III guidelines would be eligible under the new ACC-AHA guidelines. Finally, the number of adults with diabetes who are eligible for statin therapy would increase from 4.5 million to 6.7 million as a result of the lowering of the threshold for LDL cholesterol treatment from 100 to 70 mg per deciliter," the investigators wrote.

According to the ATP III guidelines, patients with established cardiovascular disease or diabetes and LDL cholesterol levels of 100 mg/dL or higher were eligible for statin therapy. Those guidelines also recommended statins for primary prevention in patients on the basis of a combined assessment of LDL cholesterol and a 10-year risk of coronary heart disease.

The new ACC-AHA guidelines differ substantially from the ATP III guidelines in that they expand the treatment recommendation to all adults with known cardiovascular disease, regardless of LDL cholesterol level, and for primary prevention they recommend statin therapy for all those with an LDL cholesterol level of 70 mg/dL or higher and who also have diabetes or a 10-year risk of cardiovascular disease of 7.5% or greater based on new pooled-cohort equations.

"These new treatment recommendations have a larger effect in the older age group (60 to 75 years) than in the younger age group (40 to 59 years). Although up to 30% of adults in the younger age group without cardiovascular disease would be eligible for statin therapy for primary prevention, more than 77% of those in the older age group would be eligible. This difference might be partially explained by the addition of stroke to coronary heart disease as a target for prevention in the new pooled-cohort equations," they wrote. Because the prevalence of cardiovascular disease rises markedly with age, the large proportion of older adults who would be eligible for statin therapy may be justifiable, they added.

"Further research is required to determine whether more aggressive preventive strategies are needed for younger adults," they said.

Though limited by a number of factors, such as the extrapolation of data from 3,773 NHANES participants to 115.4 million U.S. adults, and by an inability to accurately quantify the effects of the new and old guidelines on patients currently receiving lipid-lowering therapy (since it was unclear why therapy was initiated), the findings nonetheless suggest a need for personalization with respect to applying the new guidelines.

The new guidelines "treat risk as the predominant reason for treating patients," according to one of the study’s lead authors, Dr. Eric D. Peterson of Duke University.

However, there is a paucity of data on the whether this approach works for older adults, Dr. Peterson said in an interview.

"I’m not willing to say we will be overtreating these patients [based on the new guidelines], but we need more data; this is a pretty big leap," he said.

Conversely, the new guidelines could lead to undertreatment of younger patients with high lipid levels, he added.

"This is kind of frightening," Dr. Peterson said, explaining that a younger patient who appears to have a relatively low 10-year risk of developing cardiovascular disease, but who has high lipid levels, would not be recommended for intervention – even though such a patient has a high likelihood of eventually developing cardiovascular disease.

"There is good research saying we should treat these patients, but these guidelines don’t recommend that. If we strictly follow the guidelines, we will undertreat younger patients," he said.

It is important to remember that the new guidelines are not "the letter of law," but rather are guides.

"Some degree of personalization for the patient in front of us is definitely needed right now," he said.

Dr. Donald M. Lloyd-Jones, cochair of the ACC-AHA guidelines, said he "agrees with the careful analysis" by Dr. Pencina, Dr. Peterson, and their colleagues.

"These findings are consistent with the analyses we reported in the guideline documents using NHANES data," said Dr. Lloyd-Jones, senior associate dean and professor and chair of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago.

Of note, the majority of the difference between the estimates based on the ATP III guidelines and the ACC-AHA guidelines is due to the lower threshold for consideration of treatment, which was derived directly from the evidence base from newer primary-prevention randomized clinical trials, he said.

"The authors recognized that the reported estimate is the maximum estimate of the increase in the number of people potentially eligible for statin therapy, because the guideline recommendation is for the clinician and patient to use the risk equations as the starting point for a risk discussion, not to mandate a statin prescription," he said.

Additionally, the results "refute the alarmist claims that we saw from a number of commentators in the media a few months ago that 70-100 million Americans would be put on statin therapy as a result of the new guidelines," Dr. Lloyd-Jones said.

"With one in three Americans dying of a preventable or postponable cardiovascular event, and more than half experiencing a major vascular event before they die, evidence-based guidelines that recommend that statins be considered for about half of American adults seem about right. Furthermore, we currently recommend that about 70 million Americans be treated for hypertension, so recommending that about 50 million should be considered for statins also seems about right," he said.

This study was funded by the Duke Clinical Research Institute and by grants from M. Jean de Granpre and Louis and Sylvia Vogel. Dr. Pencina reported receiving research fees (unrelated to this study) from McGill University Health Center and AbbVie. Dr. Peterson reported receiving grants from Eli Lilly and grant support and/or personal fees from Janssen and Boehringer Ingelheim. The remaining authors reported having nothing to disclose.

Strict adherence to the new risk-based American College of Cardiology–American Heart Association guidelines for managing cholesterol would increase the number of adults eligible for statin therapy by nearly 13 million, a study suggests.

Most of the increase would be among older adults without cardiovascular disease, Michael J. Pencina, Ph.D., of the Duke Clinical Research Institute of Duke University, Durham, N.C., and his colleagues reported online March 19 in the New England Journal of Medicine.

The investigators used fasting data from 3,773 adults aged 40-75 years who participated in the National Health and Nutrition Examination Survey (NHANES) of 2005-2010 to estimate the number of individuals for whom statin therapy would be recommended under the new guidelines, published in November 2013, compared with the previously recommended 2007 guidelines from the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program.

After extrapolating the results to the estimated population of U.S. adults aged 40-75 years (115.4 million adults), they determined that 14.4 million adults would be newly eligible for statin therapy based on the new guidelines, and that 1.6 million previously eligible adults would become ineligible under the new guidelines, for a net increase in the number of adults receiving or eligible for statin therapy from 43.2 million (38%) to 56.0 million (49%), the investigators said (N. Engl. J. Med. 2014 March 19 [doi: 10.1056/NEJMoa1315665]).

Of the 12.8 million additional eligible adults, 10.4 million would be individuals without existing cardiovascular disease, and 8.4 million of those would be aged 60-75 years; among the 60- to 75-year-olds without cardiovascular disease, the percentage eligible would increase from 30% to 87% for men, and from 21% to 54% for women.

"The median age of adults who would be newly eligible for statin therapy under the new ACC-AHA guidelines would be 63.4 years, and 61.7% would be men. The median LDL cholesterol level for these adults is 105.2 mg per deciliter," the investigators wrote, adding that the new guidelines increase the estimated number of adults who would be eligible across all categories.

The largest increase would occur among adults who have an indication for primary prevention on the basis of their 10-year risk of cardiovascular disease (15.1 million by the new guidelines vs. 6.9 million by ATP III), they said.

"Furthermore, 2.4 million adults with prevalent cardiovascular disease and LDL cholesterol levels of less than 100 mg per deciliter who would not be eligible for statin therapy according to the ATP III guidelines would be eligible under the new ACC-AHA guidelines. Finally, the number of adults with diabetes who are eligible for statin therapy would increase from 4.5 million to 6.7 million as a result of the lowering of the threshold for LDL cholesterol treatment from 100 to 70 mg per deciliter," the investigators wrote.

According to the ATP III guidelines, patients with established cardiovascular disease or diabetes and LDL cholesterol levels of 100 mg/dL or higher were eligible for statin therapy. Those guidelines also recommended statins for primary prevention in patients on the basis of a combined assessment of LDL cholesterol and a 10-year risk of coronary heart disease.

The new ACC-AHA guidelines differ substantially from the ATP III guidelines in that they expand the treatment recommendation to all adults with known cardiovascular disease, regardless of LDL cholesterol level, and for primary prevention they recommend statin therapy for all those with an LDL cholesterol level of 70 mg/dL or higher and who also have diabetes or a 10-year risk of cardiovascular disease of 7.5% or greater based on new pooled-cohort equations.

"These new treatment recommendations have a larger effect in the older age group (60 to 75 years) than in the younger age group (40 to 59 years). Although up to 30% of adults in the younger age group without cardiovascular disease would be eligible for statin therapy for primary prevention, more than 77% of those in the older age group would be eligible. This difference might be partially explained by the addition of stroke to coronary heart disease as a target for prevention in the new pooled-cohort equations," they wrote. Because the prevalence of cardiovascular disease rises markedly with age, the large proportion of older adults who would be eligible for statin therapy may be justifiable, they added.

"Further research is required to determine whether more aggressive preventive strategies are needed for younger adults," they said.

Though limited by a number of factors, such as the extrapolation of data from 3,773 NHANES participants to 115.4 million U.S. adults, and by an inability to accurately quantify the effects of the new and old guidelines on patients currently receiving lipid-lowering therapy (since it was unclear why therapy was initiated), the findings nonetheless suggest a need for personalization with respect to applying the new guidelines.

The new guidelines "treat risk as the predominant reason for treating patients," according to one of the study’s lead authors, Dr. Eric D. Peterson of Duke University.

However, there is a paucity of data on the whether this approach works for older adults, Dr. Peterson said in an interview.

"I’m not willing to say we will be overtreating these patients [based on the new guidelines], but we need more data; this is a pretty big leap," he said.

Conversely, the new guidelines could lead to undertreatment of younger patients with high lipid levels, he added.

"This is kind of frightening," Dr. Peterson said, explaining that a younger patient who appears to have a relatively low 10-year risk of developing cardiovascular disease, but who has high lipid levels, would not be recommended for intervention – even though such a patient has a high likelihood of eventually developing cardiovascular disease.

"There is good research saying we should treat these patients, but these guidelines don’t recommend that. If we strictly follow the guidelines, we will undertreat younger patients," he said.

It is important to remember that the new guidelines are not "the letter of law," but rather are guides.

"Some degree of personalization for the patient in front of us is definitely needed right now," he said.

Dr. Donald M. Lloyd-Jones, cochair of the ACC-AHA guidelines, said he "agrees with the careful analysis" by Dr. Pencina, Dr. Peterson, and their colleagues.

"These findings are consistent with the analyses we reported in the guideline documents using NHANES data," said Dr. Lloyd-Jones, senior associate dean and professor and chair of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago.

Of note, the majority of the difference between the estimates based on the ATP III guidelines and the ACC-AHA guidelines is due to the lower threshold for consideration of treatment, which was derived directly from the evidence base from newer primary-prevention randomized clinical trials, he said.

"The authors recognized that the reported estimate is the maximum estimate of the increase in the number of people potentially eligible for statin therapy, because the guideline recommendation is for the clinician and patient to use the risk equations as the starting point for a risk discussion, not to mandate a statin prescription," he said.

Additionally, the results "refute the alarmist claims that we saw from a number of commentators in the media a few months ago that 70-100 million Americans would be put on statin therapy as a result of the new guidelines," Dr. Lloyd-Jones said.

"With one in three Americans dying of a preventable or postponable cardiovascular event, and more than half experiencing a major vascular event before they die, evidence-based guidelines that recommend that statins be considered for about half of American adults seem about right. Furthermore, we currently recommend that about 70 million Americans be treated for hypertension, so recommending that about 50 million should be considered for statins also seems about right," he said.

This study was funded by the Duke Clinical Research Institute and by grants from M. Jean de Granpre and Louis and Sylvia Vogel. Dr. Pencina reported receiving research fees (unrelated to this study) from McGill University Health Center and AbbVie. Dr. Peterson reported receiving grants from Eli Lilly and grant support and/or personal fees from Janssen and Boehringer Ingelheim. The remaining authors reported having nothing to disclose.

Strict adherence to the new risk-based American College of Cardiology–American Heart Association guidelines for managing cholesterol would increase the number of adults eligible for statin therapy by nearly 13 million, a study suggests.

Most of the increase would be among older adults without cardiovascular disease, Michael J. Pencina, Ph.D., of the Duke Clinical Research Institute of Duke University, Durham, N.C., and his colleagues reported online March 19 in the New England Journal of Medicine.

The investigators used fasting data from 3,773 adults aged 40-75 years who participated in the National Health and Nutrition Examination Survey (NHANES) of 2005-2010 to estimate the number of individuals for whom statin therapy would be recommended under the new guidelines, published in November 2013, compared with the previously recommended 2007 guidelines from the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program.

After extrapolating the results to the estimated population of U.S. adults aged 40-75 years (115.4 million adults), they determined that 14.4 million adults would be newly eligible for statin therapy based on the new guidelines, and that 1.6 million previously eligible adults would become ineligible under the new guidelines, for a net increase in the number of adults receiving or eligible for statin therapy from 43.2 million (38%) to 56.0 million (49%), the investigators said (N. Engl. J. Med. 2014 March 19 [doi: 10.1056/NEJMoa1315665]).

Of the 12.8 million additional eligible adults, 10.4 million would be individuals without existing cardiovascular disease, and 8.4 million of those would be aged 60-75 years; among the 60- to 75-year-olds without cardiovascular disease, the percentage eligible would increase from 30% to 87% for men, and from 21% to 54% for women.

"The median age of adults who would be newly eligible for statin therapy under the new ACC-AHA guidelines would be 63.4 years, and 61.7% would be men. The median LDL cholesterol level for these adults is 105.2 mg per deciliter," the investigators wrote, adding that the new guidelines increase the estimated number of adults who would be eligible across all categories.

The largest increase would occur among adults who have an indication for primary prevention on the basis of their 10-year risk of cardiovascular disease (15.1 million by the new guidelines vs. 6.9 million by ATP III), they said.

"Furthermore, 2.4 million adults with prevalent cardiovascular disease and LDL cholesterol levels of less than 100 mg per deciliter who would not be eligible for statin therapy according to the ATP III guidelines would be eligible under the new ACC-AHA guidelines. Finally, the number of adults with diabetes who are eligible for statin therapy would increase from 4.5 million to 6.7 million as a result of the lowering of the threshold for LDL cholesterol treatment from 100 to 70 mg per deciliter," the investigators wrote.

According to the ATP III guidelines, patients with established cardiovascular disease or diabetes and LDL cholesterol levels of 100 mg/dL or higher were eligible for statin therapy. Those guidelines also recommended statins for primary prevention in patients on the basis of a combined assessment of LDL cholesterol and a 10-year risk of coronary heart disease.

The new ACC-AHA guidelines differ substantially from the ATP III guidelines in that they expand the treatment recommendation to all adults with known cardiovascular disease, regardless of LDL cholesterol level, and for primary prevention they recommend statin therapy for all those with an LDL cholesterol level of 70 mg/dL or higher and who also have diabetes or a 10-year risk of cardiovascular disease of 7.5% or greater based on new pooled-cohort equations.

"These new treatment recommendations have a larger effect in the older age group (60 to 75 years) than in the younger age group (40 to 59 years). Although up to 30% of adults in the younger age group without cardiovascular disease would be eligible for statin therapy for primary prevention, more than 77% of those in the older age group would be eligible. This difference might be partially explained by the addition of stroke to coronary heart disease as a target for prevention in the new pooled-cohort equations," they wrote. Because the prevalence of cardiovascular disease rises markedly with age, the large proportion of older adults who would be eligible for statin therapy may be justifiable, they added.

"Further research is required to determine whether more aggressive preventive strategies are needed for younger adults," they said.

Though limited by a number of factors, such as the extrapolation of data from 3,773 NHANES participants to 115.4 million U.S. adults, and by an inability to accurately quantify the effects of the new and old guidelines on patients currently receiving lipid-lowering therapy (since it was unclear why therapy was initiated), the findings nonetheless suggest a need for personalization with respect to applying the new guidelines.

The new guidelines "treat risk as the predominant reason for treating patients," according to one of the study’s lead authors, Dr. Eric D. Peterson of Duke University.

However, there is a paucity of data on the whether this approach works for older adults, Dr. Peterson said in an interview.

"I’m not willing to say we will be overtreating these patients [based on the new guidelines], but we need more data; this is a pretty big leap," he said.

Conversely, the new guidelines could lead to undertreatment of younger patients with high lipid levels, he added.

"This is kind of frightening," Dr. Peterson said, explaining that a younger patient who appears to have a relatively low 10-year risk of developing cardiovascular disease, but who has high lipid levels, would not be recommended for intervention – even though such a patient has a high likelihood of eventually developing cardiovascular disease.

"There is good research saying we should treat these patients, but these guidelines don’t recommend that. If we strictly follow the guidelines, we will undertreat younger patients," he said.

It is important to remember that the new guidelines are not "the letter of law," but rather are guides.

"Some degree of personalization for the patient in front of us is definitely needed right now," he said.

Dr. Donald M. Lloyd-Jones, cochair of the ACC-AHA guidelines, said he "agrees with the careful analysis" by Dr. Pencina, Dr. Peterson, and their colleagues.

"These findings are consistent with the analyses we reported in the guideline documents using NHANES data," said Dr. Lloyd-Jones, senior associate dean and professor and chair of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago.

Of note, the majority of the difference between the estimates based on the ATP III guidelines and the ACC-AHA guidelines is due to the lower threshold for consideration of treatment, which was derived directly from the evidence base from newer primary-prevention randomized clinical trials, he said.

"The authors recognized that the reported estimate is the maximum estimate of the increase in the number of people potentially eligible for statin therapy, because the guideline recommendation is for the clinician and patient to use the risk equations as the starting point for a risk discussion, not to mandate a statin prescription," he said.

Additionally, the results "refute the alarmist claims that we saw from a number of commentators in the media a few months ago that 70-100 million Americans would be put on statin therapy as a result of the new guidelines," Dr. Lloyd-Jones said.

"With one in three Americans dying of a preventable or postponable cardiovascular event, and more than half experiencing a major vascular event before they die, evidence-based guidelines that recommend that statins be considered for about half of American adults seem about right. Furthermore, we currently recommend that about 70 million Americans be treated for hypertension, so recommending that about 50 million should be considered for statins also seems about right," he said.

This study was funded by the Duke Clinical Research Institute and by grants from M. Jean de Granpre and Louis and Sylvia Vogel. Dr. Pencina reported receiving research fees (unrelated to this study) from McGill University Health Center and AbbVie. Dr. Peterson reported receiving grants from Eli Lilly and grant support and/or personal fees from Janssen and Boehringer Ingelheim. The remaining authors reported having nothing to disclose.