User login
ICOO: Quality metrics needed for medical marijuana
BOSTON – Medical marijuana is now legal in 23 states, but there remains essentially no systematic approach for evaluating whether available products have the capacity to provide medical benefits, according to a status report presented at the International Conference on Opioids.
Often, medical marijuana is marketed on the basis of its psychoactive component, tetrahydrocannabinol (THC), but a substantial body of data suggests that it is the cannabidiol (CBD) content that is most responsible for appetite stimulation, antiemetic effects, and many other medicinal properties, according to Michael E. Schatman, Ph.D., executive director of the Foundation for Ethics in Pain Care, Bellevue, Wash.
“Contrary to popular belief, THC is not the most relevant cannabinoid for medical application,” Dr. Schatman said. On the premise that more is better, higher THC content generally correlates with higher cost for medical marijuana as it does for marijuana marketed for recreational use, according to Dr. Schatman. But he disagreed with that notion.
More than 100 cannabinoids are in marijuana, Dr. Schatman said. Although he maintained that CBD might be the most important constituent for many of the medicinal indications for marijuana, he acknowledged that the data are mostly suggestive. Few studies have differentiated marijuana for its therapeutic effects based on representative concentrations of different constituents even if Dr. Schatman cited clinical and experimental work correlating CBD with benefit on a variety of therapeutic targets, including inflammation.
“There is no medical marijuana but medical marijuanas,” said Dr. Schatman, suggesting that specific therapeutic benefits would be expected to differ markedly according to the constituents even if little information exists about the optimal levels of any of these constituents.
For recreational use, THC content is a reasonable quality metric, Dr. Schatman said. THC content predicts the “high” of marijuana. While inducing a state of euphoria might indeed be the goal for some medicinal marijuana applications, high THC content also poses the greatest risk of psychosis, disordered thoughts, and impaired functionality, he said. To this extent, greater THC content might not predict greater benefit.
In the absence of regulatory oversight, the marketing of marijuana rather than the science of its effect dominates all discussion, Dr. Schatman said. He cited data showing a steep increase in THC content subsequent to the growing rate of state legalizations.
“Dispensaries are selling medical marijuana with THC contents as high as 33% with names like Super Brain Damage OG,” Dr. Schatman said. Given the potential for unwanted side effects at THC dose levels likely to impair cognitive function, Dr. Schatman said it might be reasonable to question the therapeutic intent when products feature THC content at levels this high.
So far, only New Jersey has restricted THC content of medical marijuana, placing the ceiling at 10%, Dr. Schatman said. Compared to the 1970s, when street marijuana typically had THC content of about 1% to 2%, Dr. Schatman suggested that even 10% is likely to be excessive if the goal is not be get “stoned.” However, he expressed even greater concern about the declining content of CBD, which he suggested has been inversely related to THC.
“We’ve essentially bred the CBD out of marijuana,” Dr. Schatman reported. One advertisement from a medical marijuana dispensary that he reproduced prominently advertised THC levels at 20% but CBD levels at 0.38%. Whether greater medicinal benefits would be realized if those percentages were reversed is not known, but Dr. Schatman said rational clinical decisions are impossible without data.
“Until the patient knows what he or she is getting, cannabis will not necessarily be medicine in most cases,” Dr. Schatman said. He believes the marijuana should be held to the same standards of efficacy and safety as other drugs. The ideal for moving this field forward might be regulation by the Food and Drug Administration, Dr. Schatman said. But he also called for more rigorous trials of the marijuana constituents to determine which are most important for achieving the specific benefits for which marijuana is being prescribed.
Dr. Schatman is on the speaker’s bureau for Mallinckrodt.
BOSTON – Medical marijuana is now legal in 23 states, but there remains essentially no systematic approach for evaluating whether available products have the capacity to provide medical benefits, according to a status report presented at the International Conference on Opioids.
Often, medical marijuana is marketed on the basis of its psychoactive component, tetrahydrocannabinol (THC), but a substantial body of data suggests that it is the cannabidiol (CBD) content that is most responsible for appetite stimulation, antiemetic effects, and many other medicinal properties, according to Michael E. Schatman, Ph.D., executive director of the Foundation for Ethics in Pain Care, Bellevue, Wash.
“Contrary to popular belief, THC is not the most relevant cannabinoid for medical application,” Dr. Schatman said. On the premise that more is better, higher THC content generally correlates with higher cost for medical marijuana as it does for marijuana marketed for recreational use, according to Dr. Schatman. But he disagreed with that notion.
More than 100 cannabinoids are in marijuana, Dr. Schatman said. Although he maintained that CBD might be the most important constituent for many of the medicinal indications for marijuana, he acknowledged that the data are mostly suggestive. Few studies have differentiated marijuana for its therapeutic effects based on representative concentrations of different constituents even if Dr. Schatman cited clinical and experimental work correlating CBD with benefit on a variety of therapeutic targets, including inflammation.
“There is no medical marijuana but medical marijuanas,” said Dr. Schatman, suggesting that specific therapeutic benefits would be expected to differ markedly according to the constituents even if little information exists about the optimal levels of any of these constituents.
For recreational use, THC content is a reasonable quality metric, Dr. Schatman said. THC content predicts the “high” of marijuana. While inducing a state of euphoria might indeed be the goal for some medicinal marijuana applications, high THC content also poses the greatest risk of psychosis, disordered thoughts, and impaired functionality, he said. To this extent, greater THC content might not predict greater benefit.
In the absence of regulatory oversight, the marketing of marijuana rather than the science of its effect dominates all discussion, Dr. Schatman said. He cited data showing a steep increase in THC content subsequent to the growing rate of state legalizations.
“Dispensaries are selling medical marijuana with THC contents as high as 33% with names like Super Brain Damage OG,” Dr. Schatman said. Given the potential for unwanted side effects at THC dose levels likely to impair cognitive function, Dr. Schatman said it might be reasonable to question the therapeutic intent when products feature THC content at levels this high.
So far, only New Jersey has restricted THC content of medical marijuana, placing the ceiling at 10%, Dr. Schatman said. Compared to the 1970s, when street marijuana typically had THC content of about 1% to 2%, Dr. Schatman suggested that even 10% is likely to be excessive if the goal is not be get “stoned.” However, he expressed even greater concern about the declining content of CBD, which he suggested has been inversely related to THC.
“We’ve essentially bred the CBD out of marijuana,” Dr. Schatman reported. One advertisement from a medical marijuana dispensary that he reproduced prominently advertised THC levels at 20% but CBD levels at 0.38%. Whether greater medicinal benefits would be realized if those percentages were reversed is not known, but Dr. Schatman said rational clinical decisions are impossible without data.
“Until the patient knows what he or she is getting, cannabis will not necessarily be medicine in most cases,” Dr. Schatman said. He believes the marijuana should be held to the same standards of efficacy and safety as other drugs. The ideal for moving this field forward might be regulation by the Food and Drug Administration, Dr. Schatman said. But he also called for more rigorous trials of the marijuana constituents to determine which are most important for achieving the specific benefits for which marijuana is being prescribed.
Dr. Schatman is on the speaker’s bureau for Mallinckrodt.
BOSTON – Medical marijuana is now legal in 23 states, but there remains essentially no systematic approach for evaluating whether available products have the capacity to provide medical benefits, according to a status report presented at the International Conference on Opioids.
Often, medical marijuana is marketed on the basis of its psychoactive component, tetrahydrocannabinol (THC), but a substantial body of data suggests that it is the cannabidiol (CBD) content that is most responsible for appetite stimulation, antiemetic effects, and many other medicinal properties, according to Michael E. Schatman, Ph.D., executive director of the Foundation for Ethics in Pain Care, Bellevue, Wash.
“Contrary to popular belief, THC is not the most relevant cannabinoid for medical application,” Dr. Schatman said. On the premise that more is better, higher THC content generally correlates with higher cost for medical marijuana as it does for marijuana marketed for recreational use, according to Dr. Schatman. But he disagreed with that notion.
More than 100 cannabinoids are in marijuana, Dr. Schatman said. Although he maintained that CBD might be the most important constituent for many of the medicinal indications for marijuana, he acknowledged that the data are mostly suggestive. Few studies have differentiated marijuana for its therapeutic effects based on representative concentrations of different constituents even if Dr. Schatman cited clinical and experimental work correlating CBD with benefit on a variety of therapeutic targets, including inflammation.
“There is no medical marijuana but medical marijuanas,” said Dr. Schatman, suggesting that specific therapeutic benefits would be expected to differ markedly according to the constituents even if little information exists about the optimal levels of any of these constituents.
For recreational use, THC content is a reasonable quality metric, Dr. Schatman said. THC content predicts the “high” of marijuana. While inducing a state of euphoria might indeed be the goal for some medicinal marijuana applications, high THC content also poses the greatest risk of psychosis, disordered thoughts, and impaired functionality, he said. To this extent, greater THC content might not predict greater benefit.
In the absence of regulatory oversight, the marketing of marijuana rather than the science of its effect dominates all discussion, Dr. Schatman said. He cited data showing a steep increase in THC content subsequent to the growing rate of state legalizations.
“Dispensaries are selling medical marijuana with THC contents as high as 33% with names like Super Brain Damage OG,” Dr. Schatman said. Given the potential for unwanted side effects at THC dose levels likely to impair cognitive function, Dr. Schatman said it might be reasonable to question the therapeutic intent when products feature THC content at levels this high.
So far, only New Jersey has restricted THC content of medical marijuana, placing the ceiling at 10%, Dr. Schatman said. Compared to the 1970s, when street marijuana typically had THC content of about 1% to 2%, Dr. Schatman suggested that even 10% is likely to be excessive if the goal is not be get “stoned.” However, he expressed even greater concern about the declining content of CBD, which he suggested has been inversely related to THC.
“We’ve essentially bred the CBD out of marijuana,” Dr. Schatman reported. One advertisement from a medical marijuana dispensary that he reproduced prominently advertised THC levels at 20% but CBD levels at 0.38%. Whether greater medicinal benefits would be realized if those percentages were reversed is not known, but Dr. Schatman said rational clinical decisions are impossible without data.
“Until the patient knows what he or she is getting, cannabis will not necessarily be medicine in most cases,” Dr. Schatman said. He believes the marijuana should be held to the same standards of efficacy and safety as other drugs. The ideal for moving this field forward might be regulation by the Food and Drug Administration, Dr. Schatman said. But he also called for more rigorous trials of the marijuana constituents to determine which are most important for achieving the specific benefits for which marijuana is being prescribed.
Dr. Schatman is on the speaker’s bureau for Mallinckrodt.
EXPERT ANALYSIS AT THE INTERNATIONAL CONFERENCE ON OPIOIDS
ASCO: Adjuvant denosumab halves fracture risk for breast cancer patients on AIs
CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).
Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.
Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.
“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”
“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.
“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.
During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”
Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.
The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.
Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).
The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”
Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.
Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.
“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.
There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.
Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.
CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).
Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.
Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.
“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”
“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.
“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.
During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”
Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.
The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.
Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).
The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”
Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.
Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.
“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.
There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.
Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.
CHICAGO – Adjuvant denosumab is efficacious and safe for reducing fracture risk among women taking aromatase inhibitors (AIs) as part of their treatment for early breast cancer, finds the Austrian Breast & Colorectal Cancer Study Group’s study 18 (ABCSG-18).
Compared with peers randomized to placebo in the phase III trial, women randomized to the antiresorptive monoclonal antibody at the dose typically used to treat osteoporosis were half as likely to experience a first clinical fracture, first author Dr. Michael Gnant reported at the annual meeting of the American Society of Clinical Oncology. The benefit was similar whether women had normal bone mineral density at baseline or already had osteopenia.
Patients in the denosumab group did not have a significantly higher rate of adverse events, including the much-feared complication of osteonecrosis of the jaw.
“The actual fracture risk of postmenopausal breast cancer patients on AIs is substantial and may have been underestimated until today,” commented Dr. Gnant, professor of surgery at the Medical University of Vienna. “In these patients with only a modest risk of disease recurrence, adjuvant denosumab significantly reduced the bone side effects of AI treatment. We therefore believe that denosumab 60 mg every 6 months should be considered for clinical practice.”
“Today, several clinical practice guidelines advocate the use of bisphosphonates for breast cancer patients receiving AIs, however, only if they are at high risk for fractures,” he further noted. However, “patients with normal baseline bone mineral density showed a similar fracture risk but also similar benefit from denosumab as compared to patients with baseline T scores below –1, indicating that DEXA scans may be an insufficient way to assess the individual patient’s fracture risk. In view of the benefits in this particular patient subgroup, we may have to rediscuss our current clinical practice guidelines.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England, said, “It’s very important to dissect out fractures related to subsequent recurrence from fractures due to poor bone health.” Most of the reduction in fracture risk in ABCSG-18 appeared to be because of prevention of fractures before any recurrence, whereas most of that in the AZURE trial (Adjuvant Zoledronic Acid to Reduce Recurrence) of an adjuvant bisphosphonate, another type of antiresorptive agent, appeared to be because of prevention of fractures from bone metastases. “So I think we are seeing something very different with denosumab to what we’ve seen to date with a bisphosphonate,” he said.
“As oncologists, we are somewhat wedded to measuring bone mineral density as the reason for giving bone-targeted therapy to protect [against] bone loss, but there are much better ways of predicting fracture with online algorithms such as FRAX [Fracture Risk Assessment Tool] and others,” Dr. Coleman further commented. “And bone mineral density is a pretty poor predictor of fracture, so it’s perhaps not surprising that the risk reductions were fairly similar” across bone mineral density subgroups.
During a question and answer period, session attendee Dr. Toru Watanabe, Hamamatsu (Japan) Oncology Center, said, “It is really clear that the osteoporosis-related fracture is prevented by denosumab at the dose usually used for the treatment of osteoporosis. That part is very clear. My question is, the same dose is being tested for modifying overall survival or progression-free survival. Don’t you think it’s necessary to conduct some kind of dose-finding trial?”
Two studies are addressing the impact of denosumab on breast cancer outcomes, according to Dr. Gnant: the investigators’ ABCSG-18 study and the Study of Denosumab as Adjuvant Treatment for Women With High-Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE), which is using a higher initial dose and tapering after 1 year. “So we will have that indirect comparison at least. My personal expectation would be that there is a trade-off potentially between efficacy and tolerability,” he commented.
The 3,425 postmenopausal breast cancer patients in ABCSG-18 were randomized evenly to receive 60 mg of denosumab or placebo every 6 months. Denosumab is approved by the Food and Drug Administration for the prevention and treatment of fractures due to bone metastases (brand name Xgeva) and osteoporosis after menopause (brand name Prolia), as well as other indications. The study used the dose for postmenopausal osteoporosis, which is much lower than that typically used for bone metastases (120 mg every 4 weeks), Dr. Gnant noted.
Main results showed that denosumab was highly efficacious in reducing the risk of first clinical fractures, meaning those that were clinically evident and causing symptoms (hazard ratio, 0.50; P less than .0001), according to data presented at the meeting and simultaneously published (Lancet 2015 May 31).
The estimated 6-year fracture rate was about 10% in the denosumab group and 20% in the placebo group. “Please note that the frequency of clinical fractures reported in this trial that is focusing on bone health is markedly higher than fracture rates reported in previous large AI trials. Obviously, we had a tendency to underreport them in those trials,” Dr. Gnant commented. “The true magnitude of the problem in clinical practice is likely reflected in the placebo group … with approximately one out of five patients experiencing a new clinical fracture within 5-6 years of adjuvant AI treatment.”
Benefit was similar across numerous patient subgroups studied, including the subgroups of women who had a baseline bone mineral density T-score of less than –1 and women who had a baseline bone mineral density T-score of –1 or greater.
Additionally, the denosumab group had improvements from baseline in bone mineral density of the lumbar spine, total hip, and femoral neck, whereas the placebo group had worsening at all sites (P less than .0001 between groups for each site). And at 36 months, the denosumab group had significantly lower risks of both new vertebral fractures and new or worsening vertebral fractures.
“Adjuvant denosumab at this dose and schedule is safe,” Dr. Gnant maintained. The two groups had similar rates of various adverse events, with musculoskeletal disorders and vascular disorders (including hot flashes) predominating. “This means that we are in essence reporting the side effects of the underlying adjuvant AI treatment,” he noted.
There were 31 cases of dental issues, but none met diagnostic criteria for osteonecrosis of the jaw. “We can safely say that at this dose of denosumab, 60 mg twice yearly, ONJ is not an issue,” Dr. Gnant commented. Additionally, none of the women experienced atypical fractures.
Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: Denosumab reduces the risk of clinical fractures in postmenopausal women taking AIs for early breast cancer.
Major finding: The denosumab group was half as likely to have a first clinical fracture as the placebo group (HR, 0.50).
Data source: A randomized phase III trial among 3,425 postmenopausal women with early breast cancer taking AIs.
Disclosures: Dr. Gnant disclosed employment of an immediate family member with Sandoz; receipt of honoraria from Amgen, AstraZeneca, GlaxoSmithKline, NanoString Technologies, Novartis, and Roche Pharma AG; a consulting or advisory role with Accelsiors, AstraZeneca, and Novartis; and receipt of research funding from GlaxoSmithKline, Novartis, Pfizer, Roche Pharma AG, Sanofi, and Smiths Medical. The trial was sponsored by Amgen.
ICOO: Opioid self-dosing falls short of pain control
BOSTON – Many cancer patients do not pursue or at least do not achieve complete freedom from pain when permitted control over their opioid dose, according to a comprehensive analysis of published studies that evaluated patient-controlled analgesia.
“We do not know why. Patients were encouraged in these studies to titrate opioids until they were pain free or until they had side effects. Although this could be an issue of side effects, another interpretation is that complete pain control is not the goal for many individuals,” reported Dr. Brian H. Wetherington of the University of Kentucky, Lexington.
The data from this analysis were presented at the International Conference on Opioids from a comprehensive literature search that included 905 potentially relevant articles. Of these, 62 met inclusion criteria, particularly an assessment of patient-controlled opioids in patients with cancer pain. The studies also had to assess pain control with a visual analog scale (VAS) or the Neuropathy Pain Scale (NPS) using a 10-point system with 10 being the greatest level of pain imaginable.
“We were interested in evaluating whether patients, when given complete control over their opioids, would take sufficient doses to provide complete pain relief, which is often stated as the goal in pain management,” explained Dr. Wetherington, who was coauthor of a study led by his colleague at University of Kentucky, Dr. Michael Harned.
The answer was no. When the data from the 62 studies, which included 5,251 patients with cancer pain were collated, the average pain score at baseline was 5.4. At the time of assessment of pain control, the mean pain score was 2.7.
“The mean pain score for patients managing their own cancer pain on opioids was reduced from study entry but remained at the moderate to severe pain level or higher than what many health care providers would recommend,” Dr. Wetherington reported.
This review of published studies does not explain why lower pain scores are not reached, but the Dr. Wetherington and his coauthors hypothesized that patients are demonstrating their own benefit-to-risk ratio assessment.
This is thought to be the first systematic review to find that patients do not seek complete control of pain when given access to unrestricted analgesia, but several individual studies have made the same point. In one study cited by the authors, patients on a fentanyl patch only reduced their pain scores to 3.0 on average when given unlimited access to oral morphine for breakthroughs (J. Pain Symptom Manage. 1998;16:102-11).
“We think this deserves further study, because there may be lessons regarding how we think of optimal pain control. While the therapeutic target is often described as complete pain relief, these data suggest that this may not be the goal for patients when they are left to select their own level of pain control,” Dr. Wetherington explained.
The same observation regarding the failure of patients to eliminate all pain on patient-controlled analgesia has been made anecdotally by Dr. William G. Brose of Stanford (Calif.) University. However, he suggested in an interview that patients might be reluctant to rate themselves completely pain free on a subjective scale. He also believes that level of analgesia may not be the most relevant endpoint.
“We are increasingly evaluating change in patient function, which may be a more useful tool for evaluating the efficacy of pain control,” Dr. Brose said.
BOSTON – Many cancer patients do not pursue or at least do not achieve complete freedom from pain when permitted control over their opioid dose, according to a comprehensive analysis of published studies that evaluated patient-controlled analgesia.
“We do not know why. Patients were encouraged in these studies to titrate opioids until they were pain free or until they had side effects. Although this could be an issue of side effects, another interpretation is that complete pain control is not the goal for many individuals,” reported Dr. Brian H. Wetherington of the University of Kentucky, Lexington.
The data from this analysis were presented at the International Conference on Opioids from a comprehensive literature search that included 905 potentially relevant articles. Of these, 62 met inclusion criteria, particularly an assessment of patient-controlled opioids in patients with cancer pain. The studies also had to assess pain control with a visual analog scale (VAS) or the Neuropathy Pain Scale (NPS) using a 10-point system with 10 being the greatest level of pain imaginable.
“We were interested in evaluating whether patients, when given complete control over their opioids, would take sufficient doses to provide complete pain relief, which is often stated as the goal in pain management,” explained Dr. Wetherington, who was coauthor of a study led by his colleague at University of Kentucky, Dr. Michael Harned.
The answer was no. When the data from the 62 studies, which included 5,251 patients with cancer pain were collated, the average pain score at baseline was 5.4. At the time of assessment of pain control, the mean pain score was 2.7.
“The mean pain score for patients managing their own cancer pain on opioids was reduced from study entry but remained at the moderate to severe pain level or higher than what many health care providers would recommend,” Dr. Wetherington reported.
This review of published studies does not explain why lower pain scores are not reached, but the Dr. Wetherington and his coauthors hypothesized that patients are demonstrating their own benefit-to-risk ratio assessment.
This is thought to be the first systematic review to find that patients do not seek complete control of pain when given access to unrestricted analgesia, but several individual studies have made the same point. In one study cited by the authors, patients on a fentanyl patch only reduced their pain scores to 3.0 on average when given unlimited access to oral morphine for breakthroughs (J. Pain Symptom Manage. 1998;16:102-11).
“We think this deserves further study, because there may be lessons regarding how we think of optimal pain control. While the therapeutic target is often described as complete pain relief, these data suggest that this may not be the goal for patients when they are left to select their own level of pain control,” Dr. Wetherington explained.
The same observation regarding the failure of patients to eliminate all pain on patient-controlled analgesia has been made anecdotally by Dr. William G. Brose of Stanford (Calif.) University. However, he suggested in an interview that patients might be reluctant to rate themselves completely pain free on a subjective scale. He also believes that level of analgesia may not be the most relevant endpoint.
“We are increasingly evaluating change in patient function, which may be a more useful tool for evaluating the efficacy of pain control,” Dr. Brose said.
BOSTON – Many cancer patients do not pursue or at least do not achieve complete freedom from pain when permitted control over their opioid dose, according to a comprehensive analysis of published studies that evaluated patient-controlled analgesia.
“We do not know why. Patients were encouraged in these studies to titrate opioids until they were pain free or until they had side effects. Although this could be an issue of side effects, another interpretation is that complete pain control is not the goal for many individuals,” reported Dr. Brian H. Wetherington of the University of Kentucky, Lexington.
The data from this analysis were presented at the International Conference on Opioids from a comprehensive literature search that included 905 potentially relevant articles. Of these, 62 met inclusion criteria, particularly an assessment of patient-controlled opioids in patients with cancer pain. The studies also had to assess pain control with a visual analog scale (VAS) or the Neuropathy Pain Scale (NPS) using a 10-point system with 10 being the greatest level of pain imaginable.
“We were interested in evaluating whether patients, when given complete control over their opioids, would take sufficient doses to provide complete pain relief, which is often stated as the goal in pain management,” explained Dr. Wetherington, who was coauthor of a study led by his colleague at University of Kentucky, Dr. Michael Harned.
The answer was no. When the data from the 62 studies, which included 5,251 patients with cancer pain were collated, the average pain score at baseline was 5.4. At the time of assessment of pain control, the mean pain score was 2.7.
“The mean pain score for patients managing their own cancer pain on opioids was reduced from study entry but remained at the moderate to severe pain level or higher than what many health care providers would recommend,” Dr. Wetherington reported.
This review of published studies does not explain why lower pain scores are not reached, but the Dr. Wetherington and his coauthors hypothesized that patients are demonstrating their own benefit-to-risk ratio assessment.
This is thought to be the first systematic review to find that patients do not seek complete control of pain when given access to unrestricted analgesia, but several individual studies have made the same point. In one study cited by the authors, patients on a fentanyl patch only reduced their pain scores to 3.0 on average when given unlimited access to oral morphine for breakthroughs (J. Pain Symptom Manage. 1998;16:102-11).
“We think this deserves further study, because there may be lessons regarding how we think of optimal pain control. While the therapeutic target is often described as complete pain relief, these data suggest that this may not be the goal for patients when they are left to select their own level of pain control,” Dr. Wetherington explained.
The same observation regarding the failure of patients to eliminate all pain on patient-controlled analgesia has been made anecdotally by Dr. William G. Brose of Stanford (Calif.) University. However, he suggested in an interview that patients might be reluctant to rate themselves completely pain free on a subjective scale. He also believes that level of analgesia may not be the most relevant endpoint.
“We are increasingly evaluating change in patient function, which may be a more useful tool for evaluating the efficacy of pain control,” Dr. Brose said.
AT ICOO 2015
Key clinical point: Given the opportunity, patients do not titrate opioid therapy to a point of complete pain control, according to a comprehensive survey of published studies.
Major finding: In a survey of 62 published studies of cancer patients who were provided unlimited access to opioids for pain control, the average pain control was 2.7 on a scale of 10, indicating that most patients do not seek or are unable to achieve complete control with an acceptable benefit-to-risk ratio.
Data source: Retrospective data review.
Disclosures: The study was investigator initiated. Dr. Wetherington reported having no financial disclosures.
Three bisphosphonates found on par in early breast cancer
CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.
Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.
“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.
“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.
Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”
“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”
Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.
Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.
In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.
The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.
At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.
The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.
Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.
The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.
Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.
CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.
Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.
“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.
“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.
Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”
“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”
Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.
Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.
In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.
The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.
At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.
The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.
Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.
The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.
Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.
CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.
Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.
“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”
Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.
“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.
Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”
“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”
Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.
Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.
In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.
The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.
At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.
The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.
Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.
The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.
Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: Adjuvant zoledronic acid, clodronate, and ibandronate yield similar disease-free survival in early breast cancer.
Major finding: Five-year disease-free survival was 88% with no significant difference across the three bisphosphonates.
Data source: A randomized phase III trial among 6,097 women receiving adjuvant systemic therapy for stage I-III breast cancer.
Disclosures: Dr. Gralow disclosed that she has a consulting or advisory role with Genentech and Novartis, and her institution receives research funding from Amgen, Novartis, and Roche/Genentech.
ASCO: Precision medicine initiatives take wing
CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.
At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.
The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.
“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.
NCI-MATCH
NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.
Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.
Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.
If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.
The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).
“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.
TAPUR Trial
In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”
The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”
The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.
The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).
Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.
The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.
Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.
The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.
CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.
At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.
The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.
“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.
NCI-MATCH
NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.
Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.
Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.
If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.
The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).
“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.
TAPUR Trial
In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”
The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”
The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.
The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).
Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.
The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.
Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.
The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.
CHICAGO – It’s getting very personal in oncology, and that’s a very good thing.
At the annual meeting of the American Society of Clinical Oncology, major cancer organizations announced new precision medicine initiatives that will attempt to match patients who have advanced cancers with the best available therapies based not on the location or histologic subtypes of their tumors, but on specific molecular abnormalities.
The National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial will begin enrolling patients in July 2015. The study’s objective is “to understand the relative efficacy of the same therapy applied to oncogene-defined subsets across the entire cancer population as defined by site of origin or tumor histology,” said co–principal investigator Dr. Keith T. Flaherty of Harvard Medical School, Boston.
“This is the beginning, not the end, in terms of how we think about applying these therapies,” he said at a briefing that was held to announce the start of trial enrollment and a second initiative – the Targeted Agent and Profiling Utilization Registry (TAPUR) Study – by ASCO in cooperation with major pharmaceutical companies.
NCI-MATCH
NCI-MATCH is a phase II trial that will be operated through the National Clinical Trials Network. Oncologists at participating centers throughout the United States can enroll patients aged 18 years and older who have solid tumors or lymphomas that have relapsed or are refractory to conventional therapy, or who have a type of cancer for which no effective, consensus-based therapy is available.
Investigators plan to screen 3,000 patients initially, with the goal of enrolling 1,000 patients distributed among several substudies that will be evaluating specific drugs against specific molecular targets.
Patients will undergo biopsy at study entry, and their tumors will be subjected to genomic analysis to detect specific, targetable molecular abnormalities.
If a patient has a specific abnormality that is being explored in a current substudy, that patient will be further evaluated to determine whether he or she meets the eligibility criteria for that trial arm. Once enrolled, patients can remain on therapy until disease progression. The therapies will include both currently marketed agents and investigational therapies contributed by drug companies. Most of the trial arms will explore monotherapy with a targeted agent, but a few may investigate combinations which have accumulated enough safety and efficacy data to suggest that they might work against a specific molecular target.
The primary endpoint will be overall response rate, with a secondary endpoint of 6-month progression-free survival (PFS).
“This holds promise to bring faster cures to millions of Americans who so desperately need them,” ASCO past president Dr. Clifford A. Hudis said at the briefing.
TAPUR Trial
In cooperation with major pharmaceutical manufacturers (currently five, with more expected to sign on), ASCO has initiated a study designed to help answer the question, “I’ve got the tumor genome – now what do I do with it?”
The goal of the TAPUR trial, says ASCO Chief Medical Officer Dr. Richard Schilsky, is “to learn from the real world practice of prescribing targeted therapies to patients with advanced cancer whose tumor harbors a genomic variant known to be a drug target.”
The primary objectives are to describe the antitumor activity and toxicity profiles of targeted therapies, and to help patients get access to Food and Drug Administration–approved agents from which they may be able to benefit.
The trial will enroll patients with advanced solid tumors, B-cell non-Hodgkin’s lymphomas, and multiple myelomas for which there are no standard therapies. The patients must have adequate organ function and good performance status (0-2).
Patients will be matched by their personal physicians to specific therapies, if such a match exists; otherwise, they will be treated at the physician’s discretion.
The primary endpoint of the study will be overall response rates by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints will be PFS, OS, time on treatment, grade 3 or greater adverse events, and serious adverse event. The investigators plan to begin patient enrollment in the fourth quarter of 2015.
Current industry partners include AstraZeneca, Bristol Myers Squibb, Eli Lilly, Genentech, and Pfizer.
The NCI-MATCH study is funded by the National Institutes of Health. Dr. Flaherty has received NIH research grants. Dr. Hudis disclosed ties to AstraZeneca, Sanofi-Aventis, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Ortho Biotech, Pfizer, and Roche. Dr. Schilsky disclosed no relevant conflicts of interest.
AT THE 2015 ASCO ANNUAL MEETING
Less intensive childhood cancer therapy reduces late toxicities, deaths
CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.
For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.
“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.
But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.
The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.
The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.
At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).
In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).
In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.
Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.
The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).
Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.
“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.
The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.
CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.
For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.
“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.
But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.
The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.
The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.
At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).
In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).
In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.
Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.
The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).
Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.
“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.
The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.
CHICAGO – Decades-old efforts to reduce the intensity of therapies for childhood cancers are paying off, resulting in significant declines in late all-cause mortality among those who survive 5-years after a cancer diagnosis, investigators report.
For patients treated in the 1970s for childhood cancers, the 15-year cumulative mortality rate was 3.1%, compared with 2.4% for those treated in the 80’s, and 1.9% for those treated in the 90’s, reported Dr. Gregory T. Armstrong from St. Jude’s Children’s Research Hospital, Memphis.
“The improvement in cure rate of childhood cancer is really one of the success stories of modern medicine. If you go back to the 1960s, less than 30-40% of children were surviving cancer. Currently, over 82% of children will become 5-year survivors,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
“However, these 5-year survivors, as they move forward, are still at risk for late events and early mortality. As shown previously for these 5-year survivors, even after hitting the 5-year turning point, 18% will be deceased 30 years from diagnosis,” he said.
But efforts to reduce the intensity of therapy without compromising the quality of care appear to be having their effect, as seen in long-term follow-up results from patients in the Childhood Cancer Survivor Study.
The study, initiated in 1994, follows a retrospective cohort of children treated at 31 US and Canadian hospitals from 1970 through 1999 for common childhood malignancies, including leukemias, lymphomas, central nervous system malignancies, Wilms tumor, neuroblastoma, and sarcomas of soft tissues and/or bones.
The investigators looked at follow-up data on 34,033 cohort members who were alive 5 years after diagnosis, and for whom there was detailed information on the cumulative chemotherapy dose exposures and organ-specific radiotherapy dosimetry.
At a median follow-up of 21 years, 3958 (12%) of the cohort had died, and of this group 1618 (41%) were deemed to have died from health-related causes, including late effects of cancer therapy, such as cardiovascular causes (243 deaths), pulmonary problems (136), and second malignancies (751 deaths).
In each category and in all-cause mortality, there were significant reductions in the cumulative incidence of deaths over time. For example: all-cause mortality declined from 12.4% during the 1970-74 era to 6.0 from 1990-94 (P < .001), deaths from second cancers dropped from 1.8% to 1.0% over the same period (P < .001), cardiac-related deaths fell from 0.5% to 0.1% (P = .001), and pulmonary deaths declined from 0.4% to 0.1% (P = .02).
In a multivariable analysis adjusted for age at diagnosis, sex, and diagnosis and follow-up time, each 5-year interval was associated with a significant reduction in deaths from other health related causes (relative risk [RR] 0.86), subsequent neoplasm (RR 0.83), cardiac causes (RR 0.77), and pulmonary disease (RR 0.77). The confidence intervals for all variables indicated statistical significance.
Additionally, when they looked at specific cancers, they saw declines in cardiac mortality for acute lymphoblastic leukemia, Hodgkin’s lymphoma, and Wilms tumor, and a decrease in second malignancies for patients with Wilms tumor.
The reductions in deaths paralleled changes in clinical practice, notably reductions in the use of cranial radiotherapy for patients with acute lymphoblastic leukemia from 86% of patients in the 70s to 22% in the 90s, as well as reductions in abdominal radiation given to children with Wilms tumor (from 77% to 49%, respectively) and in chest radiation given for Hodgkin’s lymphoma (from 96% to 77%).
Dr. Michael P. Link, professor in pediatric cancer at Stanford University School of Medicine, the invited discussant, said the study results provide important lessons for clinicians treating adult as well as childhood cancers. He noted that reductions in the intensity of therapy and limiting exposures results in decreases in late organ toxicity, secondary cancers, and mortality.
“The translation and modification of therapy designed to reduce exposures into clinically significant reductions in all-cause late mortality is a gratifying validation of three decades of refining our therapies to accomplish the same number of cures while lowering the cost of cure,” he said.
The Childhood Cancer Survivor Study is funded by the National Institutes of Health. Dr. Armstrong and Dr. Link reported no relevant disclosures.
AT ASCO 2015
Cancer survivors’ informational needs vary by time, cancer type
A 3-year study of over 2,000 cancer survivors revealed that information seeking among cancer survivors varied over time and was often contingent on the specific type of cancer.
With the help of the University of Pennsylvania’s Annenberg School for Communication, the investigators, led by Dr. Andy Tan of the Dana-Farber Cancer Institute, Boston, surveyed cancer survivors diagnosed with colon, breast, or prostate cancer annually from 2006 to 2008. The most frequently reported topic across survivors and over time was seeking information about reducing the odds for cancer recurrence, with 28% of cancer survivors reporting that they had looked for information about recurrence. Twelve percent said that they had looked for information about the risks of their family members getting a different cancer from their diagnosis.
Information seeking increased or decreased over time based on cancer type and gender. For example, breast cancer survivors grew increasingly less likely to seek information about survivorship topics over their survivorship timeframe, but female colon cancer survivors grew more likely to seek information about how to reduce the risk of family members getting colon cancer in later years when compared with female breast cancer survivors.
Clinicians may be advised to provide information at distinct points during the survivorship period to address concerns about cancer recurrence, late effects, and family members’ risks, Dr. Tan and his associates wrote.
Read the full article here: Cancer Epidemiol. Biomarkers Prev. 2015 May 15 (doi:10.1158/1055-9965.EPI-15-0041)
A 3-year study of over 2,000 cancer survivors revealed that information seeking among cancer survivors varied over time and was often contingent on the specific type of cancer.
With the help of the University of Pennsylvania’s Annenberg School for Communication, the investigators, led by Dr. Andy Tan of the Dana-Farber Cancer Institute, Boston, surveyed cancer survivors diagnosed with colon, breast, or prostate cancer annually from 2006 to 2008. The most frequently reported topic across survivors and over time was seeking information about reducing the odds for cancer recurrence, with 28% of cancer survivors reporting that they had looked for information about recurrence. Twelve percent said that they had looked for information about the risks of their family members getting a different cancer from their diagnosis.
Information seeking increased or decreased over time based on cancer type and gender. For example, breast cancer survivors grew increasingly less likely to seek information about survivorship topics over their survivorship timeframe, but female colon cancer survivors grew more likely to seek information about how to reduce the risk of family members getting colon cancer in later years when compared with female breast cancer survivors.
Clinicians may be advised to provide information at distinct points during the survivorship period to address concerns about cancer recurrence, late effects, and family members’ risks, Dr. Tan and his associates wrote.
Read the full article here: Cancer Epidemiol. Biomarkers Prev. 2015 May 15 (doi:10.1158/1055-9965.EPI-15-0041)
A 3-year study of over 2,000 cancer survivors revealed that information seeking among cancer survivors varied over time and was often contingent on the specific type of cancer.
With the help of the University of Pennsylvania’s Annenberg School for Communication, the investigators, led by Dr. Andy Tan of the Dana-Farber Cancer Institute, Boston, surveyed cancer survivors diagnosed with colon, breast, or prostate cancer annually from 2006 to 2008. The most frequently reported topic across survivors and over time was seeking information about reducing the odds for cancer recurrence, with 28% of cancer survivors reporting that they had looked for information about recurrence. Twelve percent said that they had looked for information about the risks of their family members getting a different cancer from their diagnosis.
Information seeking increased or decreased over time based on cancer type and gender. For example, breast cancer survivors grew increasingly less likely to seek information about survivorship topics over their survivorship timeframe, but female colon cancer survivors grew more likely to seek information about how to reduce the risk of family members getting colon cancer in later years when compared with female breast cancer survivors.
Clinicians may be advised to provide information at distinct points during the survivorship period to address concerns about cancer recurrence, late effects, and family members’ risks, Dr. Tan and his associates wrote.
Read the full article here: Cancer Epidemiol. Biomarkers Prev. 2015 May 15 (doi:10.1158/1055-9965.EPI-15-0041)
FROM CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION
VIDEO: Level of e-cigarette power contributes to potentially hazardous effects
DENVER – The higher the power of an e-cigarette, the higher the concentrations of potentially hazardous substances the device produces, including acetaldehyde, acrolein, and formaldehyde.
Those are among the findings presented at an international conference of the American Thoracic Society by lead study author Dr. Daniel Sullivan, an internal medicine resident at the University of Texas Southwestern Medical Center. During his previous training at the University of Alabama, Birmingham, Dr. Sullivan and his associates used a variety of methods including liquid chromatography–mass spectrometry and enzyme-linked immunosorbent assay (ELISA) to study components and nicotine formulations typical of e-cigarette users. Under some test conditions, formaldehyde levels were comparable to those seen in traditional tobacco cigarettes, he said in a video interview.
Dr. Sullivan reported having no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @dougbrunk
DENVER – The higher the power of an e-cigarette, the higher the concentrations of potentially hazardous substances the device produces, including acetaldehyde, acrolein, and formaldehyde.
Those are among the findings presented at an international conference of the American Thoracic Society by lead study author Dr. Daniel Sullivan, an internal medicine resident at the University of Texas Southwestern Medical Center. During his previous training at the University of Alabama, Birmingham, Dr. Sullivan and his associates used a variety of methods including liquid chromatography–mass spectrometry and enzyme-linked immunosorbent assay (ELISA) to study components and nicotine formulations typical of e-cigarette users. Under some test conditions, formaldehyde levels were comparable to those seen in traditional tobacco cigarettes, he said in a video interview.
Dr. Sullivan reported having no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @dougbrunk
DENVER – The higher the power of an e-cigarette, the higher the concentrations of potentially hazardous substances the device produces, including acetaldehyde, acrolein, and formaldehyde.
Those are among the findings presented at an international conference of the American Thoracic Society by lead study author Dr. Daniel Sullivan, an internal medicine resident at the University of Texas Southwestern Medical Center. During his previous training at the University of Alabama, Birmingham, Dr. Sullivan and his associates used a variety of methods including liquid chromatography–mass spectrometry and enzyme-linked immunosorbent assay (ELISA) to study components and nicotine formulations typical of e-cigarette users. Under some test conditions, formaldehyde levels were comparable to those seen in traditional tobacco cigarettes, he said in a video interview.
Dr. Sullivan reported having no relevant financial conflicts.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @dougbrunk
AT ATS 2015
Significant response to lacosamide in a patient with severe chemotherapy-induced peripheral neuropathy
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Click on the PDF icon at the top of this introduction to read the full article.
Symptom-related emergency department visits and hospital admissions during ambulatory cancer treatment
Background People with cancer experience symptoms related to the disease and treatments. Symptom distress has a negative impact on quality of life (QoL). Attending to symptoms and side effects of treatment promotes safe and effective delivery of therapies and may prevent or reduce emergency department visits (EDVs) and unplanned hospital admissions (HAs). There is limited evidence examining symptom-related EDVs or HAs (sx-EDV/HAs) and interventions in ambulatory oncology patients.
Objective To examine factors associated with sx-EDV/HAs in ambulatory oncology patients receiving chemotherapy and/or radiation.
Methods This secondary analysis used data from a randomized controlled trial of ambulatory oncology patients (n = 663) who received the web-based Electronic Self-Report Assessment – Cancer intervention (symptom self-monitoring, tailored education, and communication coaching) or usual care with symptom self-monitoring alone. Group differences were described by summary statistics and compared by t test. Factors associated with the odds of at least 1 sx-EDV/HA were modeled using logistic regression.
Results 98 patients had a total of 171 sx-EDV/HAs with no difference between groups. Higher odds of at least 1 sx-EDV/HA were associated with socioeconomic and clinical factors. The multivariable model indicated that work status, education level, treatment modality, and on-treatment Symptom Distress Scale-15 scores were significantly associated with having at least 1 sx-EDV/HA.
Limitations This is a secondary analysis not sized to determine cause and effect. The results have limited generalizability.
Conclusion Most patients did not experience a sx-EDV/HA. Demographic and clinical factors predicted a sx-EDV/HA.
Funding National Institute of Nursing Research, National Institutes of Health, R01 NR008726; 2008-2011
Click on the PDF icon at the top of this introduction to read the full article.
Background People with cancer experience symptoms related to the disease and treatments. Symptom distress has a negative impact on quality of life (QoL). Attending to symptoms and side effects of treatment promotes safe and effective delivery of therapies and may prevent or reduce emergency department visits (EDVs) and unplanned hospital admissions (HAs). There is limited evidence examining symptom-related EDVs or HAs (sx-EDV/HAs) and interventions in ambulatory oncology patients.
Objective To examine factors associated with sx-EDV/HAs in ambulatory oncology patients receiving chemotherapy and/or radiation.
Methods This secondary analysis used data from a randomized controlled trial of ambulatory oncology patients (n = 663) who received the web-based Electronic Self-Report Assessment – Cancer intervention (symptom self-monitoring, tailored education, and communication coaching) or usual care with symptom self-monitoring alone. Group differences were described by summary statistics and compared by t test. Factors associated with the odds of at least 1 sx-EDV/HA were modeled using logistic regression.
Results 98 patients had a total of 171 sx-EDV/HAs with no difference between groups. Higher odds of at least 1 sx-EDV/HA were associated with socioeconomic and clinical factors. The multivariable model indicated that work status, education level, treatment modality, and on-treatment Symptom Distress Scale-15 scores were significantly associated with having at least 1 sx-EDV/HA.
Limitations This is a secondary analysis not sized to determine cause and effect. The results have limited generalizability.
Conclusion Most patients did not experience a sx-EDV/HA. Demographic and clinical factors predicted a sx-EDV/HA.
Funding National Institute of Nursing Research, National Institutes of Health, R01 NR008726; 2008-2011
Click on the PDF icon at the top of this introduction to read the full article.
Background People with cancer experience symptoms related to the disease and treatments. Symptom distress has a negative impact on quality of life (QoL). Attending to symptoms and side effects of treatment promotes safe and effective delivery of therapies and may prevent or reduce emergency department visits (EDVs) and unplanned hospital admissions (HAs). There is limited evidence examining symptom-related EDVs or HAs (sx-EDV/HAs) and interventions in ambulatory oncology patients.
Objective To examine factors associated with sx-EDV/HAs in ambulatory oncology patients receiving chemotherapy and/or radiation.
Methods This secondary analysis used data from a randomized controlled trial of ambulatory oncology patients (n = 663) who received the web-based Electronic Self-Report Assessment – Cancer intervention (symptom self-monitoring, tailored education, and communication coaching) or usual care with symptom self-monitoring alone. Group differences were described by summary statistics and compared by t test. Factors associated with the odds of at least 1 sx-EDV/HA were modeled using logistic regression.
Results 98 patients had a total of 171 sx-EDV/HAs with no difference between groups. Higher odds of at least 1 sx-EDV/HA were associated with socioeconomic and clinical factors. The multivariable model indicated that work status, education level, treatment modality, and on-treatment Symptom Distress Scale-15 scores were significantly associated with having at least 1 sx-EDV/HA.
Limitations This is a secondary analysis not sized to determine cause and effect. The results have limited generalizability.
Conclusion Most patients did not experience a sx-EDV/HA. Demographic and clinical factors predicted a sx-EDV/HA.
Funding National Institute of Nursing Research, National Institutes of Health, R01 NR008726; 2008-2011
Click on the PDF icon at the top of this introduction to read the full article.