Τετάρτη, 30 Σεπτεμβρίου 2020
In a national study of older Danes who had previously had a fracture and were taking bisphosphonates, the risk of having a serious though rare atypical femoral fracture (AFF) was greater after 3 to 5 years of bisphosphonate use.
The risk quickly dropped after patients stopped taking a bisphosphonate, which suggests that bisphosphonate "holidays" may be useful for some patients, the researchers say. These findings support previous work.
But the study also found that 34% of the AFFs occurred in patients who had not been taking a bisphosphonate. That rate is higher than the 6% to 22% that has been reported by others.
Doug Bauer, MD, from the University of California, San Francisco, presented the new study findings during the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting.
"We found no clear risk factor that accounts for this increased risk [for AFFs] among those not exposed to bisphosphonates," he said, "but we believe this was a real finding, as our study protocol ensured that the study radiologists were completely blinded to treatments received."
Suzanne N. Morin, MD, who was not involved in this research, pointed out that the reported AFF risks related to bisphosphonate dose and cessation are in keeping with findings of other studies, including a recent large study by Dennis M. Black, MD, and colleagues that was published in The New England Journal of Medicine.
That study found that Asians are at higher risk for AFFs than White persons. Others have reported that specific femur geometry or physique and use of glucocorticoids increase AFF risk, Morin, from the Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, told Medscape Medical News.
The current study suggests that rheumatoid arthritis may be a risk factor, she added.
The fact that the rate of AFFs among patients who had not been exposed to bisphosphonates was higher than previously reported "may be due to differences in the method they used to ascertain the fractures or in medication use," she also speculated.
The clinical implications of research to date are that "the risk of AFF should not dissuade patients and providers from short-term use of bisphosphonates (3 to 5 years)," Bauer told Medscape Medical News. He noted that most patients should not take a bisphosphonate for longer than this unless they have a very high fracture risk.
Similarly, Morin said that clinicians "should consider initiating bisphosphonate in those at high risk for fractures and reevaluate their use after 3 to 6 years, depending on individual's risk profile."
AFF Is Serious but Rare Complication of Bisphosphonate Use
"Since first reported over 10 years ago, it has become clear that AFFs are a rare but serious complication of bisphosphonate therapy," Bauer explained.
However, there is still uncertainty about the magnitude of this risk, including the absolute risk for AFFs among adults who take bisphosphonates and those who do not.
To study this, the researchers analyzed data from national healthcare and pharmacy records and a radiology image database in Denmark.
They identified almost 5000 adults who were aged 50 years or older and who experienced a subtrochanteric and femoral shaft fracture during the period 2010 to 2015.
Two expert radiologists who were blinded to the patients' clinical history or treatment identified AFF on the basis of ASBMR 2014 criteria.
The researchers compared three patient groups:
189 patients with AFF
2397 patients with typical subtrochanteric and femoral shaft fractures (no AFF)
35,946 adults older than age 50 (control persons)
Compared to patients with typical fractures, patients with AFF were younger (aged 71 vs 77), more likely to be women (79% vs 69%), and more likely to have rheumatoid arthritis (12% vs 2.5%).
Compared to patients in the other two groups, those with AFF were more likely to use corticosteroids, proton pump inhibitors, statins, and hormone replacement therapy.
They were also more likely to use bisphosphonates (58%) than patients with typical subtrochanteric and femoral shaft fractures (19%) or control patients (10%).
34% of Patients With AFFs Had No Bisphosphonate Exposure
In this national cohort of adults older than 50, the absolute rates of AFF per 10,000 person-years were as follows:
0.07 in nonusers of bisphosphonates
1.84 in those with 3 to 5 years of bisphosphonate use
4.63 in those with >7 years of bisphosphonate use
As a comparison, the rate of classic hip fracture was 43.8 per 10,000 person-years.
Compared to no bisphosphonate use, the relative risk for AFF was close to 40 times higher with more than 7 years of use, after adjusting for multiple confounders.
The risk for AFF was also significantly higher among patients with rheumatoid arthritis or hypertension and for those who used proton pump inhibitors.
"Note that age, gender, and previous fracture were not associated with the risk of AFF" after controlling for multiple confounders, Bauer stressed.
The relative risk for AFF fell significantly after it had been withheld from use for more than 1 year.
Among the 189 patients with confirmed AFF, 64 patients (34%) had never taken a bisphosphonate.
Preliminary analysis showed that among patients with AFF, those who had not been exposed to bisphosphonates were younger, more likely to be male, and less likely to have had a previous fracture, rheumatoid arthritis, or to have used corticosteroids, proton pump inhibitors, statins, or hormone replacement therapy.
The study was funded by the National Institutes of Health's National Institute of Arthritis and Musculoskeletal and Skin Diseases. Bauer and Morin have disclosed no relevant financial relationships.
The American Society of Bone and Mineral Research (ASBMR) 2020 Annual Meeting Virtual Event: Presented September 13, 2020.
Medscape Medical News © 2020
The new prostate-cancer drug darolutamide lowers the risk of death by 31% at the three-year mark for men with nonmetastatic, castration-resistant prostate cancer, according to new data from the phase-3 ARAMIS study. Finland's Orino and Germany's Bayer, which paid for the test, had previously announced that the drug, sold under the brand name Nubeqa, had produced a median metastasis-free survival of 40.4 months versus 18.4 months with placebo. The new report, in the New England Journal of Medicine, says that overall survival at three years was 83% with the drug versus 77% with placebo (P=0.003). The drug is given in conjunction with androgen-deprivation therapy. The study involved 1,509 men, all with a PSA doubling time of 10 months or less. The metastasis-free survival data served as the basis for the drug's approval by the U.S. Food and Drug Administration in July 2019. The time to pain progression, a secondary end point, was 40.3 months with darolutamide and 25.4 months with placebo (P<0.001) The treatment carries a price tag of more than $11,000 per month, according to prices on goodrx.com. Darolutamide is an androgen-receptor inhibitor. It was not compared to other treatments marketed by Astellas, Pfizer and Johnson and Johnson. Side effects were comparable in both groups, but fatigue was more common with darolutamide, seen in 13.2% versus 8.3% with placebo. All other side effects were seen in fewer than 10% of patients. "The incidence of adverse events commonly associated with androgen-receptor inhibitors, including falls, seizures, mentalimpairment disorders, and hypertension, was similar in the two groups," said the team, led by Dr. Karim Fizazi of the University of Paris-Saclay. "The incidence of fractures was slightly higher in the darolutamide group than in the placebo group; however, after adjustment for the duration of exposure, the between-group difference decreased." According to a 2014 deal, Bayer has the right to commercialize darolutamide globally while Orion will manufacture the product and receive milestone payments upon first sale in different markets. Nonmetastatic, castration-resistant prostate cancer occurs in about 15,000 of the 160,000 new cases of prostate cancer diagnosed annually in the U.S.
“[High tumor mutational burden status] identifies a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy. Tissue tumor mutational burden could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
Πέμπτη, 17 Σεπτεμβρίου 2020
The use of immunotherapy for upper gastrointestinal tumors and renal cancer, ALK- and EGFR-targeted agents in non–small cell lunger cancer (NSCLC), and the next step in personalized prostate cancer management will all be subjects of headlining presentations at the ESMO Virtual Congress 2020.
The conference will, like so many other major events, be held online this year because of the COVID-19 pandemic.
John B. Haanen, PhD, ESMO 2020 scientific chair, who is from the Netherlands Cancer Institute, Amsterdam, the Netherlands, told Medscape Medical Newsthat because the congress is being held online this year, fewer abstracts were submitted; nevertheless, "We were very happy too see...that the quality was very good."
The number of submissions was not the only problem the organizing committee had to face in transforming the ESMO Congress into a virtual meeting.
They were unable to fit the scientific and educational programs together and so have had to split them over two consecutive weekends. Moreover, many of the sessions were highly interactive and needed to be either adapted or omitted.
"So the program is somewhat different," Haanen said. He noted that "the presentations were also made shorter, especially on the educational sessions, because...we can't expect people to sit behind screens for hours listening to long presentations."
He added: "That was out of the question."
Haanen is nevertheless hopeful that the virtual meeting will be "very exciting."
Solange Peters, MD, PhD, ESMO president, who is also affiliated with the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said in a press conference that it was a "sacrifice" to move ESMO 2020 online and that "there were very sad moments" when deciding on the content.
However, there were some benefits from the change.
She said that all of the ESMO meetings this year have seen "huge" increases in the number of attendees and the geographical span or reach of each of the conferences.
"So suddenly you also realize that, what is one of the missions of ESMO being to convey education globally...was probably better reached, better achieved with the virtual format," she commented.
Turning to the program, Haanen first picked out the third presidential symposium, which will be held on Monday, September 21. This will focus entirely on upper gastrointestinal tumors in both the adjuvant and metastatic setting.
He said that in recent years, "very little progress has been made" in this area, with treatment mostly consisting of chemotherapy and chemoradiotherapy.
However, this year's presentations will explore the addition of immunotherapy either to chemotherapy or as an adjuvant treatment following completion of standard-of-care treatment for local disease.Haanen said that the results will be "very interesting...and may change current practice," something that "is very important for both doctors and their patients."
On Saturday, September 19, the first presidential symposium will include two presentations on lung cancer that Haanen said will offer some "exciting new [results] that I am sure will change clinical practice."
One will be on the CROWN phase 3 trial comparing lorlatinib and crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.
The other will present results on central nervous system disease recurrence from the ADURA phase 3 trial of osimertinib adjuvant therapy in patients with resected EGFR-mutated NSCLC.
The same session will also see new data in advanced renal cell carcinoma from CheckMate 9ER, in which the c-Met and VEGFR2 inhibitor cabozantinib (Cabometyx) was combined with nivolumab (Opdivo) and compared to sunitinib (Sutent) in untreated patients.
"Last year, there were already some exciting results of the combination of axitinib [Inlyta], either with pembrolizumab [Keytruda] or with avelumab [Bavencio]...in the first-line setting in metastatic clear cell renal cell lung cancer," Hannen said.
"Clearly there was a survival advantage over the standard of care, sunitinib," he added.
This year, not only will efficacy data from CheckMate 9ER be presented but also quality-of-life results.
"That's very important, because what everybody is afraid of is that, by adding drugs, you always get more impact on the quality of life, but you will see that the quality-of-life results are very exciting," he said.
The second presidential symposium will feature studies on prostate cancer, notably the phase 3 IPATential150 trial of abiraterone (Zytiga) plus either ipatasertib or placebo in metastatic castration-resistant prostate cancer.
Ipatasertib targets Akt, and Haanen said that "by adding it to, let's say, standard-of-care treatment...the question of course of will be, Does that have a better outcome?"
He believes the results will be a "very nice illustration" that prostate cancer management is heading in the direction of personalized treatment.
Alongside the presidential symposia, there will be a number of proffered paper sessions on the latest results in all aspects of oncology, including results from the ASCENT trial in triple-negative breast cancer, as well as a dedicated COVID-19 track.
Haanen said that the ESMO Virtual Congress 2020, coming after the AACR and ASCO annual meetings, has the "advantage" of being able to present the latest outcomes of patients treated with chemotherapy and immunotherapy against the backdrop of the pandemic.
This will include a study from the ESMO Resilience Task Force on the impact of COVID-19 on oncology professionals both in terms of their personal distress and burnout and their job performance.
"I think that is very important," Haanen said, "especially because the whole thing with COVID-19 is not yet over, and everybody is preparing for a second wave in the fall and winter.
"It may help us give us clues on how we can protect ourselves or each other to prevent burnout or other problems that we as healthcare caregivers face in this difficult period."
For next year, Peters remains hopeful that the ESMO 2021 meeting will take place as planned in Paris.
She anticipates that, indeed, ESMO meetings will be able to take place from spring next year.
This will depend on a vaccine for COVID-19 becoming widely available, although oncologists in some countries may still not be able to travel.
This means "starting probably with hybrid formats, with some of the faculty being on site and some not, [and] the same thing for the attendees," Peters said.
She suggested that for ESMO Congress 2021 to work as an on-site meeting will require at least half or two thirds of the originally anticipated number of attendees.
"I hope that Paris next year will happen," Peters said, adding that it "will probably happen with less attendees ― that's fine, but [still] with a large number of faculty and attendees."
The commentators have disclosed no relevant financial relationships.
European Society for Medical Oncology (ESMO) Annual Meeting 2020.
People who experience "sudden" out-of-hospital cardiac arrest (OHCA) may feel malaise days earlier, new research from Denmark suggests.
The new analysis shows that 2 weeks before a cardiac arrest, 54% of people had had phone, email, or in-person contact with their general practitioner, and 6.8% had gone to a hospital emergency department or outpatient clinic or had been hospitalized.
In contrast, roughly 25% and 3%, respectively, had had contact with their general practitioner or a hospital each week in the year preceding the cardiac arrest.
Nertila Zylyftari, MD, Copenhagen University Herlev and Gentofte Hospital, Hellerup, Denmark, presented these study results in a poster at the European Society of Cardiology (ESC) Congress 2020.
The findings show that clinicians and patients need to be aware that people may feel unwell before a "sudden" cardiac arrest, and they highlight the importance of applying cardiovascular disease risk scores in daily clinical practice, Zylyftari told theheart.org | Medscape Cardiology.
This is an "interesting," "important" study "that adds to the growing evidence that OHCA patients experience symptoms in the weeks leading up to their arrest," Karen Smith, PhD, director of the Center for Research and Evaluation at Ambulance Victoria, Australia, told theheart.org | Medscape Cardiology in an email.
Smith wrote an editorial about similar evidence ― a related study that involved more than 38,000 patients with OHCA in Ontario, Canada. Those researchers reported "in contrast to conventional wisdom," which regards OHCA as occurring without prior contact with the healthcare system. Findings from that study indicate that more than 1 in 4 patients with OHCA had visited the emergency department in the previous 90 days (Shuvy M: Resuscitation. 2019;141:158-185).
Although the researchers in the current study lacked information about why the patients contacted their general practitioner or went to the emergency department, some may have experienced shortness of breath, chest discomfort, and palpitations, Zylyftari speculated.
Other patients may have had vague symptoms that would make it difficult for them to be identified as being at high risk, she noted. Still others may have made their first contact with the healthcare system when they had the OHCA.
"There is a lot more work to be done to prevent OHCA and have an algorithm that could help identify at-risk patients," Zylyftari said.
In the meantime, Smith said, this study shows that "the percentage contacting a GP is high and highlights that if rapid screening clinics were available for patients to be referred to, many cardiac arrests could potentially be averted."
This work "adds evidence to the fact that campaigns about warning signs of heart attacks may actually avert cardiac arrests also if patients seek care earlier," she added.
Their research group conducted a study that showed that a comprehensive mass media campaign in Melbourne, Australia, to improve awareness of heart attack symptoms was associated with a substantial reduction in the incidence of OHCA and associated deaths (Nehme Z: Eur Heart J. 2017;38:1666–1673).
Need to Identify High-Risk Individuals
OHCA is the third leading cause of death worldwide; on average, fewer than 10% of patients survive, a fact that "emphasizes the need to identify those at risk," said Zylyftari.
The researchers identified 28,955 people in the Danish Cardiac Arrest Registry who had an OHCA during the period 2001 – 2014; the median age of the patients was 72 years, and 67% were men.
The researchers matched each patient with nine people in the general population on the basis of age, sex, and date of the cardiac arrest.
In the general population, only about 13% and 2%, respectively, had had contact with their general practitioner or a hospital in any week.
Of the 54% of patients who had contacted their general practitioner 2 weeks before their OHCA, 72% had phone or email interactions (these interactions were followed by an in-office visit in 11% of cases); 51% had an in-office visit, and 29% had a home visit.
Of the patients who had had any contact with the healthcare system 2 weeks before the cardiac arrest, 25% had a diagnosis of cardiovascular disease, including heart disease (8%) and heart failure (4.5%); 11% had respiratory disease, including chronic obstructive lung disease (4.3%); and others had experienced trauma/poisoning or had a digestive disease.
Fewer individuals from the general population had a diagnosis of cardiovascular disease (almost 9%).
"More data and research are needed on the reasons for these interactions ― for example, symptoms ― to identify warning signs of those at imminent danger so that future cardiac arrests can be prevented," said Zylyftari.
The study was funded the European Union's Horizon 2020 research and innovation program ESCAPE-NET. The researchers have disclosed no relevant financial relationships.
European Society of Cardiology (ESC) Congress 2020: Presented August 28, 2020.
Medscape Medical News © 2020
Cite this: Sudden Death Not So Sudden? Half Contacted GP in Days Prior - Medscape - Sep 09, 2020.
Intentional loss of a median of just 13% of body weight reduces the relative risk of developing type 2 diabetes by around 40% in people with obesity, among many other health benefits, shows a large real-world study in half a million adults.
Other findings associated with the same modest weight loss included a reduction in the risk of sleep apnea by 22%-27%, hypertension by 18%-25%, and dyslipidemia by 20%-22%.
Christiane Haase, PhD, Novo Nordisk, Denmark, led the work, and spoke to Medscape Medical News, together with Nick Finer, MD, senior principal clinical scientist, Novo Nordisk.
"This is powerful evidence to say it is worthwhile to help people lose weight and that it is hugely beneficial. These are not small effects, and they show that weight loss has a huge impact on health. It's extraordinary," Finer asserted.
"These data show that if we treat obesity first, rather than the complications, we actually get big results in terms of health. This really should be a game-changer for those health care systems that are still prevaricating about treating obesity seriously," he added.
The size of the study, of over 550,000 UK adults in primary care, makes it unique. In the real-world cohort, people who had lost 10%-25% of their body weight were followed for a mean 8 years to see how this affected their subsequent risk of obesity-related conditions. The results were presented during the virtual European and International Congress on Obesity (ECOICO 2020).
"Weight loss was real-world without any artificial intervention and they experienced a real-life reduction in risk of various obesity-related conditions," Haase told Medscape Medical News.
Carel le Roux, MD, PhD, from the Diabetes Complications Research Centre, University College Dublin, Ireland, welcomed the study because he says it shows those with obesity who maintained more than 10% weight loss experienced a significant reduction in the complications of obesity.
"In the study, intentional weight loss was achieved using mainly diets and exercise, but also some medications and surgical treatments. However, it did not matter how patients were able to maintain the 10% or more weight loss as regards the positive impact on complications of obesity," he highlighted.
From a clinician standpoint, "it helps to consider all the weight loss options available, but also for those who are not able to achieve weight loss maintenance, to escalate treatment. This is now possible as we gain access to more effective treatments," he added.
Also commenting on the findings, Matt Petersen, vice president of medical information and professional engagement at the American Diabetes Association, said: "It's helpful to have further evidence that weight loss reduces risk for type 2 diabetes."
However, "Finding effective strategies to achieve and maintain long-term weight loss and maintenance remains a significant challenge," he
Large Database of Half a Million People With Obesity
For the research, anonymized data from over half a million patients documented in the Clinical Practice Research Datalink (CPRD) database, which holds information from 674 general practices in the UK, were linked to Hospital Episode Statistics and prescribing data to determine comorbidity outcomes.
At baseline, characteristics for the full study population included a median age of 54, around 50% of participants had hypertension, around 40% had dyslipidemia, and around 20% had type 2 diabetes. Less than 10% had sleep apnea, hip/knee osteoarthritis, or history of cardiovascular disease. All participants had a body mass index of 25.0–50.0 kg/m2 at the start of the follow-up, between January 2001 and December 2010.
Patients may have been advised to lose weight, or take more exercise, or have been referred to a dietician. Some had been prescribed antiobesity medications available between 2001-2010. (Novo Nordisk medications for obesity were unavailable during this period.) Less than 1% had been referred for bariatric surgery.
"This is typical of real-world management of obesity," Haase pointed out.
Participants were divided into two categories based on their weight pattern during the 4-year period: one whose weight remained stable (492,380 individuals with BMI change within –5% to +5%) and one who lost weight (60,573 with BMI change –10% to –25%).
The median change in BMI in the weight-loss group was –13%. The researchers also extracted information on weight loss interventions and dietary advice to confirm intention to lose weight.
The benefits of losing 13% of body weight were then determined for three risk profiles: BMI reduction from 34.5 to 30 kg/m² (obesity class I level); 40.3 to 35 kg/m² (obesity class II level), and 46 to 40 kg/m² (obesity class III level).
Individuals with a baseline history of any particular outcome were excluded from the risk analysis for that same outcome. All analyses were adjusted for BMI, age, gender, smoking status, and baseline comorbidities.
Study strengths include the large number of participants and the relatively long follow-up period. But the observational nature of the study limits the ability to know the ways in which the participants who lost weight may have differed from those who maintained or gained weight, the authors said.
Type 2 Diabetes, Sleep Apnea Showed Greatest Risk Reductions
The researchers looked at the risk reduction for various comorbidities after weight loss compared to before weight loss. They also examined the risk reductions after weight loss compared to someone who had always had a median 13% lower weight.
Effectively, the analysis provided a measure of the effect of risk reduction due to weight loss compared to having that lower weight as a stable weight.
"The analysis asks if the person's risk was reversed by the weight loss to the risk associated with that of the lower weight level," explained Haase.
"We found that the risks of type 2 diabetes, dyslipidemia, and hypertension were reversed while the risk of sleep apnea and hip/knee osteoarthritis showed some residual risk," she added.
With sleep apnea there was a risk reduction of up to 27% (compared to before weight loss).
"This is a condition that can't be easily reversed except with mechanical sleeping devices and it is under-recognized and causes a lot of distress. There's actually a link between sleep apnea, diabetes, and hypertension in a two-way connection," noted Finer, who is also honorary professor of cardiovascular medicine at University College, London, UK.
"A reduction of this proportion is impressive," he stressed.
Dyslipidemia, hypertension, and type 2 diabetes are well-known cardiovascular risk factors. "We did not see any impact on myocardial infarction," which "might be due to length of follow-up," noted Haase.
Response of Type 2 Diabetes to Weight Loss
Most patients in the study did not have type 2 diabetes at baseline, and Finer commented on how weight loss might affect type 2 diabetes risk.
"The complications of obesity resolve with weight loss at different speeds," he said.
"Type 2 diabetes is very sensitive to weight loss and improvements are obvious in weeks to months."
In contrast, reductions in risk of obstructive sleep apnea "take longer and might depend on the amount of weight lost." And with osteoarthritis, "It's hard to show improvement with weight loss because irreparable damage has [already] been done," he explained.
The degree of improvement in diabetes due to weight loss is partly dependent on how long the person has had diabetes, Finer further explained. "If someone has less excess weight then the diabetes might have had a shorter duration and therefore response might be greater."
Lucy Chambers, PhD, head of research communications at Diabetes UK, said: "We've known for a long time that carrying extra weight can increase your risk of developing type 2 diabetes, and this new study adds to the extensive body of evidence showing that losing some of this weight is associated with reduced risk."
She acknowledged, however, that losing weight is difficult and that support is important: "We need government to urgently review provision of weight management services and take action to address the barriers to accessing them."
Finer and Haase are both employees of Novo Nordisk. Le Roux has reported no relevant financial relationships.
ECOICO 2020. Presented September 1-4, 2020. Abstract 0497.