For more than 10% of pediatric deaths in the United States, a specific cause of death is never established, despite mandated autopsies and investigations when any child dies unexpectedly. Most of these deaths occur among babies and are attributed to SUID (defined by the Centers for Disease Control and Prevention as sudden unexpected infant death), the leading cause of death among infants between 1 month and 1 year of age in high-income countries. SUID is a category of pediatric death encompassing various diagnoses that were once considered sudden infant death syndrome (SIDS), and SIDS remains its major component. Since the 1990s, the perception of SIDS has shifted from a medical mystery to a sleep accident, and public health campaigns warning about risk factors in the infant-sleep environment have supplanted the search for medical causes. Evidence suggests, however, that renewed efforts to identify biologic causes are required to further reduce unexplained infant deaths.Trends in Sudden Unexpected Infant Death by Cause, 1990 through 2019.
Few experts would argue with the current focus on prevention, which is based on associations between infant-sleep practices and SIDS rates in multiple countries. Beginning in the 1970s, SIDS mortality more than doubled in the Netherlands after physicians advocated for prone placement of infants for sleep; mortality then dropped after caregivers were advised to return to the traditional practice of placing babies on their backs.1 An association between infant sleep practices and SIDS was first identified by several researchers in the late 1980s. In 1991, the New Zealand Cot Death Study, which was initiated because Maori infants had one of the world’s highest-reported SIDS rates, showed an odds ratio for SIDS of 3.53 associated with sleeping in the prone position.2 In the United States, SIDS rates dropped by half during the Back to Sleep campaign in the 1990s. Still, rates of unexplained deaths among infants have remained largely unchanged since 1996 in the United States (where the current rate is 90.1 per 100,000 live births; see graph) and elsewhere.
During the past several decades, the concept of SIDS as a preventable suffocation event occurring in normal infants has taken hold. Public health campaigns, which typically rely on simple, clear messages, emphasize addressing sleep position and the sleep environment to prevent SIDS. Yet the Dutch had among the lowest-recorded SIDS rates in the world before and after changes in recommended sleep position, Maori infants continue to have among the highest SIDS rates, and rates of most other causes of infant death decreased nearly in parallel with SIDS rates during the period of safe-sleep success in the United States.3
Garnering less attention have been important breakthroughs in understanding possible biologic contributors. Observations from cardiorespiratory monitoring led to the association of serotonin and other neurotransmitter abnormalities in the brain stems of infants who died from SIDS with failures in autoresuscitation and arousal. Neuropathology associated with epilepsy has been observed in a substantial number of infants who died from SIDS. Numerous studies have revealed genetic differences between infants who died from SIDS and surviving, healthy infants; one study identified causative variants and plausible contributors to death in 11% of cases.4 Research on heritability in the Back to Sleep era revealed that younger siblings of babies who had died from SIDS were four times as likely as other babies to also die from SIDS; moreover, the risk of SIDS among first- through third-degree relatives was nine times as high as the risk in nonaffected families.5
Modern medicine therefore promotes a mixed, logically inconsistent message regarding SIDS: authoritative statements imply that SIDS is a consequence of unsafe sleep in biologically normal children, but there is vague acknowledgment that important biologic factors are involved in these deaths.
Although the emphasis on sleep position and environment has remained constant for decades, medicine’s capabilities have not. A relevant exemplar is the National Institutes of Health’s Undiagnosed Diseases Network, which has enhanced diagnostic capabilities and improved quality of care for people with previously undiagnosed diseases. The Undiagnosed Diseases Network now helps to establish a diagnosis for more than one quarter of patients who were previously without one, relying on standard interpretation of genetic sequencing coupled with advanced phenotyping, alternative genomic analysis, and functional validation. Another example of medicine’s expanding capabilities involves advances in molecular autopsy. The type of forensic autopsy that is practiced in most state and local systems relies largely on gross observation and basic histologic analysis conducted under a light microscope. Molecular autopsy employs genomics, transcriptomics, proteomics, metabolomics, and other subcellular biochemical and structural tools that can be used with postmortem human tissues. This avenue of molecular (subcellular) research may be especially important in the case of SIDS, for which investigators have not yet discovered any pathognomonic morphologic clues that can be detected under a microscope. As they’re typically practiced, mandated forensic investigations insulate SIDS cases from investigation by means of academic autopsies and new approaches to undiagnosed diseases, even though SIDS is, by definition, an undiagnosed disease.
Techniques and products developed in the process of reinvigorating basic-science research for SIDS might contribute to knowledge in other disease areas, including stillbirth and unexpected death among people with epilepsy. A reliable biomarker for acute asphyxia would have profound importance for forensic pathology. The addition to genetic databases of variants detected during autopsies in infants who died from SIDS — which would permit the inclusion of information from those who didn’t survive long enough to undergo medical evaluation — would expand our understanding of genetic factors in many aspects of health and disease. Epigenetic research elucidating why SIDS rates vary according to race and poverty status and why they are associated with maternal tobacco and alcohol use could contribute to a broader understanding of social and environmental determinants of health.
Employing current tools might provide new insights into SIDS as a collection of heterogeneous and undiagnosed diseases, thereby facilitating the identification of new pathologic mechanisms and expanding the documented phenotypes of known diseases. Yet one impediment to understanding risk and making headway in pathogenesis has been the failure to refine the SIDS phenotype. Death is a vague, inadequate phenotype, and SIDS occurs during sleep, so the terminal event is rarely observed. Most physicians still regard SIDS as a basic suffocation event. Although suffocations do occur, medical examiners often certify suffocation as the cause of death among infants who die during sleep on the basis of the presence of sleep-related risk factors, without physical evidence of obstructed breathing. Some kinds of observations will be made only when we move beyond the notion that healthy infants suffocate often enough to make such deaths the leading cause of postneonatal infant mortality and consider other causes, including responses to hypoxia and hypercarbia, failure to respond to moderate breathing threats brought on by alterations in serotonin, or factors specific to family histories. Often, only specialized research teams can assume the challenge of characterizing subgroups of patients who died from a single reported cause, such as SIDS.
After an infant dies from SIDS, no standard medical care is provided to the family. Along with failing to respond to families’ emotional pain and confusion, we permit postmortem assessment to focus primarily on the legalistic question of manner of death, rather than on the medical question of biologic and environmental causes. The current approach may answer questions about mistreatment, but it leaves any effort to know more about etiologic factors, including possible risks to siblings, to bereaved family members. Medicine doesn’t exhaustively attempt to explain these deaths, even though doing so would be routine in other disease areas.
We believe it’s time for renewed scientific attention to the basic problem of SIDS: how something so unexpected, dramatic, and devastating can happen to an apparently well infant. In the more than 50 years since SIDS was formalized as a medical diagnosis and the more than 25 years during which physicians and public health practitioners have shared sleep-positioning recommendations, unexplained mortality among infants has barely changed beyond early decreases. Instead of having confidence in the adequacy of the current approach, we believe it’s time for renewed urgency on the part of diagnostic science to reduce the steady toll of sudden unexpected infant deaths and better meet the needs of families facing inestimable misfortune.
Zetia and proprotein convertase subtilisin/kexin type 9 inhibitors may reduce nonfatal myocardial infarction and stroke in adults with high or very high cardiovascular risk, according to findings published in The BMJ.
These adults must also be receiving maximally tolerated statin therapy or are statin-intolerant, according to Safi U. Khan, MD, MS, a cardiovascular outcome researcher and cardiology fellow at Houston Methodist Hospital, and colleagues.
Ezetimibe and PCSK9 inhibitors may benefit patients with high cardiovascular risk. Source: Adobe Stock.
“The absolute cardiovascular benefits of the therapies depend on individuals’ baseline cardiovascular risk,” Khan and colleagues wrote.
As part of a multiprofessional BMJ Rapid Recommendations panel, the researchers conducted a network meta-analysis of 14 randomized controlled trials that assessed Zetia (ezetimibe, Merck) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The trials included 83,660 adults on statins. Khan and colleagues evaluated the patients’ level of risk, values and preferences by performing frequentist fixed-effects analyses and grading of recommendations, assessment, development and evaluation (GRADE). This information was used to ascertain the certainty of evidence in the 14 trials. The panel included cardiologists, general practitioners, general internists, endocrinologists, a geriatrician, methodologists and three patient partners. The four effective critical outcomes the panel selected were nonfatal myocardial infarction (MI), nonfatal stroke, all-cause mortality and cardiovascular mortality.
Risk reductions
Overall, evidence from the 14 trials indicated that ezetimibe and PCSK9 inhibitors may benefit high-risk patients. However, the treatments yielded little or no benefit among patients with moderate or low cardiovascular risk, according to Khan and colleagues.
Specifically, adding ezetimibe to statins reduced MI (RR = 0.87; 95% CI, 0.8-0.94) and stroke (RR = 0.82; 95% CI, 0.71-0.96) but not all-cause mortality (RR = 0.99; 95% CI, 0.92-1.06) or cardiovascular mortality (RR = 0.97; 95% CI, 0.87-1.09).
The researchers also reported that adding a PCSK9 inhibitor to statins reduced MI (RR = 0.81; 95% CI, 0.76-0.87) and stroke (RR = 0.74; 95% CI, 0.64-0.85) but not all-cause mortality (RR = 0.95; 95% CI, 0.87-1.03) or cardiovascular mortality (RR = 0.95; 95% CI, 0.87-1.03).
Likely reductions in MI and stroke
Among adults with very high cardiovascular risk, the researchers reported with moderate to high certainty that adding a PCSK9 inhibitor to statins was likely to reduce MI by 16 incidences per 1,000 and stroke by 21 incidences per 1,000. Meanwhile, adding ezetimibe was likely to reduce stroke by 14 incidences per 1,000, and adding ezetimibe to a PCSK9 inhibitor and statins may reduce stroke by 11 incidences per 1,000, according to Khan and colleagues.
The researchers reported with lower certainty that adding a PCSK9 inhibitor to statins and ezetimibe may reduce MI by 14 incidences per 1,000 and stroke by 17 incidences per 1,000 among adults with very high cardiovascular risk.
Among those with high cardiovascular risk, adding a PCSK9 inhibitor probably reduced MI by 12 incidences per 1,000 and stroke by 16 incidences per 1,000 (moderate certainty), the researchers reported. Also, adding a PCSK9 inhibitor to ezetimibe and statins may reduce stroke by 13 incidences per 1,000 (low certainty). These findings were consistent in statin-intolerant patients.
“Prescribing these lipid-lowering agents should be considered among appropriate candidates with very high or high cardiovascular risk patients to achieve desired cardiovascular benefits,” the researchers wrote.
More than 3 decades after receiving FDA approval, proton beam radiation therapy has failed to find a footing as a go-to treatment for many cancers in the United States.
About three dozen proton therapy facilities are in operation nationwide — fewer than one per state — limiting accessibility in some regions.
A big moment of change is happening in the field of proton therapy, according to J. Isabelle Choi, MD. It might be happening more slowly than some of us would like, but it is still set in motion with the research that is ongoing, she said. Source: Philip Greenberg for the New York Proton Center.
Several other factors have limited proton therapy’s adoption, including cost concerns, technological advances in photon therapy, and a lack of comprehensive and comparable data to advance the science. In addition, reimbursement from insurers remains inconsistent.
“It is truly an injustice to the patient when they would benefit from this treatment but cannot get it,” J. Isabelle Choi, MD, clinical director and director of research at New York Proton Center, radiation oncologist at Memorial Sloan Kettering Cancer Center and chair of National Association for Proton Therapy’s physician advisory committee, told HemOnc Today. “It is up to all of us to come together, do the homework, do the legwork and continue to move things forward to improve access.”
Choi and other proponents of proton therapy are optimistic that larger studies underway or planned in breast cancer, liver cancer and other common malignancies could lead health insurers to expand coverage of this modality. In addition, more proton therapy centers are expected to open across the U.S. in the next 10 years, all of which could result in a substantial increase in research uptake.
“We have made a lot of progress over the last decade and even in the last few years,” Choi said. “Hopefully, with all of us coming together, we can keep improving the landscape for our patients who would stand to benefit.”
HemOnc Today spoke with radiation oncologists about the state of proton therapy, why access remains limited for many Americans, the potentially pivotal research underway, and how and when the landscape could change.
A ‘striking’ difference
The absence of proton therapy centers in many Midwestern states runs in contrast to what, judging from imaging data, may look like a clear-cut advantage compared with photon therapy.
For instance, imaging from a study by Baumann and colleagues published in JAMA Oncology showed the targeted area proton radiation touches in head and neck cancers, compared with the wider swath of radiation when a patient is treated with photons.
“It is quite striking,” Choi said of this and other such comparisons, with proton therapy better protecting normal tissues from unnecessary radiation. “Pictures speak a thousand words, especially in this scenario.”
One of the main differences between protons and photons is the former does not have an exit dose, so it does not deliver unnecessary radiation to organs on the other side of the tumor.
“Even though we have had dramatic advances in the technology of photon radiation over the last 10 to 15 years, the dose is still scattered throughout the area being treated, and that is almost unavoidable in a lot of these cases,” Timothy P. Kegelman, MD, PhD, chief resident in the department of radiation oncology at Perelman School of Medicine at the University of Pennsylvania, told HemOnc Today.
One of proton therapy’s most common uses is in pediatric cancer care. Children benefit most because their tissues are still developing and, thus, they are at greater risk for deformity or second cancers due to radiation.
Proton therapy also is used to treat some tumors in the brain, spine, liver, head and neck, as well as for patients who have a recurrence after prior radiation treatment, according to Ronald C. Chen, MD, MPH, FASCO, FASTRO, Joe and Jean Brandmeyer endowed chair and professor in the department of radiation oncology and associate director of health equity at University of Kansas Cancer Center.
The therapy has demonstrated safety benefits when used to treat tumors near critical organs, such as the heart.
Timothy P. Kegelman
Data presented by Kegelman and colleagues at last year’s American Society for Radiation Oncology Annual Meeting showed proton therapy could reduce risk for radiation-induced heart diseases compared with conventional photon therapy. In a retrospective trial of more than 200 patients, they found mini-strokes were significantly less common after median follow-up of 29 months among patients treated with protons vs. photons (1.2% vs. 8.2%). A lower proportion of patients in the proton therapy group experienced heart attacks (2.3% vs. 9%), although the difference did not reach statistical significance.
A study by Li and colleagues, published in JAMA Network Open in June, showed intensity-modulated proton therapy (IMPT) conferred a safety benefit compared with intensity-modulated radiotherapy among 77 patients with nonmetastatic nasopharyngeal carcinoma. Multivariable logistic regression analyses showed a lower likelihood of grade 2 or higher acute adverse events with IMPT vs. IMRT (OR = 0.15; 95% CI, 0.03-0.6). Researchers also reported “rare late complications and excellent oncologic outcomes, including 100% locoregional control at 2 years.”
Baumann and colleagues reported similar benefits in their retrospective, nonrandomized study that compared proton vs. photon therapy among 1,483 patients with locally advanced cancer undergoing concurrent chemoradiotherapy. Proton chemoradiotherapy was associated with significantly lower risks for adverse events (grade 3 or higher, RR = 0.31; 95% CI, 0.15-0.66; grade 2 or higher, RR = 0.78; 95% CI, 0.65-0.93) within 90 days, with similar DFS and OS.
Larger, phase 3 studies may yield more insights that shape the future of proton therapy, but evidence seems to be accumulating in its favor, Choi said.
“Essentially all the data we have thus far have shown the overall, cumulative toxicities are decreasing with proton therapy compared with photons, and we expect that with certain disease sites this will translate to a survival benefit,” Choi told HemOnc Today.
Cost and complexities
When examining proton beam therapy’s place in the radiation oncology landscape, it may be worth considering where it is widely used in practice: pediatric cancer care.
“We would not be introducing a technology in any form to a pediatric population of children if we didn’t know that it was at least as effective as a comparison modality and that it was in many cases going to be beneficial,” Choi said.
So, what has prevented proton beam therapy from being more widely used?
Helen A. Shih
“Cost and complexity,” Helen A. Shih, MD, MS, MPH, FASTRO, associate professor of radiation oncology at Harvard Medical School, and medical director of the proton therapy program and chief of central nervous system and eye services in radiation oncology at Massachusetts General Hospital, told HemOnc Today.
“You can buy a regular, commercial radiation machine for about $2 million and spend maybe another million to get it set up the way you want it, so a $3 million investment,” Shih added. “[Costs vary widely for proton centers], but ours was $50 million. It’s all about that investment.”
Penn Medicine, which opened the Roberts Proton Therapy Center in Philadelphia in 2010, is continuing to invest in the modality. It soon will add centers in nearby Lancaster, Pennsylvania — a $48 million project — and Voorhees, New Jersey — an estimated $35 million project.
Meanwhile, The University of Texas MD Anderson Cancer Center is investing in development of a new proton therapy center equipped with dramatically more advanced imaging and treatment delivery capabilities than its existing 15-year-old proton center in Houston, according to Choi.
Although the number of proton therapy centers in the U.S. has increased over the past few years, profitability has not been guaranteed.
In 2018, The New York Times reported that although most of the nation’s proton centers were profitable, nearly a third of them had either lost money, defaulted on debt or had to overhaul finances.
Further, those who might benefit from proton therapy must consider whether it is covered by their insurance.
According to a local coverage determination, CMS considers proton beam therapy “medically reasonable and necessary” for unresectable benign or malignant central nervous system tumors; intraocular melanomas; pituitary neoplasms; chordomas and chondrosarcomas; advanced-stage and unresectable malignant lesions of the head and neck; malignant lesions of the paranasal sinus and other accessory sinuses; unresectable retroperitoneal sarcoma; and for any solid tumors in children.
United Healthcare covers proton beam therapy for patients aged younger than 19 years but limits all other coverage to localized, unresectable hepatocellular carcinoma (with documentation proving that the sparing of surrounding tissue cannot be achieved with standard radiation therapy techniques), intracranial arteriovenous malformations, ocular tumors and skull-based tumors. The insurer noted that it evaluates other requests on a case-by-case basis, and listed a dozen other common cancers — including lung, breast and gynecologic cancers — as those for which proton therapy “is unproven and not medically necessary due to insufficient evidence of efficacy.”
This underscores the importance of larger clinical trials. If researchers can enroll enough people on trials to study the efficacy of proton therapy in individual cancers, the results could lead to expanded coverage from insurers and, thus, more access for more patients.
David R. Grosshans
“Insurers should look to support these trials,” David R. Grosshans, MD, PhD, associate professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “In the end, if proton therapy has fewer side effects and, in some diseases, may actually improve disease control, this would be cost effective in the long term.”
However, some studies that potentially could show these benefits have been unable to get off the ground as insurance coverage for proton therapy remains limited.
“A recent study [by Mohan and colleagues] on patients with glioblastoma randomly assigned to proton vs. photon showed over one-third of the patients could not receive proton therapy because of insurance denials,” Choi said.
Attitudes appear to be changing, Shih said.
“I think there’s enough buy-in there — and an increasing willingness and open-mindedness and leniency from insurers to cover it — that we’re slowly doing these studies and expanding proton therapy’s use,” Shih said.
Closing the gap
For decades, photon therapy has been much more commonly used in practice than protons. It also has matured more technologically.
The effect — as Grosshans and Radhe Mohan, PhD,FAAPM, FASTRO, of the department of radiation physics in the division of radiation oncology at The University of Texas MD Anderson Cancer Center, wrote in a January 2017 article published in Advance Drug Delivery Reviews — was photon therapy seemingly catching up to proton therapy.
“Many of the limitations of proton therapy and concerns about them have been known for several decades. However, even in the face of such limitations, the gap between protons and photons at that time was sufficiently large that protons could be assumed to be superior. That is no longer the case,” Grosshans and Mohan wrote. “Over the last 3 decades, photon therapy has advanced considerably. In particular, IMRT was introduced in mid-1990s and has continued to evolve steadily. In addition, there has been continued enhancement in ancillary imaging, treatment planning and delivery technologies. In contrast, proton therapy state-of-the-art had not advanced significantly from the 1980s through the middle of the last decade. Thus, the gap between photon therapy and proton therapy had essentially vanished.”
Although those words may seem almost damning for anyone feeling bullish about proton therapy, they were printed more than 4 years ago. Technology and modern medicine can move quicker than many anticipate.
Ronald C. Chen
“In 2021, I believe that proton therapy planning and delivery technologies have advanced to the point where they now match photon therapy planning and delivery technologies,” Chen said in an interview with HemOnc Today. “This means that we can now do meaningful clinical trials to determine the potential benefit of proton therapy in different cancers.”
Grosshans agreed — to a point.
“Proton therapy is rapidly advancing, including improved imaging, as well as newer treatment planning and delivery techniques,” Grosshans told HemOnc Today. “However, there remains room for improvement if we are to match and exceed modern photon therapy.”
Proton vs. photons also is a question that must be asked and answered in each individual cancer, according to experts with whom HemOnc Today spoke.
In a 2012 study published in JAMA, Chen and colleagues set out to determine the comparative morbidity and disease control of proton vs. photon for primary prostate cancer treatment. In a nonrandomized retrospective study, they concluded that proton therapy did not demonstrate a clinical benefit and wrote there were “no significant differences among patients treated with proton therapy vs. IMRT in morbidity or receipt of additional cancer therapy, except an association with increased gastrointestinal morbidity [among patients who received proton therapy].”
Chen put that study in context 9 years later.
“Compared with today, the technology available to plan and deliver proton therapy 10 years ago was quite crude,” Chen said. “[Although] the proton particle has certain advantages over photons, because the technology for treatment planning and delivery was much less developed 10 years ago, that limited potential benefit to patients. Today, the proton technology is much more developed and more accurate than before.
“Ongoing studies — such as the PARTIQoL and COMPPARE studies, the latter led by Nancy P. Mendenhall, MD, and me — are comparing patient outcomes of modern proton therapy vs. modern photon therapy,” Chen added. “These studies will provide crucial results to address this question.”
‘Commitment’ to produce data
Confidence in the future of proton therapy among those in the field may hinge on results of those trials and others currently underway or finalizing enrollment.
“If high-level clinical evidence becomes available, proton therapy may prove to be the superior treatment,” Grosshans said.
A randomized phase 3 trial by NRG Oncology and NCI is comparing OS among patients with stage II to stage IIIB non-small cell lung cancer who received chemotherapy plus photon vs. proton therapy. The trial is estimated to be completed by the end of 2023.
In addition, the pragmatic, randomized RadComp (Radiotherapy Comparative Effectiveness) clinical trial is investigating protons vs. photons in locally advanced breast cancer. Researchers seek to determine which modality is more effective for reducing major cardiovascular events, as well as the frequency and severity of radiation toxicity. Quality-of-life outcomes also will be assessed.
RadComp is the largest such randomized trial to date, enrolling just under 1,300 patients from 23 proton centers across the country, with researchers from New York Proton Center, Mayo Clinic, MD Anderson Cancer Center, Mass General and Penn Medicine among those involved. RadComp is set for primary completion in August 2022.
“The primary driving hypothesis of this study is that because proton therapy has the ability to dramatically decrease the dose of radiation to the heart compared with photons, incidence or rates of major cardiovascular events will be significantly reduced at 10 years for patients receiving proton therapy for breast cancer,” Choi said. “There is a tremendous commitment across the proton community to produce this high-level data so that we can improve access for patients.”
NRG Oncology also is recruiting for a phase 3 trial to compare OS among patients with HCC treated with protons vs. photons. Researchers additionally will assess PFS, local progression, differences in toxicity and quality of life; estimated primary completion is set for June 2024.
A separate randomized phase 2 study by NRG and NCI will investigate proton therapy vs. IMRT for preserving brain function among patients with IDH-mutant grade II or grade III glioma. Estimated primary completion is set for January 2025.
“We have many similar trials now across disease sites — such as head and neck, esophagus, liver, prostate, lung, you name it — because we know research is going to drive access,” Choi said.
The goal, experts said, is to gain as much information as possible through research to alleviate the barriers of access and availability that have held proton therapy back for decades.
“Right now, we are in the middle of a big moment of change in the field and in the landscape of proton therapy,” Choi said. “It might be happening more slowly than some of us would like, but it is still set in motion with the research that is ongoing. And I expect that the outcomes of the research that we’re doing and data we are accumulating are going to lead to a major shift in the way we practice medicine.”
Shih estimated that perhaps as many as “80 to 100” proton facilities could be operating in the next 2 decades across the country.
“Maybe we will plateau,” Shih said. “But, it’s similar to technology with cellphones, cars and computers — as time goes by and there’s investment in these technologies, they become better and faster, the bells and whistles improve, and the cost comes down. If protons were equal to a linear accelerator in cost, we’d all be doing protons. Why wouldn’t we want less unnecessary radiation everywhere beyond the treatment target? But, it’s that margin of benefit [and] cost-effectiveness ratio balance.”
Kegelman said he is optimistic research will reveal the indications for which proton therapy is the better option for certain patients.
“Hopefully down the road, we’ll be able to disseminate that information more clearly to patients and other clinicians and say, ‘for these particular scenarios, it’s generally better to get proton therapy and it should be discussed as an option and offered to patients who can get it.’”
References:
Baumann BC, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2019.4889.
Chang JY, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.2032.
Choi JI and Simone CB 2nd. J Thorac Dis. 2017;doi:10.21037/jtd.2017.12.79.
Chung CS, et al. Int J Radiat Oncol Biol Phys. 2013;doi:10.1016/j.ijrobp.2013.04.030.
Use of proton beam therapy increased significantly among patients with cancer in the U.S. between 2004 and 2018, but Black individuals had a lower likelihood of receiving the therapy than their white counterparts.
Researchers presented the findings of two cross-sectional studies in JAMA Network Open.
Data derived from Nogueira LM, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.8970.
Rationale and methods
“Proton beam therapy can deliver a higher dose of radiation to the tumor with less damage to surrounding healthy cells,” Leticia M. Nogueira, PhD, MPH, senior principal scientist in the surveillance and health services research program at American Cancer Society, told Healio. “Therefore, proton beam therapy is potentially superior to photon-based radiation therapy to treat tumors with complex anatomy, surrounded by sensitive tissues, or for treating childhood cancer, where long-term side effects of radiation therapy are a main concern. However, proton beam therapy can cost twice as much as photon-based radiation therapy.”
In the first study, Nogueira and colleagues examined the overall patterns of use of proton beam therapy according to the American Society for Radiation Oncology’s U.S. clinical indications. Researchers divided patients into two groups: Group one included those for whom proton beam therapy is recommended and group two included those for whom evidence of proton beam therapy efficacy is still under review.
In the second study, researchers assessed whether racial disparities exist in the receipt of proton beam therapy between Black and white individuals. The cross-sectional study included 5,225,929 patients (mean age, 63.2 years; 86.4% white and 13.6% Black; 54.3% women) included in the National Cancer Database eligible to undergo proton beam therapy for various cancer types between 2004 and 2018.
Researchers used propensity score matching to ensure comparability of Black and white patients’ clinical characteristics and regional availability of proton beam therapy per the National Academy of Medicine’s definition of disparities.
Key findings
Results of the first study showed use of proton beam therapy in the U.S. increased overall for all new cancer diagnoses — from 0.4% in 2004 to 1.2% in 2018 (annual percent change [APC], 8.12; P < .001).
Researchers reported significant increases (P < .001) in group one from 2010 to 2018 (0.4% to 2.2%; APC = 21.97) and in group two from 2014 to 2018 (0.03% to 0.1%; APC = 30.57). In group two, they observed the largest increases between 2010 and 2018 in proton beam therapy targeted to the breast (0% to 0.9%; APC = 51.95) and to the lung (0.1% to 0.7%; APC = 28.06; P < .001 for both). The only decrease in use occurred in prostate cancer between 2011 and 2014 (1.4% to 0.8%; APC = 16.48; P = .03); however, use for this cancer site rebounded to 1.3% in 2018 (APC = 12.45; P < .001).
The second study revealed Black patients had a lower likelihood than white patients of receiving proton beam therapy (0.3% vs. 0.5%; OR = 0.67; 95% CI, 0.64-0.71).
In addition, researchers observed increased racial disparities among those included in group one (0.4% vs. 0.8%; OR = 0.49; 95% CI, 0.44-0.55) compared with those in group two (0.3% vs. 0.4%; OR = 0.75; 95% CI, 0.7-0.8). The disparities observed among group one patients increased throughout time (APC = 0.09; P < .001), with the greatest increase observed in 2018.
Researchers also found patients in group one most likely to have private health insurance (55.4%) during 2018, whereas most of those in group two had Medicare (52.5%).
Leticia M. Nogueira
“Of note, the racial disparity in receipt of proton beam therapy was greatest for the two most common U.S. childhood cancers — rhabdomyosarcoma and central nervous system cancers. Matching on socioeconomic status or health insurance coverage type did not eliminate these disparities,” Nogueira said. “As the number of facilities offering proton beam therapy in the U.S. increased, so did the racial disparity in receipt of proton beam therapy. Therefore, increasing availability of therapeutic advances without addressing structural determinants of racial disparities can worsen, instead of ameliorating, racial disparities in receipt of quality cancer treatment.”
Implications
Black individuals continue to have worse access to quality cancer care in the U.S., and modifiable factors, other than availability of new therapeutic options, need to be addressed to eliminate racial disparities in cancer care and outcomes, Nogueira said.
“Future research should evaluate the contribution of oncology referral patterns, provider intrinsic bias and institutions’ policies and practices, such as provision of transportation services and clinical trial enrollment practices, to racial disparities in receipt of quality cancer care,” she added.
Healthy adults experienced no increase in atrial arrythmias and less supraventricular tachycardia on days they consumed vs. abstained from caffeinated coffee as well as an increase in wearable-measured physical activity in the CRAVE study.
Results presented at the American Heart Association Scientific Sessions also revealed a 54% increase in premature ventricular contractions with coffee consumption; those who metabolized caffeine more quickly experienced a heightened response to premature ventricular contractions with coffee exposure.
Source: Adobe Stock
Gregory M. Marcus
“Overall, the acute yet everyday physiological effects of coffee are complex,” Gregory M. Marcus, MD, MAS, associate chief of cardiology for research and endowed professor of atrial fibrillation research at the University of California, San Francisco, said during a press conference at the American Heart Association Scientific Sessions. “These data add to the growing evidence that those with supraventricular tachycardia or AF or those at risk for those diseases should not necessarily avoid coffee. However, those prone to ventricular arrythmias may benefit from coffee abstinence, but genetic differences influence risk.”
Device-measured responses to coffee
Most coffee-related research has been observational and prone to confounding, with examined long-term effects less relevant to immediate consequences, Marcus said.
The researchers sought to capture the real-time physiologic consequences of coffee consumption in healthy adults using multiple wearable devices.
For CRAVE, 100 healthy volunteers (mean age, 38 years; 51% women; 48% white) were fitted with a continuously recording ECG device (Zio Patch, iRhythm), a wrist-worn Fitbit to measure step counts and sleep, and a continuous glucose monitor (Dexcom). Participants also downloaded a smartphone app for collection of geolocation data (Eureka, UCSF); participant DNA was genotyped for caffeine metabolism-related single nucleotide polymorphisms.
Researchers randomly assigned volunteers to consume or avoid coffee every day for 14 days, communicated via daily texts and reminders.
To measure adherence, participants pressed a button via the Zio patch to timestamp every coffee drink and completed daily surveys recounting coffee consumed the previous day. All date-stamped receipts with coffee purchases were reimbursed. Visits to coffee shops were tracked via geofencing.
Adherence assessments revealed compliance with coffee assignments by every metric employed, Marcus said (P < .01 for all). In the intention-to-treat analyses, random assignment to consume coffee was associated with a 54% increase in premature ventricular contractions (95% CI, 19-200; P = .001), 1,058 additional Fitbit-measured steps per day (95% CI, 441-1675; P = .001) and 36 fewer minutes of Fitbit-measured sleep per night (95% CI, 22-50; P < .001). There were no between-group differences in CGM-measured glucose.
Discussing the findings, Marcus acknowledged that enrolling only regular coffee drinkers could bias the findings.
“Individuals perhaps most prone to coffee-induced problems, such insomnia, palpitations or arrythmias that occur with coffee, may have been excluded,” Marcus said. “If anything, we would think that that would lead to us underestimating heart effects, rather than explaining any false positives.”
‘Innovative but small’ study
Elaine Hylek, MD, MPH, professor of medicine at Boston University School of Medicine and member of the AHA’s Committee on Scientific Sessions Programming, said CRAVE was “an innovative but small study,” calling the findings on atrial arrythmias “somewhat reassuring.”
Hylek said, “if anything, it seems individuals were increasing their physical activity; hopefully that would translate into better CV health. Hopefully, for healthy individuals, we do not have to be too worried about the finding of the [premature ventricular contractions]. For [measured] sleep, it would be nice to know if that was fitful sleep. Were these individuals feeling rested the next day?”
Hylek said the clinical relevance and meaning of a person with a brief episode of AF is still an understudied area.
“We can’t necessarily extrapolate any findings to the persistent and permanent AF group,” Hylek said.
To date, data on this topic have been conflicting and have resulted from observational studies. But this is a question that we get asked very frequently by patients. These facts underscore the importance of the CRAVE trial.
The study suggests that coffee consumption does not increase the risk of atrial arrhythmias, but it increases the premature ventricular contraction count. It increases exercise activity and reduces sleep. Despite the importance of the trial, the sample size was relatively small (only 100 participants), and the research participants were healthy volunteers. They are very different from the average patient we see in clinical practice. Also, the study included short-term outcomes. I would love to see more data on long-term outcomes, including harder endpoints such as sustained ventricular arrhythmias and sudden cardiac death.
While we still need more data, I think these results should give us some reassurance that coffee consumption does not appear to increase the risk for AF. The association with premature ventricular contractions and ventricular arrhythmias deserves further study.
I like the fact that the researchers effectively utilized a digital health platform to conduct the study. I commend them on the very creative design.
HF may be an independent predictor of insomnia symptoms, according to a presentation from the American Heart Association Scientific Sessions.
“Several factors contribute to insomnia symptoms in heart failure, including advancing age, depression, comorbidities, symptom burden and pain,”Rida Gharzeddine, PhD, RN, assistant professor at Rutgers-Camden School of Nursing, New Jersey, said during a presentation. “However, it is unclear if heart failure itself independent of those associated factors contribute to insomnia symptoms.”
Researchers examined the association of HF with insomnia symptoms after adjusting for sociodemographic, clinical and lifestyle factors. These factors included age, sex, race, ethnicity, education, marital status, income, poverty level, sleep-disordered breathing, obesity, depression symptoms, comorbid diseases, smoking, alcohol consumption and physical activity.
Gharzeddine and colleagues conducted a secondary data analysis of data from the Health and Retirement Study using multiple logistic regression. Of 17,910 patients, 1,189 had HF.
In the unadjusted model, the results revealed that people with HF were nearly two times more likely to have insomnia symptoms (OR = 1.95; P < .001); however, HF maintained a significant association with insomnia symptoms (OR = 1.15; P < .05), even after adjusting for sociodemographic, clinical and lifestyle factors.
When researchers analyzed each insomnia symptom separately, they found that HF significantly predicted difficulty initiating sleep (OR = 1.23; P < .01) in the fully adjusted model, as well as continuing to show a trend with difficulty maintaining sleep and early morning awakening.
“In summary, heart failure predicted difficulty initiating sleep and the global insomnia symptoms [were] variable. These results, such as the neural-hormonal compensatory mechanism of heart failure, may play a role by exerting an alerting effect and leading to a hyperarousal state during the day and before sleep initiation,” Gharzeddine said. “Further research to investigate the sympathetic and the hypothalamic-pituitary-adrenal axis stimulation is needed and to confirm our hypothesis.”
Poor sleep health was associated with increased risk for experiencing CVD, according to data published in Scientific Reports.
Researchers reported that for each component (regularity, satisfaction, alertness, efficiency, duration and sleep actigraphy) of a composite sleep health measure, participants experienced an incrementally larger risk for CVD compared with those with healthy sleep.
“Insufficient or poor sleep is a significant risk factor for heart disease. Studies have mostly used single sleep measures (often focusing only on sleep duration, quality or insomnia). However, a composite of multidimensional sleep health may be more predictive of heart disease than single sleep measures,” Soomi Lee, PhD, assistant professor in the College of Behavioral and Community Sciences at the University of South Florida School of Aging Studies, and colleagues wrote. “Our approach lends itself to characterizing a ‘sleep health’ message that will be more effective in motivating the public to engage in multiple sleep health behaviors that may have synergistic effects on decreasing the risk of heart disease.”
For this study, researchers utilized the data of 6,820 individuals (mean age, 53 years) from the Midlife in the U.S. study (MIDUS) to evaluate whether composite measures of sleep health were associated with CVD. Researchers assessed two sleep health composites: the first, based on self-report only, assessed regularity, satisfaction, alertness, efficiency and duration of sleep; the second was based on each of the previous self-reported variables plus sleep actigraphy.
The outcome of CVD was also self-reported (MI, angina, valvular disease, atrial septal defect, ventricular septal defect, CAD, CHD, ischemia, arrhythmia, heart murmur, HF and/or other). Hypertension was excluded as a sleep health-related CVD.
Sleep health and CVD risk
After full adjustment, researchers reported a significant association between self-reported sleep health and risk for heart disease, with each unit increase in measures of poor sleep health associated with a 54% greater risk for CVD (adjusted RR = 1.54; P < .001). For each unit increase in measures of poor sleep health from the second composite including actigraphy, researchers observed a 141% greater risk for CVD (aRR = 2.41; P < .001).
Lee and colleagues proceeded to conduct a sensitivity check using unweighted sleep health composites and reported generally consistent yet weaker findings, with a 14% greater risk for CVD with each additional dimension of poor sleep (aRR = 1.14; P < .001). The association between poor sleep health and CVD failed to meet statistical significance in the sensitivity check using the unweighted self-reported second composite plus actigraphy (aRR = 1.22; P = .073).
Subgroup analyses by sex and race
Lee and colleagues noted that women reported more sleep health problems based on the first composite but not the second composite that included actigraphy. Although men were more likely to report CVD compared with women, sex did not moderate the association between sleep health and risk for CVD.
Although Black individuals experienced the highest number of unhealthy sleep variables and the highest prevalence of CVD, researchers reported that sleep health and CVD risk were more strongly related in white participants compared with all other races in the self-reported second composite plus actigraphy (P = .001).
Moreover, the slope for the association between more sleep health problems and increased risk for CVD was similar between both Black and white participants (P = .151), but other races and ethnicities did not follow the same pattern.
“The current study shows the importance of considering ‘co-existing sleep health problems’ within an individual to assess the risk of heart disease,” the researchers wrote. “Findings revealed having more sleep health problems may increase the risk of heart disease in middle adulthood. Results were consistent between two independent samples using different sleep health composites (using self-report only and both actigraphy and self-report). Despite known differences in the prevalence of sleep and heart disease by sex and race, the association between sleep health and the risk of heart disease did not generally differ by sex and race in our study. The findings highlight the importance and utility of assessing multidimensional sleep health in predicting the risk of heart disease and potentially other health outcomes.”
Patients with more severe obstructive sleep apnea, measured by the apnea-hypopnea index, were more likely to have incident venous thromboembolism, researchers reported in Chest.
“We found that VTE was more common in patients with OSA, as we expected. However, much of this risk seems to be driven by obesity, which may be the common risk factor
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that predisposes patients to both OSA and VTE,” Michael V. Genuardi, MD,MS, FACC, assistant professor of clinical medicine at the Center for Sleep and Cardiovascular Outcomes Research at the University of Pittsburgh School of Medicine and the division of cardiology at the Perelman School of Medicine at the University of Pennsylvania, told Healio. “Separate from obesity, patients who have low oxygen saturation levels overnight are also at increased risk of developing blood clots.”
Researchers evaluated clinical outcomes of 31,309 patients (mean age, 50.4 years; 50.1% women) who were undergoing overnight polysomnography in six sleep laboratories at the University of Pittsburgh Medical Center from July 2004 to December 2018. The researchers assessed associations between OSA severity and incident VTE.
Michael V. Genuardi, MD, MS, FACC
During a mean follow-up period of 5.3 years, 1,791 incident VTE events, the primary outcome, occurred.
Every 10-event per hour increase in the apnea-hypopnea index was associated with a 4% increase in risk for incident VTE in age- and sex-adjusted analyses (HR = 1.04; 95% CI, 1.02-1.06). However, when the researchers adjusted for BMI, the association disappeared (HR = 1.01; 95% CI, 0.99-1.03).
The researchers reported an independent association with nocturnal hypoxemia and incident VTE. Patients with more than 50% sleep time spent with oxyhemoglobin saturation of less than 90% had a 48% increased risk for VTE compared with patients without nocturnal hypoxemia (HR = 1.48; 95% CI, 1.16-1.69).
According to the researchers, the association between elevated apnea-hypopnea index and risk for VTE may be largely explained by differences in patient adiposity.
“We found that patients who have low oxygen saturation levels overnight are at higher risk of VTE,” Genuardi said. “More research is needed to understand this risk factor, since it may broadly apply to patients with multiple underlying medication conditions, including obstructive and central sleep apnea, chronic lung disease, and congestive heart failure.”
Chronic respiratory symptoms in young adulthood were associated with increased risk for cardiovascular disease and all-cause mortality in midlife, independent of CV risk factors, smoking and lung function, researchers reported in Chest.
“Little evidence currently exists regarding the association between chronic respiratory symptoms in young adulthood and cardiovascular outcomes in midlife,”Weijing Feng, MD, PhD, from the department of cardiology at the State Key Laboratory of Organ Failure Research at Guangdong Provincial Key Lab of Shock and Microcirculation at Nanfang Hospital in Guangzhou, China, and colleagues wrote. “Furthermore, identifying the contribution of chronic respiratory symptoms early in life, prior to the onset of CVD and related risk factors, may inform our understanding of how dysfunction in [the] respiratory system affects long-term CVD progression and prognosis.”
Researchers evaluated 4,621 participants aged 18 to 30 years from the Coronary Artery Risk Development in Young Adults (CARDIA) study. They identified chronic respiratory symptoms using respiratory symptom questionnaires.
During a median follow-up of 30.9 years, 284 incident CVD events and 378 deaths occurred.
In the cohort, 2,525 participants (mean age, 24.8 years; 52.9% women) had no chronic respiratory symptoms in young adulthood, 1,182 (mean age, 25.1 years; 55.2% women) had one, 611 (mean age, 24.9 years; 57.8% women) had two and 303 (mean age, 25.3 years; 63% women) had three or four.
Chronic respiratory symptoms were associated with increased risk for CVD events for any respiratory symptom (HR = 1.51; 95% CI, 1.18-1.93), cough or phlegm (HR = 1.57; 95% CI, 1.18-2.09), wheeze (HR = 1.31; 95% CI, 1.01-1.68), shortness of breath (HR = 1.73; 95% CI, 1.25-2.41) and chest illnesses (HR = 1.32; 95% CI, 1.01-1.71) after adjusting for demographic characteristics, CV risk factors, smoking and lung function.
Researchers observed similar findings for all-cause mortality.
The HR for CVD increased by 97% (HR = 1.97; 95% CI, 1.34-2.91) and all-cause mortality by 75% (HR = 1.75; 95% CI, 1.23-2.47) when researchers compared participants with no chronic respiratory symptoms and those with three or four symptoms.
“[These findings] suggest that identifying chronic respiratory symptoms in young adulthood may help provide prognostic information regarding future cardiovascular health,” the researchers wrote.
Genetic, environmental and lifestyle factors influence the risk for food sensitization and food allergies during the first thousand days of life, according to a literature review published in Annals of Allergy, Asthma & Immunology.
Erin C. Davis, PhD, postdoctoral fellow in the department of pediatrics’ division of allergy and immunology at the University of Rochester School of Medicine and Dentistry and the Center for Food Allergy at Golisano Children’s Hospital, University of Rochester Medical Center, in Rochester, N.Y., based their findings on a PubMed search of articles in English on food allergy (FA) and food sensitization (FS), prioritizing studies published after 2015.
Source: Adobe Stock
The review explored the genetic risks for food allergy, links between atopic dermatitis (AD) and food allergy, dietary allergen exposures in early life, maternal antigen consumption during pregnancy and lactation, breastfeeding and formula feeding, introduction to solid foods, lifestyle and environmental exposures, the gut microbiome and metabolome in food allergy and potential early immune biomarkers of food allergy.
Genetic risks for food allergy include the number of parents or siblings with a history of allergic disease, although the researchers caution that some of this association may be due to the family’s practice of prolonged avoidance or late introduction of the allergen.
Specifically, researchers have found connections between the major histocompatibility complex genes, which encode the human leukocyte antigen complex, and FA development including sensitization to peanut, cow’s milk and egg.
The review also found that approximately one of every three children with AD are prone to immediate-type IgE-mediated FA. One hypothesis suggests the impaired skin barrier that patients with AD experience allows epicutaneous sensitization to foods before oral ingestion.
Noting that infants may be exposed to allergens early in life, the researchers said that the mechanisms behind sensitization or tolerance likely vary based on how that exposure occurred.
For example, the researchers said, infants may be exposed to allergens in utero or through human milk or infant formula before they begin solid foods. Environmental or household exposures to allergens are plausible as well.
However, the researchers found scarce and contradictory findings about the relationship between maternal intake of allergenic foods and infant FA risks, even though major food allergens have been detected in amniotic fluid and human milk. The American Academy of Pediatrics does not recommend maternal dietary restrictions to prevent atopic disease.
Studies that have evaluated the protective effect of breastfeeding against FA have been mixed, the researchers continued. Human milk includes immunomodulatory components that shape the early life microbiome and immune system, but variations between women influence the risk for disease.
Early introduction to solid foods appears to have a significant impact, as the researchers cited the Learning Early About Peanut trial, which demonstrated how the early and sustained intake of peanut could be protective against peanut allergy. Also, the Enquiring About Tolerance Study found a 67% lower risk for FA with early introduction when children are aged 1 to 3 years.
The growing adoption of a Westernized lifestyle that limits less industrialized exposures to microbial influences may contribute to increasing rates of FA and FS as part of the hygiene hypothesis, the researchers further found.
For instance, larger family sizes are related to lower incidences of AD and hay fever. Exposure to pets and vaginal delivery also are associated with lower risks for allergic diseases. Farming lifestyles can be protective as well.
Such early exposures to diverse populations of microorganisms may train the immune system to mount tolerogenic responses during exposures later in life to environmental or food allergens, the researchers said.
The gut microbiome, meanwhile, also is a factor mediating the association between increases in the prevalence of allergic disease and industrialization. There may be an association between FA and FS development and less mature microbiomes, the researchers said, although studies have provided limited data.
Finally, the researchers found studies demonstrating associations between a differential infant immune profile and FS and FA. The loss of immune cell populations and potential hyper-responsive profiles could increase risks for aberrant responses including sensitization, the researchers said.
Multiple factors drive disease pathogenesis, including genetics as well as maternal and infant allergen exposure, human milk composition and other environmental factors, the researchers concluded, with tolerance or sensitization likely depending on the route of first exposures and possibly genetic risk.
Further, the researchers called for additional observational studies and clinical trials that span from early pregnancy through childhood so novel biomarkers and risk factors for predicting susceptibility for FS and FA could be uncovered.
Trends in Sudden Unexpected Infant Death by Cause, 1990 through 2019.
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