Updating cardiac screening guidelines for survivors of childhood cancer

Findings suggest that there is a long-term benefit in screening survivors at elevated risk for congestive heart failure. 

One of the first studies to analyze the effectiveness of screening survivors of childhood cancer for early signs of impending congestive heart failure (CHF) finds improved health outcomes but suggests that less frequent screening than currently recommended may yield similar clinical benefit. The researchers, in a study published in the Annals of Internal Medicine, utilized a simulation-based model to estimate the long-term benefits associated with routine screening.

The study’s findings suggest that the current CHF screening guidelines for survivors of pediatric cancer should be re-examined. The current guidelines recommend that survivors treated with chemotherapy agents known to affect long-term heart health be screened as often as every year, with a schedule dependent on their level of CHF risk. The new study suggests that screening survivors less often may be nearly as effective in detecting heart disease early. Some survivors might be better served by a different method of screening than the one currently used.

It is important to monitor survivors so we can reduce the late effects of treatment whenever possible, but we may be asking them to be tested too often, which burdens both individuals and the health care system,” says senior author Lisa Diller, MD, chief medical officer of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “We think it is worthwhile to review the current CHF screening guidelines.

Our findings suggest that there is a long-term benefit in screening survivors at elevated risk for CHF,” says lead author Jennifer Yeh, PhD, of the Center for Health Decision Science at Harvard School of Public Health. “Yet less frequent screening than currently recommended may be reasonable when other factors are considered. We hope these results can help inform the ongoing discussion about screening childhood cancer survivors.”

As cure rates of pediatric cancers have risen, increasing numbers of survivors are at a substantially higher risk of heart disease, including congestive heart failure, compared to the general population. The increase in risk varies depending on several factors, including whether a patient was treated with anthracyclines, a class of drugs known to cause heart disease, and/or radiation to the heart. For instance, those who received no or low (<250 mg/m2) cumulative doses of anthracyclines have a relatively low lifetime risk of developing CHF, while those who received large (≥250 mg/m2) cumulative doses are at higher risk.

The Children’s Oncology Group (COG) currently recommends that survivors undergo screening by echocardiography for asymptomatic left ventricular dysfunction (ALVD). If left untreated, this clinically silent condition can progress to CHF, so clinicians typically prescribe beta blockers and ACE inhibitors to patients with signs of ALVD. COG recommends that patients at high risk of developing CHF be screened every year or two and those at low risk be screened every two or five years.

Survivors are screened for decades and face risks for other late effects, as well,” Diller says. “We need to consider carefully how often we ask survivors to be screened over the course of their lives, given the substantial cumulative economic impact and anxiety that screening may cause.”

To estimate the clinical benefits and cost-effectiveness of the current heart screening guidelines, Diller, Yeh and their co-author, cardiologist Anju Nohria, MD, of Brigham and Women’s Hospital, constructed a computer model of a virtual cohort of 15-year-olds who had survived cancer at least five years. Using data from the Childhood Cancer Survivors Study and the Framingham Heart Study, the researchers modeled the cohort’s CHF risk and clinical progression over the course of survivors’ lifetimes. Their analysis suggests that routine screening may prevent as many as one in 12 cases of CHF.

The authors then used Medicare data to estimate the costs and value (expressed in cost per quality-adjusted life year [QALY]) of different screening schedules (i.e., every 1, 2, 5 or 10 years) and methods (echocardiography versus cardiac magnetic resonance imaging [cMRI]) for the different CHF risk groups (i.e., low, high).

At a cost-effectiveness threshold of $100,000/QALY, the model’s results indicate that echocardiographic screening might not be the best value for resources invested to reduce lifetime CHF risk among survivors at low risk of developing the disease. On the other hand, the data suggest that biennial echocardiography screening may be a high-value strategy for high-risk survivors.

The simulation’s data also suggested that cMRI may be preferable to echocardiography as a screening method, with cMRI’s greater cost per test balanced by its greater sensitivity. According to the model, cMRI-based screening of low-risk survivors every 10 years and high-risk survivors every five years was more cost effective than any echocardiography-based schedule.

Lastly, the data suggest that it may be most beneficial to treat high-risk survivors before signs of ALVD even appear. For instance, proactively treating all high-risk patients in the virtual cohort with ACE inhibitors and beta blockers reduced their lifetime CHF risk more than if they received an echocardiograph every two years, although additional clinical studies on the benefit of the treatments are needed to support this strategy in practice.

The researchers relied on simulation modeling using the best available clinical and epidemiologic data because of the immense logistical obstacles to conducting prospective randomized clinical studies of survivors’ long-term cardiovascular outcomes. The number of survivors that clinical studies would need to enroll and follow for years is challenging given how rare childhood cancers are. Yet guidance on the health benefits associated with current recommendations is needed.

Our findings suggest that current recommendations for cardiac assessment may reduce systolic CHF incidence, but less frequent screening than currently recommended may be preferred,” the study concludes. “Possible revision of current recommendations is warranted.”

Yeh et al., (1014). Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: A model-based estimation of the clinical and economic effects. Ann. Intern. Med., 160(10):661-671. doi:10.7326/M13-2266 [Abstract]

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Getting chemo first may help in rectal cancer

First things first. If cancer patients are having trouble tolerating chemotherapy after chemoradiation and surgery, then try administering it beforehand. Reordering the regimen that way enabled all but six of 39 patients to undergo a full course of standard treatment for rectal cancer, according to research to be presented at the American Society for Clinical Oncology annual meeting in Chicago.

Studies have shown that only about 60 percent of rectal cancer patients comply with postoperative chemotherapy, said lead researcher Dr. Kimberly Perez, assistant professor of medicine in the Warren Alpert Medical School of Brown University and a cancer physician at Rhode Island Hospital. In the phase II trial, “Complete Neoadjuvant Therapy in Rectal Cancer” (CONTRE), more than 90 percent of the patients were able to complete a regimen of mFOLFOX6 when it was moved to the front of the line.”The thought was, what can we do to make it more tolerable and get the benefit that we wanted,” said Perez, who will speak at 4 p.m. CDT on Saturday, May 31, 2014 at ASCO. “It’s encouraging because we were able to get the numbers up of patients who were able to get all the chemotherapy indicated.

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Only 60 percent of rectal cancer patients comply with chemotherapy after surgery. More patients complied and got the full benefit of chemotherapy when they received it first. For 13 patients in the study, the tumor (left) had disappeared when it was time for surgery. Credit: CONTRE Trial/Lifespan/Brown University

Almost all of the patients came into the study with rectal bleeding, but that symptom abated for all of them during treatment, Perez said.Regarding the cancer itself, a majority of patients, 32 of whom entered the trial at stage III and seven of whom were less advanced at stage II, responded at least to some degree to the induction chemotherapy and chemoradiation treatments. By the time they got to surgery, 13 patients had no tumor left (“pathologic complete response”), 10 got all they way back to stage I, seven were at stage II, and eight remained at stage III.

The study occurred too recently, however, to provide a measure of overall survival, Perez acknowledged. The last patient finished surgery in January 2014. The rate of side effects such as neutropenia, an adverse impact on the immune system, was not unusual.

The results of the CONTRE trial are now feeding into the development of a new national rectal cancer trial spearheaded by NRG Oncology, Perez said. That protocol will involve chemo first, then chemoradiation with biological anti-cancer agents, and finally surgery. Brown Univeristy Oncology Group and the Cancer Center of Rhode Island Hospital and associated satellites will be one of the study sites, Perez said.

 Presented at the American Society for Clinical Oncology annual meeting 2014 in Chicago.

‘Til sickness do us part: How illness affects the risk of divorce

In the classic marriage vow, couples promise to stay together in sickness and in health. But a new study finds that the risk of divorce among older married couples rises when the wife—but not the husband—becomes seriously ill.

“Married women diagnosed with a serious health condition may find themselves struggling with the impact of their disease while also experiencing the stress of divorce,” said Amelia Karraker, a researcher at the University of Michigan Institute for Social Research, who presents her findings May 1 at the annual meeting of the Population Association of America.Karraker and co-author Kenzie Latham of Indiana University-Purdue University Indianapolis analyzed 20 years of data on 2,717 marriages from the Health and Retirement Study, conducted by the Institute for Social Research since 1992. At the time of the first interview, at least one of the partners was over the age of 50.

The researchers examined how the onset of four serious physical illnesses—cancer, heart problems, lung disease and stroke—affected marriages.

They found that, overall, 31 percent of marriages ended in divorce over the period studied. The incidence of new chronic illness onset increased over time as well, with more husbands than wives developing serious health problems.

“We found that women are doubly vulnerable to marital dissolution in the face of illness,” Karraker said. “They are more likely to be widowed, and if they are the ones who become ill, they are more likely to get divorced.”

While the study did not assess why divorce is more likely when wives but not husbands become seriously ill, Karraker offers a few possible reasons.”Gender norms and social expectations about caregiving may make it more difficult for men to provide care to ill spouses,” Karraker said. “And because of the imbalance in marriage markets, especially in older ages, divorced men have more choices among prospective partners than divorced women.”We did not have information on who initiated divorce in this study. But it’s important to keep in mind that in most cases, it’s women who do so. So it could be that when women become ill and their husbands are not doing a very good job caring for them, they would rather that he just go and they rely on friends and family who will take care of them.”

Given the increasing concern about health care costs for the aging population, Karraker believes policymakers should be aware of the relationship between disease and risk of divorce.

“Offering support services to spousal caregivers may reduce marital strain and prevent divorce at older ages,” she said. “But it’s also important to recognize that the impetus for divorce may be health-related and that sick ex-wives may need additional care and services to prevent worsening health and increased health expenditures.”

Karraker is a National Institute on Aging Postdoctoral Fellow at the ISR Population Studies Center.

Population Association of America 2014 Annual Meeting May 1-3 Boston, Massachusetts

New model can predict therapy outcomes in prostate cancer with bone metastasis

A new computational model that simulates bone metastasis of prostate cancer has the potential to rapidly assess experimental therapy outcomes and help develop personalized medicine for patients with this disease, according to data published in Cancer Research, a journal of the American Association for Cancer Research.

“Bone remodeling is a balanced and extremely well regulated process that controls the health of our bones and the levels of circulating calcium,” said Leah M. Cook, Ph.D., postdoctoral fellow in the Department of Tumor Biology at the Moffitt Cancer Center in Tampa, Fla. “Active prostate cancer cells in the bone environment can speak the same language of the bone remodeling cells, and disrupt the delicate bone remodeling process. They promote extensive bone destruction and formation that in turn yields nutrients, allowing the prostate cancer cells to grow, thus creating a vicious cycle.”

“The mathematical model we created simulates this vicious cycle, and allows us to predict the impact of potential therapies on cancer cells and normal cells of the bone,” said Arturo Araujo, Ph.D., postdoctoral fellow in the Department of Integrated Mathematical Oncology at the Moffitt Cancer Center. “Unlike biological models, we can freeze the mathematical model at any time point in order to explore what each cell is doing at that particular point in time.”

To create the computational model, which they call “hybrid cellular automata,” Araujo, Cook, and colleagues created simulations of different cell types involved in bone metastasis of prostate cancer, including two types of bone cells called osteoclasts and osteoblasts, and prostate cancer cells. They then created algorithms to simulate the interactions of these cells among themselves and with other bone metastasis-related factors in the microenvironment, including the proteins TGF-beta, RANKL, and other bone-derived factors.

The researchers found that when they introduced a single metastatic prostate cancer cell to the model, it was able to simulate bone metastasis seven out of 25 times, accurately creating the vicious cycle. This phenomenon is difficult to reproduce using preclinical animal models, which is critical in determining the best time to apply therapies in order to obtain maximum efficiency, explained Araujo.

Further, the fact that the model failed to generate a bone lesion 18 out of 25 times reflects reality, where not every metastatic cancer cell that invades bone in prostate cancer patients succeeds in forming a viable lesion, he added.

In parallel to developing the computational model, the researchers grew prostate cancer cells that metastasize to bone in mice and found that the tumor growth rate predicted by the computational model was comparable to the tumor growth rate in mice, thus validating their simulations. The model was also able to identify some critical players and events in the process of bone metastasis.

To test if the model could predict treatment outcomes, they applied two standard-of-care treatments, bisphosphonates and an anti-RANKL therapy, and found that the anti-RANKL therapy fared better than bisphosphonates, which is what is seen in prostate cancer patients with bone metastasis treated with these therapies, according to Araujo. The model predicted that improving the efficacy of anti-RANKL delivery to the prostate cancer-bone microenvironment might yield better outcomes.

With further improvements, the model can be individualized to determine personalized medicine for prostate cancer patients, Araujo noted.

“By integrating mathematics with robust biological data, we are beginning to develop powerful tools that allow us to rapidly assess how factors contribute to prostate cancer progression in bone,” said Araujo. “Ultimately, we feel that the ability to customize these models based on inputs from each patient’s cancer biopsy will help medical oncologists determine the best treatment strategies, so that significant improvements in survival and quality of life can be made.”

Araujo et al., (2014). An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer. Cancer Res., 74: 2391-2401 [Abstract]

Vitamin D deficiency may be linked to aggressive prostate cancer

Vitamin D deficiency was an indicator of aggressive prostate cancer and spread of the disease in European-American and African-American men who underwent their first prostate biopsy because of abnormal prostate-specific antigen (PSA) and/or digital rectal examination (DRE) test results, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Vitamin D is a steroid hormone that is known to affect the growth and differentiation of benign and malignant prostate cells in prostate cell lines and in animal models of prostate cancer,” said Adam B. Murphy, M.D., MBA, assistant professor in the Department of Urology at the Northwestern University Feinberg School of Medicine in Chicago. “In our study, vitamin D deficiency seemed to be a predictor of aggressive forms of prostate cancer diagnosis in European-American and African-American men.

“The stronger associations in African-American men imply that vitamin D deficiency is a bigger contributor to prostate cancer in African-American men compared with European-American men,” added Murphy. “Vitamin D supplementation may be a relevant strategy for preventing prostate cancer incidence and/or tumor progression in prostate cancer patients.”

The most accurate way to measure how much vitamin D we have in our body is to measure levels of 25-hydroxyvitamin D (25-OH D) in our blood. The normal range of 25-OH D is 30 to 80 nanograms per milliliter (ng/ml).

In this study, European-American and African-American men had 3.66 times and 4.89 times increased odds of having aggressive prostate cancer (Gleason grade of 4+4 or higher), respectively, and 2.42 times and 4.22 times increased odds of having tumor stage T2b or higher, respectively, if their 25-OH D levels were less than 12 ng/ml at the time of prostate biopsy. In addition, African-American men had 2.43 times increased odds of being diagnosed with prostate cancer, if their 25-OH D levels were less than 20 ng/ml.

Between 2009 and 2013, Murphy and colleagues enrolled 667 men, ages 40 to 79 years, who were undergoing their first prostate biopsy at one of five urology clinics in Chicago following an abnormal PSA or DRE. Serum 25-OH D levels were measured at recruitment. Of the study participants, 273 were African-American and 275 were European-American, and 168 men from each group had a prostate cancer diagnosis from their biopsy.

The researchers found that the mean 25-OH D levels were significantly lower among African-American men (16.7 ng/ml) compared with European-American men (19.3 ng/ml). The highest 25-OH D level was 71 ng/ml in European-American men, while it was only 45 ng/ml in African-American men.

They categorized the study group into those whose 25-OH D levels were less than 12 ng/ml, less than 16 ng/ml, less than 20 ng/ml, and less than 30 ng/ml, and found a dose-response relationship between tumor grade and vitamin D level for both European-American and African-American men, and the association held true even after adjusting for potential confounders including diet, smoking habits, obesity, family history, and calcium intake.

The researchers also found an association between lower 25-OH D levels and those at high and very high risk for prostate cancer, per National Comprehensive Cancer Network (NCCN) criteria, which take into account prediagnosis PSA levels, tumor stage, and Gleason grade.

While no association was found between vitamin D deficiency and prostate cancer diagnosis in European-American men, this association was significant in African-American men. Further, the association with disease aggressiveness and cancer spread was stronger for African-American men than for European-American men. Skin color, which determines cumulative vitamin D levels from exposure to sun, may partly explain the discrepancies observed between European-American and African-American men, explained Murphy.

“We will next evaluate genetic polymorphisms in the pathways of vitamin D metabolism to better understand the risk alleles underlying this association,” said Murphy. “Vitamin D deficiency seems to be important for general wellness and may be involved in the formation or progression of several human cancers. It would be wise to be screened for vitamin D deficiency and treated.”

Rick Kittles, Ph.D., an associate professor of medicine and epidemiology at the University of Illinois in Chicago, is a co-author and collaborator on this project.

Murphy et al., (2014). Vitamin D deficiency predicts prostate biopsy outcomes. Clin. Cancer Res.20(9):2289–2299 [Abstract]

Better sleep predicts longer survival time for women with advanced breast cancer

Higher sleep efficiency in women with advanced breast cancer is significantly associated with lower mortality

A new study reports that sleep efficiency, a ratio of time asleep to time spent in bed, is predictive of survival time for women with advanced breast cancer.

Results show that higher sleep efficiency was significantly associated with lower mortality over the ensuing six years, an effect that remained after adjusting for baseline prognostic factors such as age, estrogen receptor status and treatments received. Mean survival was 68.9 months for efficient sleepers compared with 33.2 months for participants with poor sleep efficiency. Further analysis found that a 10 percent increase in sleep efficiency reduced the estimated hazard of subsequent mortality by 32 percent. There was no association between sleep duration and survival.

“We were surprised by the magnitude of the relationship between sleep quality and overall survival even after we accounted for medical and psychological variables that typically predict survival,” said lead author Oxana Palesh, PhD, assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University and research director of the Stanford Cancer Survivorship. “Good sleep seems to have a strongly protective effect, even with advanced breast cancer.”

The study involved 97 women with advanced breast cancer who had a mean age of 55 years. Objective sleep parameters were measured by wrist actigraphy for three consecutive days. Overall, participants spent about eight hours in bed at night but slept for only about 6.5 hours. Study results are published in the May 1 issue of the journal Sleep.

“This study emphasizes the importance of assessing sleep quality among women with breast cancer,” said American Academy of Sleep Medicine President Dr. M. Safwan Badr. “Healthy sleep is critical for physical health, quality of life and overall well-being.”

According to the authors, this is the first study to demonstrate the long-term detrimental effects of objectively quantified sleep on survival in women with advanced cancer. Although the mechanism of the relationship between sleep quality and advanced breast cancer survival is unclear, they suggested that sleep disruption may lead to diminished immune function or impaired hormonal stress responses that are more directly responsible for the decrease in survival.

The authors also noted that further research is needed to replicate this finding using a prospective, controlled, experimental design to determine whether improving sleep can improve survival.

“There are effective treatments for sleep disruption in the general population, and some of them have shown to be effective in cancer survivors as well,” said Palesh. “But much more research is needed to develop and test interventions that are adapted for cancer patients and survivors. These interventions might not only improve quality of life, but can potentially improve survival.”

Palesh et al., (2014). Actigraphy-measured sleep disruption as a predictor of survival among women with advanced breast cancer. Sleep37(5): 837-842 [Abstract]