Early deaths from childhood cancer up to 4 times more common than previously reported

Treatments for childhood cancers have improved to the point that 5-year survival rates are over 80 percent. However, one group has failed to benefit from these improvements, namely children who die so soon after diagnosis that they are not able to receive treatment, or who receive treatment so late in the course of their disease that it is destined to fail.

A study published in the Journal of Clinical Oncology explores this challenging population, finding that death within a month of diagnosis is more likely in very young children and those from minority racial and ethnic groups even independent of low socioeconomic status. The study uses a large national database to find that the rate of deaths within one month of diagnosis has been previously under-reported in clinical trial data, with early deaths from some pediatric cancer subtypes up to four times as common as had been implied by clinical trial reports.

During my pediatric residency a teenager came in with leukemia, but had so much cancer when he presented that he had multi-organ failure and died within about 24 hours of coming to our attention, before we could even start treatment. I wanted to find out who these kids are in hopes that as a system we could learn to spot them earlier, when treatment still has a chance of success,” says Adam Green, MD, investigator at the University of Colorado Cancer Center and pediatric oncologist at Children’s Hospital Colorado. Green originated this study during his clinical fellowship at Dana Farber Cancer Institute, working with Carlos Rodriguez Galindo, MD.

Green and colleagues used data from the Surveillance, Epidemiology and End Results (SEER) database, finding 36,337 cases of pediatric cancer between the years 1992 and 2011. Of these young patients, 555 or 1.5 percent died within one month of cancer diagnosis. Overall, the strongest predictor of patients who would die soon after diagnosis was age below one year.

In general, babies are just challenging, clinically, because they can’t tell you what they’re feeling. Parents and physicians have to pick the ones with cancer from the ones with a cold, without the patient being able to tell you about symptoms that could be diagnostic. Babies tend to get aggressive cancers, it’s hard to tell when they’re getting sick, and some are even born with cancers that have already progressed. These factors combine to make very young age the strongest predictor of early death in our study,” Green says.

Additionally, black race and Hispanic ethnicity predicted early death, even beyond the influence of socioeconomic status. Green hopes that future studies will be able to discover whether biologic or cultural factors may be responsible for these disparities, or if higher rates of early death in minority populations could be due to factors built into insurance and health care systems.

He also points out that the rate of early deaths due to pediatric cancers is higher than previously reported.

Most of what we know about outcomes for cancer patients come from clinical trials, which have much more thorough reporting rules than cancer treated outside trials. However, these kids in our study aren’t surviving long enough to join clinical trials,” Green says.

For example, the paper shows that a clinical trial against childhood Acute Myeloid Leukemia (AML) reported early death in 16 of 1,022 young patients, or 1.6 percent of these cases. In contrast, the SEER database, which collects about 15 percent of all cancer outcomes across the United States (representing a geographic and socioeconomic cross-section), shows 106 early deaths in 1,698 diagnoses, or 6.2 percent of all cases, almost four times as high as previously reported. When comparing the rates of early deaths seen in the SEER database to rates of early deaths reported in clinical trial data, early death was higher for all cancer subtypes (0.7 versus 1.3 percent in non-infant ALL; 2.0 versus 5.4 percent in infant ALL; 1.4 versus 3.8 percent in hepatoblastoma; 0.04 versus 0.5 percent in Wilms tumor).

I had a hunch this was a bigger problem than we thought. Now we see that is indeed the case,” says Green.

Now that Green has shown the fact of early death in this population, he hopes to work with CU Cancer Center colleagues to design a national prospective study that could more closely examine the factors associated with this outcome. “So that whenever a family has a child who dies of cancer within a month of diagnosis, we could contact the family to gather information about timing of symptoms and their experience accessing care. We can already act on our findings in this current study to improve early identification of these patients. But with prospective, patient-level data, we can move from understanding the scope and risk factors for early death to identifying problems in the diagnostic process we can fix,” Green explains.

The overall goal of this ongoing line of research is to change potential early deaths to long-term survivors.

This is a population that deserves our attention,” Green says.

Green et al.  Death Within 1 Month of Diagnosis in Childhood Cancer: An Analysis of Risk Factors and Scope of the Problem. Journal of Clinical Oncology (2017) DOI: 10.1200/JCO.2016.70.3249 [Article]

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Treatment significantly reduces chemotherapy-induced hearing loss in children

Investigators from Children’s Hospital Los Angeles and 37 other Children’s Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer,” said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, who was lead author and chair of the study. “It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors.” Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.

Freyer et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncology, 2016; DOI: 10.1016/S1470-2045(16)30625-8 [Abstract]

Eye movement affected in former childhood cancer patients

Nowadays, the lives of the majority of all children with cancer can be spared. However, the cure for the disease comes with a price: some of the survivors will suffer long-term injury from the treatment. A study from Lund University in Sweden now shows that commonly used chemo toxins impair the eyesight in childhood cancer survivors in a way that indicates an impact on the central nervous system.

It was not the former patients’ visual acuity that had been damaged; rather their eye motor skills – the eyes’ ability to follow moving objects.”We observed that most of these patients were not able to move their eyes smoothly and steadily, but jerkily and fitfully. Eye movement like that makes it harder to focus on moving objects in traffic, for instance. It can also cause headaches and dizziness“, says reader Per-Anders Fransson at Otorhinolaryngology in Lund.

The study included 23 childhood cancer survivors, at the current age of 20 to 30, and compared them to 25 healthy people of the same age. Only a few in the first group experienced no visual disorders, headaches and dizziness. The degree of the problem appeared to be related to the degree of which the eye motor skills had been affected, which suggests damage to the central nervous system from the chemotherapy.

It has been previously known that cisplatin, methotrexate, and ifosfamide – the types of chemo which the subjects of the study had been treated with – can penetrate the so-called blood-brain barrier, and thereby damage the nervous system. What has not been known, however, is whether the eye motor skills could be affected, and the consequences of that.An average of 15 years had passed since the patients underwent cancer treatment. The study could not determine whether any of them had experienced side-effects which by now had worn off, but it’s clear that the majority of them are still suffering the effects of their treatment. Age, at the time of treatment, appears to play an important role: those who were youngest at the time of treatment were the most affected.

A child’s brain has not completely developed, which makes it more susceptible to the influence of foreign substances“, says Thomas Wiebe, consultant in paediatric oncology.

He argues that for the time being, despite the risks, we must continue to use the medicines in question – after all, curing the cancer and saving lives is most important. However, the Lund University study reinforces the importance of coming up with new and better treatments. In the future, the new knowledge, and the diagnostic method described in the study will enable oncologists to pay closer attention to any side-effects, in which case it may be possible to reduce the dosage or change medications.

Thomas Wiebe also finds that Swedish healthcare needs to focus more on the growing group of childhood cancer survivors. Only a third of them are completely free from side-effects, while the rest experience anything from mild to severe effects from their treatment.

Today, childhood cancer patients are monitored in paediatric clinics until they turn 18, but after that there is insufficient follow-up. We have introduced a ‘delayed effect clinic’ here in Lund, but it lacks sufficient resources, and the rest of the country has even less resources!“, he says.

Because the survivors of childhood cancer may experience problems not only with their balance and vision, but also with for instance cardiovascular diseases, fertility, growth and cognition, they presumably turn to various forms of care in search of help. If there was a good system for diagnosis and follow-up, they could receive the support they need right away.

When it comes to balance and visual disturbances, there is an exercise programme that can significantly minimise problems. Simply being diagnosed is also valuable so you don’t have to wonder why you are experiencing things such as dizziness and fainting“, says Professor of Otorhinolaryngology Måns Magnusson.

Einarsson et al. Oculomotor deficits after chemotherapy in childhood. PLoS ONE. 2016; 11(1): e0147703. doi:10.1371/journal.pone.0147703 [Article]

Bone loss associated with leukemia therapy occurs sooner than previously thought

Investigators at Children’s Hospital Los Angeles have found that significant bone loss – a side effect of chemotherapy for acute lymphoblastic leukemia (ALL) – occurs during the first month of treatment, far earlier than previously assumed. Results of the study will be available online in advance of publication in the journal Bone.

ALL is the most common pediatric cancer. Forty years ago, only one in five children survived this disease. Today with the development of powerful chemotherapies, over 90 percent of patients can expect to be cured. Unfortunately, there are some significant side effects to these life-saving therapies, including loss of bone density resulting in an increased risk for bone fractures during and even after therapy. Previous studies to determine the changes to bone density during ALL therapy had focused on the cumulative effects of chemotherapy after months or even years of treatment.

In clinic, we would see patients with fractures and vertebral compression during the very first few weeks of treatment,” said Etan Orgel, MD, MS, first author on the study and an attending physician in the Survivorship & Supportive Care Program at the Children’s Center for Cancer and Blood Diseases at CHLA. “But we were unaware of any study that specifically examined bone before chemotherapy and immediately after the first 30 days of treatment – which would allow us to understand the impact of this early treatment phase.

In a prospective study in newly diagnosed patients 10 to 21 years of age, the investigators explored leukemia-related changes to bone at diagnosis, and then the subsequent effects of the first – or induction – phase of chemotherapy. Using quantitative computerized tomography (QCT) – a newer technique more accurate for use in growing bone – they determined that leukemia did not dramatically alter the properties of bone before chemotherapy (in comparison to similar age- and sex-matched control patients).

During the 30-day induction phase, however, bone mineral density of the lower spine decreased by more than 25 percent with significant thinning of the dense cortex occurring in the bones of the leg. To help clinicians relate to these findings, the team also measured bone mineral density using the older but more widely available technique of dual-energy x-ray absorptiometry (DXA) and found that it underestimated these changes as compared to QCT measurements.

Now that we know how soon bone toxicity occurs, we need to re-evaluate our approaches to managing these changes and focus research efforts on new ways to mitigate this common – yet significant – adverse effect,” said Steven Mittelman, MD, PhD, principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles and senior author on the study.

Orgel et al. Early Injury to Cortical and Cancellous Bone from Induction Chemotherapy for Adolescents and Young Adults Treated for Acute Lymphoblastic Leukemia. Bone 2016; http://dx.doi.org/10.1016/j.bone.2016.01.027 [Abstract]

Two studies examine long-term outcomes in childhood and young adult cancer survivors

JAMA Oncology published two studies and a related editorial focused on long-term outcomes in survivors of childhood or young adult cancer.

In the first study, Kathrine Rugbjerg, PhD, and Jørgen Olsen, MD, DMSc, of the Danish Cancer Society Research Center, Copenhagen, examined the risk for hospitalization up to 34 years after a diagnosis of adolescent and young adult cancer survivors. The study included 33,555 five-year cancer survivors diagnosed from 1943 through to 2004 with a comparison group from the general population. The authors identified 53,032 hospitalizations in cancer survivors for one or more of 97 disease categories.

Cancer survivors had an overall increased risk of hospitalization compared with those in the general population. Cancer survivors at highest risk for hospitalizations were leukemia, brain cancer and Hodgkin lymphoma survivors.

Survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases requiring hospitalization. The morbidity pattern, which is highly dependent on the type of cancer being treated, underscores the need for further implementation of strict evidence-based sex-, age- and cancer-specific follow-up plans for survivors, thereby increasing the likelihood for early detection and ultimately prevention of treatment-induced morbidities.

In the second study, Kevin Krull, PhD, of St. Jude Children’s Research Hospital, Memphis, and coauthors examined neurocognitive and patient-reported outcomes in adult survivors of childhood osteosarcoma, a type of bone cancer. The study included 80 survivors of osteosarcoma who were an average age of nearly 39 years and almost 25 years past diagnosis. The cancer survivors were compared with 39 community members unrelated to the cancer survivors. Long-term survivors had lower average scores in reading skills, attention, memory and processing speed. However, plasma concentration of methotrexate following high-dose intravenous administration during chemotherapy was not associated with neurocognitive outcomes at nearly 25 years after diagnosis.

Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. … Our results demonstrate the need for increased attention in this diagnosis, with prospective studies to delineate the evolution of impairment over the course of therapy and long-term survival,” the authors conclude.

In a related editorial, Karen E. Effinger, MD, MS, and Michael P. Link, MD, of the Stanford University School of Medicine, California, write: “Advances in cancer therapy have led to increased survival; there are more than 9 million 5-year survivors of cancer in the United States. As this number continues to grow, focus on improved health and quality of life becomes a priority. … Going forward, we must apply our knowledge of late effects to improve monitoring and interventions for patients. While the progress made in the management of cancer in children and young adults has been gratifying, we must remember the words of Giulio D’Angio, who reminds us that ‘cure is not enough.'”Rugbjerg et al. Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4393 [Article]Krull et al. Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma. JAMA Oncol. Published online November 19, 2015. doi:10.1001/jamaoncol.2015.4398 [Abstract]

Youngest bone marrow transplant patients at higher risk of cognitive decline

St. Jude Children’s Research Hospital study identifies small group of patients at risk for intellectual decline after bone marrow transplantation; results set stage for new strategies to preserve IQ and fight cancer.

Toddlers who undergo total body irradiation in preparation for bone marrow transplantation are at higher risk for a decline in IQ and may be candidates for stepped up interventions to preserve intellectual functioning, St. Jude Children’s Research Hospital investigators reported. The findings appear in the current issue of the Journal of Clinical Oncology.

The results clarify the risk of intellectual decline faced by children, teenagers and young adults following bone marrow transplantation. The procedure is used for treatment of cancer and other diseases. It involves replacing the patient’s own blood-producing stem cells with those from a healthy donor.

Researchers tracked IQ scores of 170 St. Jude patients before and for five years after transplantation, making this the most comprehensive effort yet to determine how the procedure affects intelligence. The patients ranged in age from 4 months to 23 years when their transplants occurred. The procedure had little lasting impact on the IQ scores of most patients.

For the great majority of patients, these findings provide reassurance that transplantation will not have a significant negative impact on cognitive development,” said corresponding author Sean Phipps, Ph.D., chair of the St. Jude Department of Psychology. “We have also identified a high-risk group of younger patients who may benefit from more intensive interventions, including developmental stimulation and other rehabilitative therapies designed to prevent a decline in intellectual functioning and aid in recovery.

The high-risk group includes patients whose transplants occurred when they were aged 3 years or younger and involved total body irradiation (TBI). TBI is used to prepare patients for transplantation by killing remaining cancer cells and protecting the transplanted cells from their immune systems. TBI is associated with a range of short-term and long-term side effects. At St. Jude, therapeutic advances have significantly reduced the use of TBI in bone marrow transplantations.

Previous studies of bone marrow transplantation survivors reported conflicting results about the long-term impact of age and TBI on cognitive abilities.

Before transplantation, the average IQ scores of all patients in this study were in the normal range. One year after transplantation, average IQ scores of patients aged 5 and younger had declined sharply. But scores of most patients rebounded in subsequent years. Five years after the procedure, IQ scores for most patients, even the youngest survivors, had largely recovered and fell within the range of normal intelligence.

Patients in the high-risk group were the lone exception. IQ scores of patients who were both aged 3 or younger when their transplants occurred and who received TBI failed to recover from the first-year decline. Five years after transplantation, these survivors had average IQ scores in the low-normal range of intelligence. Their scores were more than 16 points lower than the scores of patients who were just as young when their transplants occurred but did not receive TBI.

Of the 72 patients in this study whose transplants included TBI, researchers found there was a long-term impact on intellectual functioning only of patients who were aged 3 or younger at transplantation.

The significant first-year decline reflects the intensity of transplantation, which our results suggest leads to greater disruption in development in the youngest children than was previously recognized,” said the study’s first author Victoria Willard, Ph.D., a St. Jude psychology department research associate.

“These findings are good news for most parents whose children must undergo transplantation and provide another reason for hope of good long-term outcomes. For those whose children are in the newly recognized high-risk group, increased attention and activities designed to stimulate cognitive development may help to prevent reduced IQ following transplantation,” Phipps said.

Willard et al. Cognitive outcome after pediatric stem-cell transplantation: Impact of age and total-body Irradiation. J. Clin. Oncol. 2014;32(35): 3982-3988 [Abstract]

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]