Severe Health Problems Plague Survivors of Childhood CA

Kristin Jenkins

September 18, 2017

The most extensive assessment to date of chronic health conditions in survivors of childhood cancer, and the first to quantify absolute and excess morbidity, reveals that by age 50 years, nearly all patients in this high-risk population have twice as many severe health conditions as members of the general public.

Use of a new statistical model to retrospectively characterize the cumulative incidence and burden of 168 graded chronic health conditions in 3010 cancer survivors from the St Jude Lifetime Cohort Study (SJLIFE) shows that 99.9% suffer from severe chronic health conditions by the age of 50, says a research team led by Nickhill Bhakta, MD, MPH, of the Department of Global Pediatric Medicine at St Jude Children's Research Hospital, Memphis, Tennessee.

By mid-life, 96% of survivors had an average of 17 chronic health conditions, five of which were severe or disabling (grade 3), life-threatening (grade 4), or fatal (grade 5), the study authors report. The findings were published online September 7 in the Lancet.

A second cancer was diagnosed in 37% of survivors by age 50. Most other chronic health conditions involved spinal disorders and pulmonary disease. By comparison, an average of nine chronic health conditions were observed in 277 matched community control persons by the age of 50, with two conditions of grades 3 to 5 in severity (P < .0001).

This cumulative burden of disease remains "the true price of cure," say Dr Bhakta and colleagues. "Our findings have wide-ranging implications for health-care delivery, clinical research, and health policy. For clinicians, the complex patterns of chronic health conditions (CHC) contributing to cumulative burden in different subgroups of survivors highlights the health-care needs of this population, which surpass those commonly provided for in routine practice."

The 10-year survival rate for pediatric cancer patients is now more than 80%, and long-term survival is increasing. Currently, there are more than 400,000 childhood cancer survivors in the United States.

We hope that these findings will translate into better care for survivors. Dr Nickhill Bhakta

This study "highlights the complexity of their medical needs, and we hope that these findings will translate into better care for survivors, both in terms of managing long-term problems such as cardiovascular diseases and secondary cancers, but also by raising awareness of the more immediate and acute health problems that can often be left untreated," said Dr Bhakta in a statement.

Comparing Survivors to General Population

The investigators retrospectively collected data from the SJLIFE study on all pediatric cancer survivors who lived for at least 10 years from the time of their initial diagnosis and who were aged 18 years or older as of June 30, 2015. (The ongoing cohort study was initiated in April, 2007.) Survivors were matched with SJLIFE community control participants on 5-year age blocks in each sex. Analysis included 21 treatment exposure variables.

Using a new statistical mode that puts multiple and recurrent conditions into a single metric, they identified patterns of illness and detailed the characteristics of condition-specific morbidity in different subgroups of survivors.

"Our data go much further and provide a comprehensive landscape of morbidity," the study authors write. "In clinical and research settings, general health practitioners and clinical investigators can use the information we provide to address risks as part of patient care, assess trade-offs between exposures and different chronic health conditions to aid the design of future clinical trials, and inform the development of follow-up guidelines."

Adjusted analyses show that the cumulative mortality burden and the frequency and severity of chronic health conditions are affected by a number of factors, including age at diagnosis, treatment era, and treatment type ― particularly when the latter involves higher doses of radiation to the brain and chest.

The cumulative burden of grade 1-5 chronic health conditions at age 50 years was highest in survivors of central nervous system (CNS) malignancies and lowest in survivors of germ cell tumors (an average of 24 vs 14 health conditions, respectively), the study showed.

"Survivors Not All the Same"

These data provide evidence that "survivors are not all the same," Dr Bhakta told Medscape Medical News. "While we expected some heterogeneity, we did not expect the differences to be quite so large that every subgroup was distinct from one another," he explained. A single "one- size-fits-all" algorithm cannot be applied to effectively manage these patients, he added, noting, "Quality care delivery is hard and takes a lot of work."

Two distinct patterns of morbidity were observed: the early-onset effects of cancer therapy, and late-occurring medical conditions that developed more rapidly in aging survivors than in matched community control persons. For example, survivors of CNS malignancies were more likely to experience hearing loss or neuropathies shortly after treatment, whereas survivors of hematologic cancers were more likely to experience cumulative cardiovascular problems and secondary cancers in adulthood.

"The increased risk of illness in survivors occurs at all ages, not just following cure," Dr Bhakti told Medscape Medical News. "The magnitude of this difference compared to a general population control group, when taking into account all disease measures, was both striking and unexpected."

These results also highlight several new avenues for study, said Dr Bhakta. These include early recognition of subgroups of survivors who would benefit from early intervention; the treating of diseases that cause health problems that patients say have the worst effects on quality of life; and determining ways to deliver effective healthcare to this population.

Although the current global standard for management of survivors of childhood cancer includes adjunctive survivorship care clinics and close adherence to survivorship guidelines in primary healthcare settings, more is needed, the study authors say. "The combination of poor access to services and high rates of health conditions we find in our analysis highlight the need for improved survivorship care, including access to specialist services."

In the United States, childhood cancer survivors with chronic, severe health conditions are often unable to work, are cut off from health insurance, and do not have access to care. "Survivors of childhood cancer experience multiple preexisting conditions and are a complex group with exposures to multiple different types of treatment modalities that can cause a multitude of long-term illnesses," Dr Bhakta told Medscape Medical News. "Guaranteeing access to healthcare providers who are comfortable with the details of survivorship screening and care is critical. It's important to consider how to best deliver this care and ensure it is efficiently done."

In an accompanying comment, Miranda M. Fidler, PhD, of the International Agency for Research on Cancer in Lyon, France, and Michael M. Hawkins, DPhil, director of the Center for Childhood Cancer Survivor Studies at the University of Birmingham, in the United Kingdom, agree that more research into specialized care is needed. "Given the numerous and diverse morbidity profiles in the population of survivors of childhood cancer, specialized health-care delivery, particularly for the most at-risk survivors identified, could clearly lead to improvements, and further research into the efficacy and costs are warranted."

The editorialists note that the current study's findings may not be generalizable to patients treated with newer therapies. They point to research demonstrating decreases in risks for morbidity and mortality in patients who underwent treatment more recently.

Dr Bhakta and colleagues acknowledge this point in their article, noting that in their study, most of the survivors were diagnosed between 1980 and 1994 and that survivors who were diagnosed more recently would have been treated with modern, targeted cancer therapies that may be associated with fewer chronic health conditions.

The editorialists also highlight another limitation: there is a potential for bias from the community control population, which was small and not randomly chosen.

This truly important data set exquisitely demonstrates how complicated it is to take care of cancer survivors. Dr Torunn Yock

Noting that most of the survivors were diagnosed between 1980 and 1994, Dr Bhakta and colleagues acknowledge that modern, targeted cancer therapies could make it possible for pediatric cancer patients who were diagnosed more recently to experience fewer chronic health conditions.

When asked to comment, Torunn I. Yock, MD, MCH, director of pediatric radiation oncology at Massachusetts General Hospital and associate professor at Harvard Medical School, Boston, also underscored the importance of specialized care. "This truly important data set exquisitely demonstrates how complicated it is to take care of cancer survivors," he told Medscape Medical News.

"Specialized cancer survivorship clinics that employ guidelines based on these data are needed to screen for severe late effects and provide early intervention. Hopefully, data such as these will provide fodder to support the resolve of Americans to commit to a fuller level of healthcare coverage," Dr Yock added.

The findings provide important clinical context, he said. Previous studies demonstrated a high rate of chronic medical conditions in survivors of childhood cancers, but these studies did not compare that rate to rates of chronic health problems in aging adults who were not exposed to cancer therapies, he explained. "We now know that the burden is much higher in our cancer survivors, and the risks depend on the treatments they received, their age, and the era in which they were treated."

This study and others demonstrate that radiotherapy is a leading cause of major morbidity in cancer survivors ― even in the modern era of 3D CT-based radiation planning, Dr Yock pointed out. "An important next step," he told Medscape Medical News, "would be to apply the same rigor to collection of late effects in childhood cancer survivors by reviewing 3D plans for exact dosimetry to organs and correlating this with late effects. In this era of proton radiotherapy and intensity modulation, we are better able than ever to spare normal tissues from unnecessary radiation."

Projects such as the Pediatric Proton Consortium Registry at Massachusetts General Hospital is centrally archiving 3D treatment plans and collecting late effects data for this purpose, said Dr Yock. "It would be very useful to have these efforts combined so that we can continue to craft better and less morbid treatments for our pediatric cancer patients and to include modern photon-based radiotherapy."

This study was funded by the US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities. The study authors and the authors of the comment report no relevant financial relationships. Dr Yock reports relationships with IBA, Protom, and Mim-Cloud.

Lancet. Published online September 7, 2017. Abstract, Comment

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