Pediatric cancer survivorship: the costs associated with the cure

Pediatric cancer survivors face increased health risks as they age. How is the medical community responding?

As the data about pediatric cancer survivorship have expanded during the last two decades, the oncology community has begun facing new challenges in cancer survivorship, late effects of cancer treatment and the tracking of pediatric cancer patients as they age into adulthood.

“We have been successful during the past several decades in improving outcomes and progressively increasing cure rates for children with cancer, such that now, nearly 80% of childhood cancer patients are cured of their disease,” Gregory Reaman, MD, professor of pediatrics at George Washington University, Children’s National Medical Center, Washington, D.C. and chairman of the Children’s Oncology Group, told HemOnc Today.

Gregory Reaman, MD, Chairman of the Children’s Oncology Group. Photo by Bryan S. Blanken

“But the blessing has been a bit of a double-edged sword. As we cure increasing numbers of children and follow them for lengthy periods of time, we recognize that there is indeed a cost associated with cure,” he said.

These costs manifest in what Reaman called “significant collateral damage” and come about as a result of either the cancer itself or the modalities used in cancer treatment: radiation therapy, chemotherapy, surgery or any combination of these.

“It remains somewhat discouraging that when we look at large cohorts of survivors, we find that a significant number of patients have life-altering, life-threatening, even long-term associated health problems related to their cancer and their cancer therapy,” Reaman said.

HemOnc Today spoke with a number of experts dedicated to the issues surrounding pediatric cancer survivorship and the complications — and potential solutions — for cancer survivors as they move into adulthood and older age.

Late effects

“We really don’t know the ultimate magnitude of late effects and the impact that they are going to have as this patient group ages over time,” said Les Robison, PhD, chair of the St. Jude Children’s Research Hospital department of epidemiology and cancer control. “We don’t know what’s going to happen in the fourth, fifth and sixth decades as this population ages.”

The Childhood Cancer Survivor Study (CCSS) is an NCI-funded research project that involves one of the largest groups of patients being studied long-term. Researchers with the CCSS currently have data out to 30 years from the time of diagnosis in a cohort of patients treated in the 1970s.

“It’s a continual issue to understand where we are in this trajectory of survivorship for what we consider the first wave of cancer survivors, because the survival rate increased so rapidly between the late ’60s and early ’70s. They are the first bolus of survivors that we can look at,” said Robison, who is the principal investigator of the CCSS.

Numerous papers highlighting CCSS data have been published. In 2006 in The New England Journal of Medicine, the CCSS group published data on 10,397 pediatric cancer survivors compared with 3,034 of the survivors’ siblings. Among the survivors (mean age 26.6 years), 62.3% had a chronic condition and 27.5% had a life-threatening condition. The relative risk for a pediatric cancer survivor, in comparison with a sibling, to have a chronic condition was 3.3 (95% CI, 3.0-3.5); the relative risk for a severe or life-threatening condition was 8.2 (95% CI, 6.9-9.7).

At 30 years from the time of diagnosis, the cumulative incidence of chronic health conditions was 73.4% (95% CI, 69.0-77.9). The cumulative incidence of severe, disabling or life-threatening conditions or death due to a chronic condition was 42.4% (95% CI, 33.7-51.2).

Kevin Oeffinger

“We’re just going over some of the CCSS cohort mortality data, and it’s becoming clear that these patterns of late mortality are shifting quite dramatically, with deaths due to new cancers, cardiac events, pulmonary events — clearly, this population has a significant increase [in mortality],” Robison said.

Data from an abstract from Castellino et al at this year’s ASCO Annual Meeting indicated an increase in mortality among CCSS survivors of Hodgkin’s lymphoma. The study results indicated that men who survived Hodgkin’s lymphoma who had received anthracycline vs. radiation alone were at an increased risk for mortality (HR=3.2; 95% CI, 1.8-5.6). Conversely, women who received radiation above and below the diaphragm were at increased risk compared to those who got chemotherapy alone; this was true at any radiation dose, both <30 Gy (HR= 4.5; 95% CI, 1.2-17.4) and >30 Gy (HR=3.5; 95% CI, 1.1-11.6).

“There are some outcomes that are so obviously related to the therapy and are not modified by other factors, such as health behaviors,” said Kevin Oeffinger, MD, director of Memorial Sloan-Kettering Cancer Center’s Program for Adult Survivors of Pediatric Cancer.

“For example, somebody that has high-dose radiation to an extremity to treat a sarcoma and then develops another sarcoma of a different type 10 years later, you know that it is related to the radiation,” Oeffinger said. “However, many of the late effects that we see are really just an exaggeration or an accentuation of a patient’s genetics and lifestyle, and we just hasten that aging process, if you will, by 15 or 20 years.”

Problems that are common in the general population occur at a much younger age in pediatric cancer survivors: myocardial infarction at 30 years old rather than at 60 years old, for example.

“As another example, 20% of women who survived Hodgkin’s disease and received standard-dose mantle radiation are diagnosed with breast cancer by age 45. Recognizing that women in the general population infrequently develop breast cancer at a young age, there is a notable excess risk at a young age in these cancer survivors,” Oeffinger said.

Research published in the Journal of the American Medical Association in June 2007 contributed to an overall understanding of late effects as well. Researchers from the Late Effects Study Group and Outpatient Clinic and other institutions in the Netherlands conducted a retrospective cohort study of 1,362 pediatric cancer survivors treated between 1966 and 1996. Median follow-up in the patients was 24.4 years; 75% of survivors had at least one adverse event and 24.6% had five or more adverse events. Forty percent of the survivors had at least one severe, life-threatening or disabling event.

Falling off the radar

One of the factors that compounds the difficulties facing care of pediatric cancer survivors is the rate at which they “fall off the radar.” As survivors reach their teenage years and beyond, they become more mobile, go to college, start their careers, and tend to separate from the cancer center where they were treated, according to Oeffinger. “It’s not surprising that they disconnect,” he said.

CCSS data published in 2004 in the Annals of Family Medicine showed that as pediatric cancer survivors aged, they were significantly less likely to report a general physical exam, a cancer-related visit or a visit to a cancer center. As the interval from diagnosis of cancer increased, survivors of bone and central nervous system tumors, Hodgkin’s disease and leukemia became increasingly less likely to report a cancer-related visit.

Other factors that affect this falling off may relate to family and patient education. “We do a lot of education for the family while the child is going through therapy. But remember that education is primarily targeted to the parent. We provide some age- and developmentally appropriate education to the child. But as [the children] get older, not surprisingly, some parents may choose not to spend much time talking about that because it brings up fears and a sense of uncertainty,” Oeffinger said.

“Realizing that there are still going to be about 20% to 30% of patients who you simply are not able to educate for whatever reason or barrier there may be ... they are going to fall through the cracks,” he said.

Transitioning to adult care

So what can be done to address the needs of the pediatric cancer survivor population?

“What’s really lacking is the development of survivorship programs with adult health care providers,” said Reaman. “When children with cancer survive, they survive for decades. It’s not appropriate for pediatric specialists to be continuing to provide ongoing subspecialty care, advice and management for young adults and older adults, particularly in areas like obstetrics and gynecology or in cardiovascular disease,” he said.

Reaman said that establishing clinics and programs to transition care from the pediatric oncologist to an adult health care setting, with a focus on the issues specific to cancer survivorship, is necessary.

“Training in a large community of people who are interested in survivorship issues and quality of life is just now beginning to gain awareness, and the need for it is significant. But the real need is for pediatric oncologists working with these adult caretakers to begin to successfully, effectively transition care of their older adolescent and young adult patients to an adult health care system and environment,” Reaman said.

David Poplack

The concept of survivorship guidelines and effectively transitioning care is on the radar of the Children’s Oncology Group and the Texas Children’s Cancer Center at Baylor College of Medicine. Together, they are developing the Passport for Care.

Passport for Care individualizes a pediatric cancer survivor’s follow-up care guidelines based on their unique treatment summary. This information will be available at all times to health care providers, as well as patients, via a web-based interface. The Passport for Care has been implemented for use by health care providers at the Texas Children’s Cancer Center. It will ultimately be available to all COG clinics.

“Probably the single most useful piece of information we can give to our cancer survivors is a treatment summary,” said Oeffinger, who is involved in the development of the Passport for Care program. “It includes the cancer diagnosis and type of treatment the patient received: for example, if they received radiation, the field of radiation and the dose; or if they had chemotherapy, the type of chemotherapy. We also like to include cumulative or total doses for some of the key agents. A single-page treatment summary like that can be extremely helpful,” he said.

“The Passport for Care is something we’ve wanted to do for the last 20 years, but the technology finally caught up with the idea,” said David Poplack, MD, director of the Texas Children’s Cancer Center. Poplack, with Michael Fordis, MD, and Marc Horowitz, MD, at Baylor, is developing the Passport for Care.

“What you have in this country are long-term survivors who are bouncing around from health care provider to health care provider, not getting the care they need. You may have someone who was treated at age 4 in San Diego for Wilms’ tumor and that person shows up at age 28 in Waterville, Maine, seeing a family practitioner because he has blood in his urine. So the survivor may not remember what type of cancer he had, never mind that they might not know the therapy he received,” Poplack said.

In addition to providing this kind of information to survivor and caregiver, the Passport for Care also allows survivors to feel empowered. “Survivors want to be in control,” Poplack said. And although the program is not fully developed yet, Poplack envisions Passport for Care as going a step further and providing individualized resources to patients — such as matching patients to specific resources in their local area via ZIP code.

Financial issues

Some roadblocks to proper care of pediatric cancer survivors, however, remain financial in nature. “There are some financial issues, no question. The financial issues really relate to whether or not insurers, third-party payers including Medicaid and Medicare, actually see this as an expense that needs to be covered,” Reaman said. “Younger individuals are much more hampered by a lack of access to third-party coverage and by a general unwillingness on the part of third-party insurance carriers to cover this kind of care.”

According to Melissa M. Hudson, MD, director of the Cancer Survivorship Division at St. Jude Children’s Research Hospital, pediatric patients are increasingly being given treatment summaries, similar to the Passport for Care model, that outline cancer-related health risks and screening recommendations as they leave pediatric care and enter into the adult health care setting.

Melissa M. Hudson

“What I’ve heard from the medical oncology community is that medical oncologists do not routinely provide a summary addressing cancer-related health risks and health screening,” Hudson said.

“Legislation supporting reimbursement for this service may encourage more providers to take the time to organize this important document,” she said.

“Knowing that this group is increasing in numbers and is medically vulnerable, whatever the government or legislation can do to facilitate [these patients’] care is going to be important. It’s not going to happen in the scheme of how busy practices are; it has to be streamlined and it has to be reimbursable,” Hudson said.

Focusing efforts and St. Jude Lifetime

The best focus of efforts going forward, according to Hudson, should be on rigorously designed studies that can characterize groups at risk for poor outcomes. “As with other screening or intervention programs, you need to identify who is at highest risk for adverse outcomes and focus your screening efforts and resources onto the group where you will have the greatest potential for impact,” Hudson said. “The only way we will be able to accomplish this with accuracy is to follow these patients systematically years after their cancer experience.”

One problem with carrying out research at single institutions is that most centers do not have a sufficiently large population under active surveillance. If patients drop off and lose contact with their clinical care providers at institutions where research is being carried out, the populations of these studies may become more and more selected, or even self-selected, Robison said.

“Because they are the patients that continue to come back, we may get a very distorted picture of the spectrum of problems that these survivors face. From that standpoint, it’s incredibly important to keep the level of quality of the research exceedingly high,” Robison said.

At St. Jude, Robison, Hudson and their colleagues have begun enrolling patients into the St. Jude Lifetime Cohort Study, a study that will complement the CCSS and push research toward more clinically based assessments. The goal of the St. Jude Lifetime Cohort Study is to establish the prevalence of problems in this cohort and in particular “to identify groups who have subclinical changes that may benefit from intervention or prevention methods,” Hudson said.

“We will define various levels of follow-up care. So if a patient has had limited treatment — for example, resection and only a few months of chemotherapy for a kidney tumor — evaluation every five years may be sufficient,” Hudson said. “Survivors in groups at high risk for complications based on specific treatments may potentially come back every year. The whole group will continue with lifetime follow-up, and we’ll be in contact with them via newsletters and website activities to keep them engaged in the cohort.”

The researchers from St. Jude Lifetime Cohort Study aims to invite more than 4,000 survivors of childhood cancer to return for clinical evaluation. “We have strategized that in the first year, we will target leukemia survivors who are 30 years or more from their diagnosis and treatment, and Hodgkin’s survivors who are 35 or more years from their diagnosis and treatment,” Hudson said.

“Our plan is to stagger enrollment so we can fully characterize groups of survivors by diagnosis, age and time from therapy so we can provide information to our colleagues and to the medical literature about what we’re learning. Our hope is to recruit enough of a group that is going to be representative of that diagnostic type,” she said.

Evolution will continue

The field and research into pediatric cancer survivorship will continue to develop and evolve, according to Reaman. “We need to be continuing to not only provide care for these survivors but also continue to provide that care within the context of clinical research so that we can help them and also help the next generation of patients and survivors,” he said.

The simple message is that, moving forward, the largest population of cancer survivors will be survivors of childhood cancer. This is the population of survivors that will have the longest period of survival during which they are at risk for health-related complications.

“We as a cancer community need desperately to work together — with pediatrics, pediatric oncology, appropriate pediatric subspecialties, medical oncology and appropriate internal medicine subspecialties — to develop meaningful transition plans so that the children who become adults can in fact have the appropriate level of surveillance and care for what we recognize is going to be a continuum of clinical problems,” Reaman said. – by Evan Young

For more information:

• Castellino SM, Tooze J, Geiger AM, et al. Risks of mortality in 5 year survivors of Hodgkin’s Lymphoma (HL) in the Childhood Cancer Survivor Study (CCSS). #10006. Presented at: the 2008 ASCO Annual Meeting; May 30-June 3, 2008; Chicago.
• Geenen MM, Cardous-Ubbink MC, Kremer LCM, et al. Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA. 2007;297:2705-2715.
• Hudson MM, Mertens AC, Yasui Y, et al. Health status of adult long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. JAMA. 2003;290:1583-1592.
• Oeffinger KC, Hudson MM. Long-term complications following childhood and adolescent cancer: foundations for providing risk-based health care for survivors. CA Cancer J Clin. 2004;54:208-236.
• Oeffinger KC, Mertens AC, Hudson MM, et al. Health care of young adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med. 2004;2:61-70.
• Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572-1582.
• Oeffinger KC, Robison LL. Childhood cancer survivors, late effects, and a new model for understanding survivorship. JAMA. 2007;297:2762-2764.
• Twombly R. Childhood Cancer Survivor Study doubles to examine late effects of new treatments. J Natl Cancer Inst. 2007;99:1574-1576.