Studies highlight hospitalization, neurocognitive risks among AYA cancer survivors

Two studies published in JAMA Oncology focused on the long-term hospitalization risks and neurocognitive outcomes of survivors of adolescent and young adult cancers.

Results of a cohort study conducted in Denmark by Kathrine Rugbjerg, PhD, and Jørgen H. Olsen, MD, DMSc, both of the Danish Cancer Society Research Center in Copenhagen, showed survivors of adolescent and young adult cancers faced an increased long-term risk for hospitalization compared with the general public. Further, a greater number of hospitalizations occurred in this population than were initially expected.

Kevin R. Krull

In a second study, Kevin R. Krull, PhD, a faculty member in the departments of epidemiology/cancer control and psychology at St. Jude Children’s Research Hospital, and colleagues observed that long-term survivors of osteosarcoma are at risk for neurocognitive impairment. This risk appeared associated with current chronic health conditions rather than original treatment with high-dose methotrexate.

“Several large studies have been published on the general disease burden of survivors of childhood cancer; however, the disease pattern of survivors of adolescent and young adult cancer is only incompletely described,” Rugbjerg and Olsen wrote. “Because the pattern of cancers in adolescents and young adults differs from that in children and middle-aged adults and the biology of adolescent and young adult cancers is suggested to be distinct, research on the disease burden of this particular group of cancer survivors is important for planning preventive initiatives.”

Persistent risk for hospitalization, adverse events

Rugbjerg and Olsen sough to examine the relative and absolute excess risk for hospitalizations up to 34 years after diagnosis of adolescent and young adult cancer compared with population comparisons. The classified hospitalizations within 12 main diagnostic groups — which were further categorized into 97 specific diseases — or for injuries and violence.

The researchers used the Danish Patient Register to identify 33,555 cancer survivors (61% women) who were diagnosed between 1943 and 2004 when they were aged between 15 years and 39 years. The comparison arm included 228,447 cancer-free controls who were matched to the cancer cohort by sex and birth year.

Rugbjerg and Olsen followed survivors and controls through December 2010, for a median of 14 years (range, 0-34). During this time, 31% (n = 10,488) of cancer survivors and 18% (n = 41,012) of controls died.

The researchers identified 53,032 hospitalizations among cancer survivors. The expected number of hospitalizations — based on the appropriate sex-, age-, and calendar period–specific hospitalization rates of the comparison cohort — was 38,423, resulting in a standardized hospitalization rate ratio (RR) of 1.38 (95% CI, 1.37-1.39).

The highest risks occurred in patients diagnosed with diseases of the blood and blood-forming organs (RR = 2; 95% CI, 1.87-2.14), infectious and parasitic diseases (RR = 1.69; 95% CI, 1.61-1.77) and malignant neoplasms (RR = 1.63; 95% CI, 1.59-1.68).

Researchers calculated an absolute excess risk — or the additional risk for survivors for hospitalization — of 2,803 (95% CI, 2,712-2,893) per 100,000 person-years. The highest ratios occurred in patients with malignant neoplasms (18% of the total absolute excess risk), diseases of the digestive organs (15%) and diseases of the circulatory system (14%).

Further, survivors of the 10 most common adolescent and young adult cancers faced a significantly increased risk for diseases in the 12 main diagnostic groups. The highest risk occurred in survivors of leukemia (RR = 2.21; 95% CI, 2.02-2.42), brain cancer (RR = 1.93; 95% CI, 1.86-2) and Hodgkin’s lymphoma (RR = 1.87; 95% CI, 1.8-1.94).

The researchers observed that cancer survivors had more comorbid conditions than controls. For example, 11.6% (n = 3,750) of cancer survivors were hospitalized for diseases in at least three disease categories at any time before age 60 years, compared with 8.6% (n = 18,523) of controls.

Rugbjerg and Olsen acknowledged the lack of sufficient information about cancer treatment recorded in the Danish Cancer Registry as a study limitation.

“Survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases requiring hospitalizations,” the researchers wrote. “The morbidity pattern which — as described herein — 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.”

Link between osteosarcoma, neurocognitive impairments

The survival rate of childhood osteosarcoma has risen from below 20% in the 1970s to above 70% today, according to Krull and colleagues.

“This progress is largely due to advances in treatment, including adjuvant chemotherapy with IV high-dose methotrexate,” they wrote. “Because high-dose methotrexate has been associated with neurotoxic effects among survivors of childhood acute lymphoblastic leukemia, the Children’s Oncology Group recommends neurocognitive screening for all survivors of childhood and adolescent cancer exposed to high-dose methotrexate.”

The researchers sought to examine neurocognitive, neurobehavioral, emotional and quality-of-life outcomes in long-term survivors of childhood osteosarcoma.

The study included data from 80 survivors of osteosarcoma (mean age, 38.9 ± 7.6 years; mean time since diagnosis, 24.7 ± 6.6 years) recruited from the St. Jude Lifetime Cohort Study and 39 controls (mean age, 39 ± 11.7 years).

Survivors demonstrated lower mean scores in reading skills (–0.21 [95% CI, –0.32 to –0.1] vs. 0.05 [95% CI, –0.13 to 0.23]), attention (–0.78 [95% CI, –1.32 to –0.24] vs. 0.24 [95% CI, –0.07 to 0.55]), memory (–0.24 [95% CI, –0.48 to 0] vs. 0.27 [95% CI, –0.08 to 0.62]) and processing speed (–0.15 [95% CI, –0.35 to 0.05] vs. 0.74 [95% CI, 0.44 to 1.03]).

However, the results of a pharmacokinetic analysis found that high-dose methotrexate maximum plasma concentration (estimate = 0), median clearance (estimate = –0.11) and median/cumulative exposure (estimate = 0) did not appear associated with neurocognitive outcomes.

Self-reported physical health status, as well as clinically ascertained chronic conditions, did appear associated with neurocognitive and neurobehavioral outcomes. Survivors reported lower physical functioning (P < .001) and poorer general health (P = .003) than population norms, both of which correlated with variability in sustained attention (physical functioning, P = .02; general health, P = .05). Poorer general health also appeared linked to slower processing speed (P = .005).

The incidence of any grade 3 or grade 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary or endocrine condition correlated with poorer memory (t = 3.03; P = .002) and slower processing speed (t = 2.93; P = .006).

Michael P. Link

The researchers acknowledged study limitations, including the relatively small cohort size. Further, they noted that a lack of multivariable modeling may have allowed for omitted-variable bias.

“Limitations notwithstanding, our study is the first to use objective neurocognitive testing to demonstrate impairment in long-term survivors of childhood osteosarcoma, to analyze the relationship between neurocognitive outcomes and pharmacokinetic parameters of high-dose methotrexate therapy, and to demonstrate associations between this impairment and chronic health conditions in the survivors,” Krull and colleagues wrote. “We recommend initial screening for neurocognitive deficits in survivors of osteosarcoma as they enter long-term follow-up, and periodically thereafter as they manifest new chronic health conditions.”

Care beyond the cure

In an accompanying editorial, Karen E. Effinger, MD, MS, instructor of pediatric hematology and oncology at Stanford University School of Medicine, and Michael P. Link, MD, Lydia J. Lee professor of pediatric cancer at Stanford University School of Medicine, wrote that advances in cancer care have precipitated a need for a better understanding of patient treatment after cures have been achieved.

“Going forward, we must apply our knowledge of late effects to improve monitoring and interventions for patients,” Effinger and Link wrote. “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, MD, who reminds us that ‘cure is not enough.’” – by Cameron Kelsall

References:

Edelmann MN, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.4398.

Effinger KE and Link MP. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.4392.

Rugbjerg K and Olsen JH. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.4393.

Disclosure: The researchers, Effinger and Link report no relevant financial disclosures.