Sleep Apnea in Hodgkin’s Lymphoma, Methotrexate and Neurocognitive Impairment

Survivors of childhood Hodgkin’s Lymphoma have been an unrecognized group for a number of years because they don’t receive direct neurotoxic therapies. So, children’s oncology groups in North America define neurotoxic exposures as cranial radiation, high dose intrathecal, or methotrexate; high dose, intravenous methotrexate, or cytarabine and neurosurgery and Hodgkin’s Lymphoma survivors don’t receive any of them.

They’ve been unrecognized as a risk group for a number of years. However, we see that they struggle when they hit adulthood. And we’ve been looking at their cognitive function in a number of ways. We see that they do develop problems with attention, memory, and processing speed when they hit young adulthood and older adolescents.

And this has a significant impact on their daily life functions. The deficits that they display are not as pronounced as you would expect for a child with a brain tumor or a child who gets direct cranial radiation. But they do demonstrate problems at higher rates compared to their siblings and community controls.

And it’s an area that we need to investigate a little bit.

We see that the impairment since Hodgkin’s Lymphoma survivors are diagnosed during adolescence they can often get through primary school. Without significant difficulties, because most neurocognitive impairments in cancer survivors manifest over time. It takes a few years for them to really have an impact.

Being diagnosed in adolescent the problems begin to emerge during their young adulthood years. So, they often get through. 12th grade without problems but may begin experiencing problems in college or in their employment. We do see that the memory and attention problems that they experience are associated with lower educational attainment and are more likely to be underemployed or unemployed compared to their peers and their siblings.

Yeah, we’re shifting now. 10, 15 years ago many of the survivors received chest radiation, and thoracic radiation that included the chest and neck. This caused increased rates of cardiac and pulmonary problems. And we’re seeing that those cardiac and pulmonary problems are associated with the memory and attention problems they receive.

The treatment landscape is shifting now so that typically only the very high risk or those that may relapse are receiving the thoracic radiation. But we’ve been replacing that with higher doses of. Anticyclones and (inaudible) and other chemotherapy agents that can have some similar effects.

They can also affect cardiac and pulmonary problems to a lesser degree, but the increased risk is still there. So, we’re cautiously optimistic, but following survivors during their treatment, we have new protocols now where we’re looking at cognitive and other functions before and after.

Treatment and continue to follow them in hopes that we can fully understand the mechanisms, some of the treatment approaches. I should say not all of the treatment approaches may be contributing to the cognitive problems. We have evidence that these long-term survivors also have some chronic inflammation that tends to be going on.

And that inflammation in Hodgkin’s Lymphoma survivors actually begins before treatment as part of the disease itself. And so, we’re looking at this actively right now to determine how much of the problems that we see long-term are associated with the treatment and how much is a persistent inflammatory response associated with the disease.

Yes, there’s one important area that we’ve begun to discover. And we haven’t published on this yet as we have a large R01 grant that is continuing to collect data. But it is beginning to become clear that our Hodgkin’s Lymphoma survivors are substantially elevated risk for obstructive sleep apnea too.

We think the sleep apnea may be associated with their treatment exposure, the cardiac and the pulmonary complications. But it may also be associated with that inflammatory process that I mentioned that may be in the disease itself. The rates that we’re beginning to see though are concerning because they’re approaching 50% and if 50% of long-term survivors.

Obstructive sleep apnea. That’s substantially higher than what we’d see in the general population. This is an area that needs to be studied closely because untreated obstructive sleep apnea can put undue stress on the cardiovascular system leading to increased risk for myocardial infarction and stroke and further cognitive complications.

So this is an important consideration. And if survivors or their families are at all concerned about disrupted sleep at night, I would encourage them to seek out a consultation with their primary care provider and maybe get a sleep study to identify whether that is indeed.

 

Kevin R. Krull, Ph.D., Member, St. Jude Faculty, Endowed Chair in Cancer Survivorship at St. Jude Children’s Research Hospital. In this video, he speaks about the article in ASH Clinical News – Long-Term Childhood Hodgkin Lymphoma Survivors Have Increased Risk of Neurocognitive Impairment.

 

 

Neurocognitive impairment is more common in long-term survivors of juvenile Hodgkin lymphoma (HL). According to a study published in Blood, exercise and smoking are modifiable risk factors for this impairment that could be used as therapy targets to improve functional results.

 

A total of 1,781 adult HL survivors were enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS) cohort for the cross-sectional study. In addition, the researchers included 3,196 siblings from the CCSS cohort as a comparison group. At the time of the study, the average ages of survivors and siblings were 37.5 and 33.2 years, respectively. In HL survivors, the median period from diagnosis was 23 years.

 

Participants’ neurocognitive function (Neurocognitive Questionnaire), emotional distress (Brief Symptom Inventory-18), health-related quality of life (QoL; Medical Outcomes Short Form-36), social attainment (e.g., education, income, employment, and independent living), smoking, and physical activity were all assessed through cross-sectional surveys.

 

In a study that controlled for age, gender, and race/ethnicity, HL survivors were shown to be considerably more likely than siblings to have impairments in a variety of neurocognitive domains, including:

 

* organization (relative risk [RR] = 1.32; 95% CI 1.01-1.73)

* memory (RR=1.72; 95% CI 1.21-2.44)

* emotional regulation (RR=1.56; 95% CI 1.23-1.99)

* task efficiency (RR=1.37; 95% CI 1.01-1.85)

 

Current and previous smokers who survived HL showed the highest risk of memory, emotional regulation, and task efficiency deficits. Those who exercised according to the Centers for Disease Control and Prevention (CDC) guidelines had a lower chance of task efficiency (RR=0.69; 95 percent CI 0.51-0.93) and organization (RR=0.59; 95 percent CI 0.44-0.78) impairment. Obesity was linked to a higher risk of task efficiency (RR=1.64; 95 percent CI 1.26-2.13) and memory deficits (RR=1.61; 95 percent CI 1.04-2.47) in survivors.

 

HL survivors had a higher risk of anxiety (RR=1.31; 95 percent CI 1.01-2.85) and depression (RR=1.33; 95 percent CI 1.08-1.64) than their siblings. Current smoking was linked to a greater risk of anxiety and depression in survivors, but those who exercised according to CDC guidelines had a decreased risk of depression.

 

While HL survivors had a higher chance of impairment in all QoL dimensions than siblings, pain domains were not different. Smoking and obesity were modifiable risk factors related to deterioration in eight of the QoL dimensions in HL survivors. Physical exercise, on the other hand, was linked to a lower probability of impairment in each QoL dimension.

 

All four neurocognitive domains, anxiety, and depression, as well as all QoL domains, were linked to impairment in grade 2 cardiovascular and neurologic disorders.

 

HL survivors were more likely than siblings to be unemployed (RR=2.02; 95 percent CI 1.68-2.42) or working part-time (RR=1.71; 95 percent CI 1.31-2.23), and to earn less than $20,000 (RR=1.80; 95 percent CI 1.35-2.40). Task efficiency impairment was also linked to a higher likelihood of poor income (RR=1.42; 95 percent CI 1.08-1.87) and unemployment (RR=3.41; 95 percent CI 1.91-6.07). Although memory impairment (RR=1.89; 95 percent CI 1.02-3.48) and depression (RR=1.87; 95 percent CI 1.01-3.46) were linked to a higher chance of unemployment, anxiety (RR=0.37; 95 percent CI 0.17-0.81) was linked to a lower risk.

 

Clinicians can use the Children’s Oncology Group guidelines to conduct risk-based screening for numerous chronic health issues that are frequent in HL survivors and thereby target modifiable risk factors to enhance long-term outcomes, according to Dr. Krull.