COMMENTARY

Childhood Cancer Survivors: Genetic Clues Help Prevent Late Effects

Robert H. Carlson, MBA

Disclosures

November 14, 2016

While important incremental gains have been made across many tumor types, the treatment of cancer in children stands out as a major success story: Five-year survival rates for childhood cancer now exceed 80%, and all-cause late mortality among survivors at 15 years has dropped from 10.7% among those diagnosed in the 1970s to 5.8% among survivors diagnosed in the 1990s.[1]

And although the main focus of research continues to be the 20% of children who are not surviving, researchers are also recognizing the heavy burden of long-term morbidity and premature mortality directly related to treatment.

Individual Patient Variability

"We are shifting to understand how we can prevent these long-term side effects to treatment, but the problem is interindividual variability," said Smita Bhatia, MD, a professor and vice chair of outcomes for pediatrics at the University of Alabama at Birmingham Comprehensive Cancer Center. "Increasing the dose of chemotherapy or radiation increases the risk for complications, but it doesn't do so predictably. Some children get tremendously high doses of exposure but escape long-term complications, and others get a small amount but develop complications."

Dr Smita's group and others are systematically studying the genome in order to identify genetic predisposition markers for some of the late effects that are encountered, in turn identifying children at higher risk and also those at lower risk despite the same exposure.

"Our hope is that down the road we will be able to create a risk prediction score whereby, at diagnosis, we will be able to say that child A is at no risk or low risk of developing these long-term complications, and therefore we can continue with the prescribed treatment," said Dr Bhatia, "or that child B is at very high risk, and therefore we need to alter the therapy or use a lower dose, depending on the relationship between the genes, the treatment, and the risk."

Common Long-term Effects of Treatment

For example, vincristine causes toxicity to the peripheral nerves in about 30% of children with acute lymphoblastic leukemia treated with the drug. Genome-wide analysis has revealed a novel single nucleotide polymorphism (SNP) in the gene encoding CEP72 that is associated with increased risk and severity of vincristine-related peripheral neuropathy.[2]

"This specific gene increases the sensitivity of neurons to vincristine," said the study's senior author, William E. Evans, PharmD, chair of pharmacogenomics at and former director and CEO of St. Jude Children's Research Hospital. "By itself it doesn't cause problems, but when you put it with the drug, it approximately doubles the risk for neurotoxicity, and in patients who have the predisposition the neurotoxicity is more severe."

If these findings are confirmed, they may provide a basis for safer dosing of this widely prescribed anticancer agent, Dr Evans said.

Another commonly prescribed drug class, platinum agents (and especially cisplatin), is known to cause a significant amount of hearing loss in children.[3]

Pediatric oncologists approach this problem with screening and intervention with prostheses for hearing loss. Screening during treatment may also allow physicians to consider changing therapy if the patient develops hearing loss, said Lisa Diller, MD, chief medical officer at Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

There are currently otoprotective agents being investigated that are thought to protect the inner ear from the effects of platinum. Dr Diller said these are in clinical trials and may eventually be given at the same time as platinum drugs.

The risk for cardiotoxicity in childhood cancer survivors is substantial, with a very clear dose-response relationship between anthracycline exposure and heart failure, a life-threatening disease typically occurring 20-30 years later. Several groups are investigating the entire pathway from exposure to anthracyclines to cardiotoxicity and the mechanisms of action.

Dexrazoxane is a commonly used cardioprotectant for adult cancer patients treated with anthracyclines, but it is not approved for use in pediatric patients because of concerns about secondary cancers. However, the authors of a recent literature review say the evidence suggests that dexrazoxane should be considered as a part of therapy for young patients treated with anthracyclines.[4]

"The cardioprotection offered by dexrazoxane has been known and there have been several studies on the immediate or short-term protection it offers," said Dr Bhatia, who did not take part in the aforementioned review. "There are pediatric cancer patients who were treated with anthracyclines with or without dexrazoxane, and our group and others are bringing these children back into the clinic after years to truly understand whether dexrazoxane has afforded protection or not," Dr Bhatia said.

The Children's Oncology Group is also conducting a placebo-controlled clinical trial testing carvedilol in patients who had previous anthracycline treatment, to determine whether it will prevent cardiac changes from developing, said Stephen P. Hunger, MD, chief of the Division of Oncology at Children's Hospital of Philadelphia.

Cost-Benefit Ratio

There is a cost to changing treatment by reducing doses or substituting other drugs with the expectation of reducing long-term side effects, but no one has attempted to set a cost-benefit ratio, said Dr Diller.

"Genetic markers are increasingly being identified that tell us which pediatric patients are at highest risk for [heart failure] after exposure to an anthracycline, but what hasn't been done is genetic testing before treatment, at the time of diagnosis," Dr Diller said.

 
That's where the field is going—understanding individual genetic variability from patient to patient
 

A clinician making a decision about whether to use a cardioprotective agent might be swayed by a genetic test that identifies the patient at very high risk, Dr Diller said. But conversely, theoretically there may be patients who, based on their genetic profile, are never going to get congestive heart failure no matter how much anthracycline treatment they receive, and who could tolerate much more in the hope of a potentially better cure rate.

"That's where the field is going—understanding individual genetic variability from patient to patient in terms of their ability to handle high doses of chemotherapy that we give them, and the expected late effects," Dr Diller said.

Challenges

What surprises and encourages Dr Diller is that clinicians are changing their treatment plans using data that the survivorship research community have observed.

"The data suggest that this is working, that there is a reduction in some problems that were observed in the first generation of childhood cancer survivors," Dr Diller said. "We use less cranial radiation for leukemia, for example, and we are more cognizant of the risk for [heart failure] associated with anthracyclines."

"As those changes were made in the late 1990s and early 2000s, we are seeing those kids growing up with fewer problems than the generation before them," she said.

What concerns Dr Diller is that researchers have not had the same opportunity to follow patients receiving the newer biologic agents making their way into pediatrics to understand these drugs' late effects.

"We anticipate that they will have fewer long-term side effects, but we don't know that, and we won't know that unless we study them," she said.

Communicating a Future Care Plan

Over the past decade, pediatric oncologists have become very aware of the need for a survivorship care plan, a summary of the patient's treatment and the expected late effects.

"It has become a standard of care to produce a treatment summary for pediatric cancer patients who complete therapy," Dr Diller said. "Primary care physicians seeing an adolescent or young adult who doesn't have a care plan should counsel them to go back to their oncologist or to identify a clinic that sees survivors, to generate a treatments–and late-effects profile."

Childhood cancer survivor clinics now create care plans—electronic or paper copies—of the exposure that the child has received, what they are at risk for, what should be done in terms of surveillance for and early detection of these complications, and the health education that patients should receive.

"We provide the patients and their families with this information so that they can take it with them to the primary care physician or to other pediatric oncologists if they are going to be followed elsewhere," Dr Bhatia said.

Dr Diller said that when she started her career, pediatric cancer survivors would come in not knowing anything about their care or the risks.

"Some wouldn't even know the kind of cancer they had," Dr Diller said. "Now there's more of a focus on making sure that the patients understand their diagnosis and how they were treated, and that the primary care providers understand the diagnosis and how the patients were treated."

Dr Diller said that general practitioners could produce these guidelines through the Children's Oncology Group website and others.

While electronic health records might seem like a potential place for such plans, unfortunately they are not portable and are not accessible across different sites, Dr Bhatia said.

"In an ideal world, electronic health records would talk to the electronic health records of the patient years later, but that is not the reality," said Dr Bhatia.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....