Disclosures: Bhatia, Effinger and Lewis report no relevant financial disclosures.
November 24, 2020
6 min read
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Pediatric cancer treatment can cause long-term dental, bone, skin, liver, immunity issues

Disclosures: Bhatia, Effinger and Lewis report no relevant financial disclosures.
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Late effects of pediatric cancer treatment may not be readily apparent to primary care clinicians or specialists who follow childhood cancer survivors over the long term.

When assessing a patient who underwent cancer treatment years or even decades ago, a provider might not link current symptoms to events in the patient’s medical history.

“I think a lot of physicians feel that if a patient completed cancer treatment without experiencing any treatment effects, these effects are not going to surface later, but that’s not the case,” Karen E. Effinger, MD, MS, assistant professor of pediatrics at Emory University School of Medicine and medical director of the survivor program at Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, said in an interview with Healio.

“For example, I had one patient who had seen a cardiologist as an adult, and the cardiologist was certain that this patient’s heart disease was not due to their childhood cancer treatment,” she said. “I said, ‘Well, it is, and here is why it is.’ In fact, we often see these effects develop at least 10 to 15 years after treatment. This is exactly the timeline we would expect.”

Karen Effinger, MD, MS
Karen Effinger

Overall, Effinger said physicians who handle these survivors may benefit from increased awareness about the potentially far-reaching impact of pediatric cancer treatment.

“I do think that in the case of our adult survivors, or even our childhood survivors, there is a lot that physicians don’t realize,” she said.

Dental, liver problems

As is the case with all body systems and structures, teeth undergo profound changes during childhood. When a growing child receives strong treatment to eradicate cancer, the child’s teeth and gums are vulnerable to damage.

“Most people aren’t aware that children who receive treatment for cancer, especially those less than 5 years of age, are at risk for dental problems,” said Effinger, who is section leader for the Children’s Oncology Group Long-Term Follow-Up Guidelines task force on oral, dental, gastrointestinal and hepatic late effects. “If a child receives high doses of medications, a bone marrow transplant or radiation that encompasses the mouth or jaw, it can impact the teeth.”

Effinger noted that children whose permanent teeth have not developed at the time of cancer treatment may experience agenesis of permanent teeth.

“For these young kids in whom the teeth have not formed yet, the permanent dentition may not come in; they will only have their baby teeth,” she said. “Or sometimes, when the permanent dentition comes in, the teeth will be very small, which is called microdontia, or they will come in in the wrong spot.”

These survivors may also have problems with weakened enamel, leading to increased cavities, and shortened dental roots, leading to difficulty being fitted for braces.

Effinger said the correlation between pediatric cancer treatment and dental problems is not necessarily well known to patients, or even to dentists.

“Some pediatric dentists are afraid to treat our patients after therapy,” she said. “Most are fairly aware, but we have run into situations where they need a little help with that. They just need to know these are things to watch out for.”

Cancer treatment during childhood also can affect the gastrointestinal system and liver. According to Effinger, bone marrow transplantation or radiation to the abdomen can result in GI symptoms such as diarrhea or constipation. Other agents, such as certain chemotherapy drugs and radiation, can cause liver toxicity.

“The liver is a fairly hearty organ,” Effinger said. “It is able to regenerate, and so it can tolerate a lot, but some of these treatments can cause liver damage.”

Excess iron deposits in the liver related to red blood cell transfusions, hepatic fibrosis and, rarely, cirrhosis are among the potential late effects seen in pediatric cancer survivors, Effinger said. Researchers increasingly have begun to suspect a connection between pediatric cancer treatment and fatty liver disease, she said.

“Our survivors, especially patients who receive a lot of steroids during treatment, can sometimes gain a lot of weight, and the way that is metabolized may be associated with fatty liver disease,” she said. “There isn’t a direct correlation between any of our treatments and fatty liver disease, but that’s another area we’re starting to monitor more in our patients.”

Recovering immune function

Although hematopoietic stem cell transplantation can be a lifesaving treatment for children with leukemia and lymphoma, it can leave patients vulnerable to various immune and dermatologic late effects.

“The immune effects are primarily due to prolonged immune suppression,” Smita Bhatia, MD, MPH, director of the Institute for Cancer Outcomes and Survivorship, the Gay and Bew White endowed chair in pediatric oncology, and professor and vice chair of the department of pediatrics at The University of Alabama at Birmingham School of Medicine, as well as a HemOnc Today Editorial Board Member, said in an interview with Healio.

“Any time you have a transplant, especially an allogeneic transplant, the body needs to grow back its immune system. Sometimes, it doesn’t fully grow back to where it was before transplant.”

For example, Bhatia said, the immune system might fail to “remember” that the patient previously had measles, mumps or rubella, or that they had been vaccinated for these diseases.

“So, you need to get the patient tested to see if they retain immunity mounted in response to previous infections or vaccinations,” she said. “If they haven’t, they will need to receive those shots again.”

Dermatologic effects

Dermatologic late effects also can occur among individuals who received pediatric cancer treatment. In some cases, these effects may be related to immune late effects. Scleroderma often is a consequence of chronic graft-versus-host disease.

“Chronic graft-versus-host disease can present as hardening or thickening of the skin that can alter the skin’s ability to serve as a barrier to the outside world, resulting in an increased risk for infections,” Bhatia said.

Chronic rash is another potential dermatologic effect of transplantation. According to Bhatia, pediatricians or other clinicians who follow these survivors over the long term will benefit from becoming familiar with these possible effects.

“I would urge [pediatricians] to maintain contact with the transplant center and, likewise, transplant centers to maintain contact with the pediatrician,” she said. “If a rash occurs, or if they see changes in skin texture or quality, they should have a conversation with the transplant program to see if any of the medications need to be altered or if further workup is needed.”

Pediatricians or other primary care physicians who follow these survivors also should keep in mind that individuals who have undergone transplantation often have compromised immune systems.

“The main thing to be concerned about is that the immune system takes time growing back to baseline,” Bhatia said. “Any time a child has a fever or looks unwell, they should be checked to see if there is a serious infection.”

Musculoskeletal late effects

Individuals who have been treated for pediatric cancers also may experience musculoskeletal effects, which can occur at any time in the patient’s life, according to Valerae O. Lewis. MD, chair of the department of orthopedic oncology at The University of Texas MD Anderson Cancer Center and member of Healio’s Navigating Survivorship Peer Perspective Board.

“There’s no age limit to when you would expect something to show up,” Lewis told Healio. “There are some things that happen immediately after surgery or treatment, and then there are things that can happen later in life. These can be related to chemotherapy, anesthesia or surgery if they needed better reconstruction. There isn’t any defined area; you just need to watch these individuals. It’s long-term.”

Lewis said radiation can lead to various musculoskeletal late effects among pediatric cancer survivors. These may include fibrosis of the muscles, avascular necrosis, or decreased range of motion and dysesthesia. Lewis said the effects of radiation can be particularly long-lasting, and fibrosis may worsen over time.

“Radiation oncologists have gotten better and better with targeted radiation,” Lewis said, “but as an orthopedic oncologist, the fibrosis is what I worry about.”

Reconstruction failure also is a common late effect of surgery for pediatric cancers, Lewis said.

“Sometimes, these patients are unable to return to their normal baseline, because we don’t want them to break or loosen their reconstruction,” she said.

Other musculoskeletal late effects appear to worsen when the survivor is less active, Lewis said. Conditions such as osteopenia can progress to osteoporosis due to reconstruction-related disuse. Additionally, those treated as children with chemotherapy or steroids may have significant joint problems. She said although these survivors often respond to physical therapy, some require surgery.

Lewis said physicians should encourage children who receive cancer treatment to stay active.

“One of the things you want these kids to do, when they can, is to stay engaged in physical activity,” Lewis said. “Whether it’s stretching, yoga, Pilates or swimming, you want them to stay active. This will help with any type of limb salvage surgery and with chemotherapy. The more active these children are, they better off they are as adults.”

For more information:

Smita Bhatia, MD, MPH, can be reached at sbhatia@peds.uab.edu.

Karen E. Effinger, MD, can be reached at karen.effinger@emory.edu.

Valerae O. Lewis, MD, can be reached at volewis@mdanderson.org