Possible longterm side effects

Dr. Giulio J. D'Angio, MD, wrote, "Vigilance is essential if the blossoms of success in pediatric oncology are not to bear bitter fruit. Cure is not enough." At diagnosis, parents do not know what price their child will ultimately pay for reprieve from leukemia. For the majority of children with low or intermediate ALL, the price is low. Short-term effects are discomfort, a bald head, and occasional school absences. Long-term effects—sometimes none.

For children with high-risk ALL, AML, CML, or those who have relapsed and require more intensive treatment, the price for life may be higher: subtle or pronounced learning disabilities, impaired endocrine system, growth difficulties, and many other possible consequences.

Descriptions of a few of the possible long-term effects follow. Femalefertility

Younger girls are more resistant to damage to the ovaries from chemotherapy than are older teenagers. There have, however, been rare cases of ovarian failure in young girls who have been given high doses of cyclophosphamide as part of their treatment for leukemia. Additionally, one study discovered damaged ovaries in a percentage of girls who received spinal radiation. In the vast majority of cases, prepubertal girls who have been treated for leukemia exhibit normal growth, sexual development, and fertility.

Most teenagers who are treated with chemotherapy after puberty for leukemia retain normal ovarian function. If teenagers do not resume having periods after treatment ends, or if they develop symptoms such as hot flashes or breast discharge, a pediatric endocrinologist should be consulted.

The chances of becoming pregnant and having a normal pregnancy and birth after treatment with chemotherapy for leukemia are excellent. Data from the National Cancer Institute show that offspring born to cancer survivors have the same risk of birth defects as the general population. However, all women treated with chemotherapy drugs that can cause heart damage (doxorubicin, daunomycin, cyclophosphamide) or who had radiation to the chest or spine should be monitored closely during pregnancy and delivery.

Fertility issues for children or adolescents who have undergone bone marrow transplants are covered in Chapter 20, Stem Cell Transplantation. Precocious and delayed puberty are covered in Chapter 12, Radiation Therapy.

Male fertility

Use of methotrexate, vincristine, cyclophosphamide (Cytoxan), and prednisone causes a rapid decrease in sperm count in teens who have passed puberty. Normal sperm production and motility generally return in the second year of maintenance.

After treatment with chemotherapy for leukemia, males rarely have difficulty going through puberty. This does not mean that males are fertile. Males have cells that produce testosterone and cells that produce sperm. Therefore, a male could have normal testosterone-producing cells but abnormal sperm-producing cells. Survivors who received cyclophosphamide, radiation to the testes, or total body radiation should have testosterone levels and sperm count checked.

For all sexually mature males, sperm banking should be discussed with the oncologist prior to treatment. Sperm can be kept viable for ten to fifteen years, and this may allow some teens the opportunity to become fathers later in life.

Heart problems

Heart problems may occur months or decades after treatment with anthracyclines (adriamycin, idarubicin, or daunomycin), high-dose cyclophosphamide, or chest irradiation. Symptoms can include shortness of breath, fatigue, poor exercise tolerance, rapid heartbeat, and irregular heartbeat.

The heart damage is usually related to the cumulative dose of anthracyclines. This means that children who got higher doses, especially at a younger age, are at the most risk. Heart problems can range from mild changes seen on an electrocardiogram or echocardiogram to sudden death from cardiac failure (very rare). For adults, the dose at which incidence of heart failure begins to increase is 550 mg/m2, but there is growing evidence that for children who have received more intensive treatment including high-dose cyclophosphamide and stem cell transplantation, or who have received radiation to the heart, the critical total anthracycline dose may be much lower.

Any child whose total dosage of doxorubicin, daunomycin and idarubicin exceeds 150 mg/m2, who had chest irradiation (not routine diagnostic x-rays), who received highdose cyclophosphamide prior to bone marrow transplantation, or who had any dose of anthracyclines before the age of 5 is at risk for future cardiovascular problems. Children over 5 who received less than 150 mg/m2 of anthracyclines are at much less risk, but still require some follow-up. Because early diagnosis and prompt treatment are crucial, many experts now recommend that any child who has received potentially cardiotoxic therapies should undergo an annual exam, including a physical examination and thorough history. How often survivors need a chest x-ray, 12-lead electrocardiogram, and echocardiogram depends on the dose of chemotherapy, the age at which the child received the medication, radiation therapy field and dose, and many other factors.

For those children whose cardiac monitoring the first year off treatment is normal, most institutions recommend an EKG and echocardiogram every 2 to 5 years. Any pregnant woman with a history of anthracycline treatment should have her heart function followed closely throughout the pregnancy, and should alert her physician about her cancer treatment history.

Whether survivors who were treated with high doses of anthracyclines should engage in isometric exercise (weight lifting, wrestling, football, rock climbing) is controversial. Consult with your oncologist if your child or teen wishes to engage in these activities.

My daughter's high-risk protocol required an echocardiogram before treatment began, and periodically during treatment. When I asked why she never had one after the baseline, I was told by the fellow that she needed the drugs so it didn't really matter if she had cardiac changes. When I asked at end of treatment about the echocardiogram, I was told that since she only received a total of 175 mg/m2, an echocardiogram would only be given if symptoms developed. When I pulled out the Children's Cancer Group's recommendations on the subject and handed them over to my hometown pediatrician, he ordered an echocardiogram for her

Dental abnormalities

Dental abnormalities can be a side effect of treatment for leukemia, especially for children who are treated with cranial radiation. The most common problems are failure of the teeth to develop (agenesis), arrested root development, microdontia (unusually small teeth), and enamel abnormalities. Several parents report difficulties in insurance covering dental or orthodontic problems caused by radiation and/or chemotherapy. If you are a member of this group, collect articles on the studies which show that a relationship exists between treatment for leukemia and dentofacial development, and bring them to your childs oncologist. Ask the oncologist to write a letter to the insurance company using the research to support his position that the dental work is cancer-treatment related.

Jeremy has had many dental problems. He lost his gums in front of his lower front teeth. To correct this, they took skin from the roof of his mouth and did a skin graft. He also had an eyetooth that just broke off at the root and fell out.

Gina needed oral surgery to expose one of her molars. She also needed extensive work on her bite and wore braces and appliances. Another molar has a hook on the root and the braces could not budge it, so that will require more surgery. This will be followed by another round of extensive orthodontic work. My other three children had minimal orthodontic work for cosmetic reasons only.

Persistent weakness

Most children are remarkably resilient, and after treatment ends they resume normal activities at age-appropriate levels. But there are some children, particularly those who received cranial radiation, who have chronic problems with strength and coordination. As the population of leukemia survivors grows, it is hoped more attention will be focused on studying persistent weakness and investigating ways to prevent or overcome it.

When my daughter Christine ended treatment at age 6, she was very weak, and had trouble with balance and coordination. For instance, she couldn't walk a balance beam holding an adult's hand, she couldn't skip or play hopscotch. She decided to take ballet and gymnastics, and we took her for many long walks and bike rides (with training wheels) to help her regain her strength. We made physical activities fun. I talked to her school gym teacher, her ballet instructor, and gymnastics teachers, and asked them to be supportive and encouraging. It's been a year since she ended treatment, and although she still has training wheels on her bike, she walks a balance beam with grace and assurance, can dribble a basketball, and is able to do almost all of the movements for ballet.

Judd finished his treatment at age 6 and had some muscular weakness. He tried organized sports, but preferred individual sports like skiing. Over several years, he gradually regained his strength and coordination so that his athletic ability was average.

We had Justin tested through the school district, and the district is giving him his physical therapy. He's weak in the hips and walks with his feet turned out. He's resistant to taking physical risks; for instance, he sits down and slides off things rather than jumping off. He just loves to go to physical therapy.

Rachel is two years off treatment and starting kindergarten. She has trouble skipping and galloping, and cannot hop on one foot. I worry about competitiveness during gym classes.

Immune system problems

Sometimes children have persistent problems with the immune system after treatment ends. Immunoglobulins (antibodies) are protein molecules. The immunoglobulins are classified into many different sub-types (e.g., A, B, G, I, M). These molecules attack foreign material in the body such as bacteria, viruses, and pollen. After treatment for leukemia, some children do not maintain adequate numbers of immunoglobulins to fight off infections. These children need to get infusions of IgG to help bolster their immunity, but this is not common.

IgG has made a world of difference for Marc (and us!). Marc started getting an IgG infusion every 4 weeks about a year ago. We haven't had any hospital admits since then for infections. Prior to that, we averaged, literally, four ER visits a month for fevers for almost a year. While everything has a risk (and side effects), the IVIG seems to have been a good deal for us so far At our clinic, they premedicate Marc with Tylenol and Atarax (he can't take Benadryl) and the infusion goes smoothly. On occasion, he has had some problems with itching for a few days after infusions, but a dose or two of Atarax takes care of it.

Learning disabilities, delayed growth, and premature or delayed puberty are most commonly associated with cranial radiation and are covered in Chapter 12. Coping strategies for dealing with learning disabilities are explored in Chapter 15, School. For detailed information on possible late-effects from childhood cancer, read Childhood Cancer Survivors: A Practical Guide to Your Future, by Nancy Keene, Wendy Hobbie, and Kathy Ruccione.

The above information is about possible long-term effects from cancer treatment. Certain groups of children and teenagers are more, or less, at risk for side effects than others. The risk for your child depends on many factors, including the type of leukemia, total dosage of individual drugs, combinations of different types of chemotherapy, location and dose of radiation, and age at diagnosis.

As with all the information contained in this book, please consult with your oncologist if you have any questions or concerns. The field of cancer treatment is constantly evolving and improving, and the experts in the field are years ahead of the published material. They can explain to you the reasons for their recommendations, and should show you the books or articles that support their position if you ask to see them.

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