Primary Care for Adult Survivors of Childhood Cancer

Adult Survivors of Childhood Cancer

• >400,000 survivors of childhood/adolescent cancer (diagnosed under 20yo)
• Big advances in ALL therapy (1967- CNS directed therapy, 1982- triple intrathecal, etc.)
• Late effects of cancer include effects on cardiovascular health, pulmonary health, thyroid/endocrine, fertility, bone health and more
• Some adult survivors such as those receiving radiation may be at risk for secondary malignancies

The Childhood Cancer Survivor Study (CCSS)

CCSS is a retrospectively ascertained cohort of 38,036 childhood cancer survivors diagnosed between 1970 and 1999. It also includes over 5,000 siblings of survivors who serve as the comparison group for the study. This study has led to multiple publications and articles over time. 

In a 2006 article entitled Chronic Health Conditions in Adult Survivors of Childhood Cancer, the frequencies of chronic conditions in 10,397 survivors and 3034 siblings were calculated.

The above figure shows the cumulative incidence of chronic health conditions in these patients. according to the original diagnosis and the severity of the later condition. Among the survivors of various types of childhood cancer, the severity of subsequent health conditions was scored as either mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening or disabling (grade 4), or fatal (grade 5). 

A 2008 study, Medical care in long-term survivors of childhood cancer: a report from the childhood cancer survivor study, evaluated whether childhood cancer survivors receive regular medical care focused on the specific morbidities that can arise from their therapy.

• 17.8% reported survivor-focused care that included advice about risk reduction or discussion or ordering of screening tests
• Among survivors who received medical care, those who were black, older at interview, or uninsured were less likely to have received risk-based, survivor-focused care
• Among patients at increased risk for cardiomyopathy or breast cancer, 511 (28.2%) of 1,810 and 169 (40.8%) of 414 had undergone a recommended echocardiogram or mammogram, respectively

A 2016 study, Adult childhood cancer survivors’ narratives of managing their health: the unexpected and the unresolved, aimed to identify the different ways that adult survivors of childhood cancer manage their medical and psychological challenges. It found that variation exists in the ways in which childhood cancer survivors frame their health, their perceived significance of health challenges, strategies used to manage health, interactions with healthcare professionals and the health system, and parental involvement.

5 main narratives were identified that captured the ways that adults managed their medical and psychological challenges, including trying to forget cancer, trusting the system to manage my follow-up care, being proactive about my health, stumbling from one problem to the next, and struggling to find my way: 

• “Being a cancer survivor has no impact on anything, I just live a normal life. I have virtually no medical issues. I just forget about a lot of these things. The last thing I want to do is relive that horror. I routinely miss appointments. I avoid doctors, if I can. Those things [late effects and risks] are not worth worrying about.”
• “Most of the time I get it and then there’s other times where I’m really confused, like this situation is because of this and this is because of this and am I okay and I’m confused now because it’s all jumbled together. When I’m listening to the doctors they use kind of like big words so I’m not really good with big words, I don’t know what you’re talking about but, okay, keep going, I’ll catch up in a minute… I’ll have them explain it to me a little bit and see if I can get it, which for the most part I can’t.”

Recapping the above: 

• Given advances in therapy there are more and more survivors of childhood cancer
• Adult survivors of Childhood cancer are at increased risk of the development of certain chronic conditions
• Many adult survivors of Childhood cancer are not getting survivorship focused care
• Psychosocial effects of cancer survivorship are important and adult Survivors of Cancer’s perceptions of their health may also impact the care they receive

Chemotherapy

Case 1

John (He/Him/His) is a 34 yo man with a past medical history of leukemia. He is presenting as he has had mild shortness of breath mainly with exertion. You review his records and note that he received anthracycline therapy as a part of his treatment. He had a baseline EKG from 10 years ago from his survivorship clinic that showed normal sinus rhythm with no abnormalities.

• What are you worried about? What other questions might you ask?

Cardiovascular Screening

• Anthracyclines (dose-related) are associated with cardiomyopathy, subclinical LV dysfunction, heart failure, arrhythmia and prolonged QTc
• Chest/spine/abdomen radiation are associated with cardiomyopathy, subclinical LV dysfunction, heart failure, arrhythmia, prolonged QTc, pericarditis, pericardial fibrosis, valvular disease, and CAD/MI
• All patients with these exposures should have had a baseline EKG at the completion of their cancer treatment
• Younger patients (<25yo) may present with abdominal symptoms as a presenting sign of cardiac dysfunction
• Screening echocardiogram timeline depends on dose of anthracycline and amount of radiation

Case 2

Jessica (she/her) is a 23 yo woman presenting to your clinic for a new patient visit. Upon interview, you find that she has had recent hot flashes and has not had a period for 3 months. She underwent menarche at age 12 and had monthly periods until age 19. You find out that between age 18-20yo Jessica underwent treatment for Ewing’s sarcoma that included chemotherapy. She doesn’t remember all of her chemotherapy agents, but she did receive cyclophosphamide.

• What would you do next?

Fertility 

It is important to discuss puberty, sexual function, and menstruation in adult survivors of childhood cancer. 

Therapies that affect fertility: 

• Alkylating agents (e.g., Busulfan, Carmustine (BCNU), Chlorambucil Cyclophosphamide, Ifosfamide, Lomustine (CCNU), Mechlorethamine Melphalan, Procarbazine, Thiotepa)
• Radiation (abdomen/pelvis and the brain)
• Surgical removal of the ovaries/testes

For individuals with a uterus/ovaries who are having abnormal menstrual cycles consider checking FSH, LH, and estradiol to assess for premature ovarian failure, and referral to OBGYN. 

• Also consider thyroid testing and prolactin level in those who received radiation therapy

For individuals with testes who have had a history of delayed puberty, prior low-normal testosterone levels or other concerns for testosterone insufficiency, consider evaluating testosterone levels. 

For patients having issues or who have questions about fertility, consider referral to a fertility specialist/reproductive endocrinology. 

It is also important to consider pregnancy complications (cardiac effects from anthracyclines, increased risk of miscarriage, and/or premature labor in certain types of radiation) and to ensure your patient has at least an initial evaluation with maternal fetal medicine when considering becoming pregnant.

Patients may have fertility recovery years after cancer treatment. 

Case 3

Bailey (they/them) is a 35 yo patient with a past medical history of NHL. They are complaining of generalized fatigue, hair thinning, and dry skin. They did have radiation therapy as a part of their treatment.

• What do you think is going on? What would you do?

Thyroid

Head/Brain/Spine (cervical/total) total body radiation is associated with hypothyroidism, hyperthyroidism, thyroid nodules and thyroid cancers. 

• Yearly thyroid exam and TSH/T4 testing
• Referral for ultrasound if any palpable nodules

Those who underwent thyroidectomy should already be on thyroid hormone replacement and should have been initially evaluated by an endocrinologist. 

MIBG used for diagnostic (not treatment) purposes does not put patients at increased risk for thyroid dysfunction. 

Case 4

Mrs. Smith (she/her) is a 32 yo woman with a history of rhabdomyosarcoma with radiation to the chest and abdomen in remission presenting for routine physical examination. She notes that she read online that she may be at higher risk for certain types of cancers as she gets older and asks you if she needs any type of screening.

• What types of cancer would you screen Mrs. Smith for? At what intervals would you screen her?

Secondary Malignancies

AML

• Increased risk in those who have received alkylating agents, heavy metal toxicity (e.g., carboplatin, cisplatin)
• No specific screening but evaluate for bleeding, bruising, fatigue, pallor, petechiae, purpura, and bone pain yearly up to 10 years after therapy
• Obtain CBC if any concerning history or physical exam findings
• Should have had at least a baseline CBC once in remission

Lung

• Chest/axilla/total body radiation is associated with increased risk of lung malignancy
• No specific screening guidelines
• Can consider earlier chest imaging in those with other risk factors such as smoking but no specific timeline

Thyroid

• Yearly thyroid exam for those with history of head, brain, spine, or total body radiation

Breast

• Chest/axilla/total body radiation associated with increased risk of breast cancers
• Mammogram: Yearly, beginning 8 years after radiation or at age 25, whichever occurs last
• Breast MRI: Yearly, as an adjunct to mammography beginning 8 years after radiation or at age 25, whichever occurs last

Colorectal

• Those with a history of abdomen, pelvic, spine (lumbosacral, whole), and total body radiation are at increased risk for colorectal malignancies

Psychological / Social Issues

A 2018 systematic review, Mental health of long-term survivors of childhood and young adult cancer: A systematic review, aimed to describe the prevalence and spectrum of mental health problems found in adult survivors of childhood cancer. 

Psychological issues included

• Issues with interpersonal relationships
• Increased somatic distress/somatization
• Poor self-esteem
• Depression/mood disorders
• Antisocial behavior
• PTSD
• Schizophrenia
• Behavioral problems NOS
• ODD
• Suicidal ideation
• Drug and alcohol misuse

Factors increasing likelihood of mental health problems included

• High-dose anthracycline
• Cranial irradiation
• Sarcoma or CNS tumor
• Poor physical health
• Female gender
• Poor social support
• Reduced disease acceptance
• Other stressful life events
• Reduced family functioning

MANY other long-term effects…

• Dental/oral hygiene/salivary gland dysfunction
• Vision/early cataracts
  • Associated with
    • Radiation (head/brain/total body): cataracts, retinopathy, keratitis, xeropthalmia, glaucoma, maculopathy, lacrimal duct issues and many more
    • Steroids: cataracts
    • GVHD 2/2 hematopoietic stem cell transplant: xerophthalmia (keratoconjunctivitis sicca)
    • Enucleation: irritation, changes in equity
    • Busulfan (alkylating agent): cataracts
  • Check visual acuity and fundoscopic exam yearly
• Ototoxicity
  • Hearing loss, tinnitus, vertigo, otosclerosis with radiation
  • Associated with radiation (brain/head/total body) and heavy metals (carboplatin and cisplatin)
  • Check hearing test every 5 years over the age of 13
• Pulmonary toxicity and fibrosis
  • Associated with
    • Radiation (chest/axilla/total body): pulmonary fibrosis, pneumonitis, restrictive and obstructive lung disease, and increased risk of secondary lung cancer
    • Chemotherapy: Alkylating agents (Busulfan, Carmustine, Lomustine ) and Anti-tumor (Bleomycin): pulmonary fibrosis and interstitial pneumonitis
    • GVHD: bronchiolitis obliterans, chronic bronchitis, bronchiectasis
  • Check baseline PFTs–repeat if changes in history/exam or prior to anesthesia
  • Avoid tobacco use!
  • Influenza and Pneumococcal vaccines
• Osteopenia/Osteoporosis/Osteonecrosis
  • Associated with methotrexate, dexamethasone/prednisone, hemopoietic stem cell transplant; patients may develop ovarian hormone deficiency/premature ovarian failure as a result of cancer treatment
  • Baseline DEXA scan
  • Encourage good vitamin D and calcium intake either via diet or supplementation
  • Weight bearing exercises
  • Treat other exacerbating conditions (for example those with hormone deficiency)
  • Refer to endocrinology for patients with premature osteoporosis or multiple fractures
• Neuropathy
• Neurocognitive defects
• Cerebrovascular abnormalities
• Hypopituitarism
• Functional Asplenia
• Obesity/dyslipidemia
• Diabetes/abnormal glucose metabolism
• Hepatic dysfunction
• Renal dysfunction
  • Associated with ifosfamide (alkylating agent) and heavy metals (cisplatin, carboplatin), radiation (pelvis/abdomen/lumbar spine/total spine/total body), hemopoietic stem cell transplant, and nephrectomy
  • Check baseline renal function (BMP/Mag/Phos)
  • Blood pressure at least once yearly
  • In patients with nephrectomy, check urine protein once yearly: creatine ratio and BMP to calculate eGFR and CrCl
  • Caution with NSAIDs in any renal dysfunction or in nephrectomy patients
• GU abnormalities
• Strictures/bowel adhesions
• Complications after BMT and chronic GVHD
• Skin abnormalities

Additional Resources!

• Children’s Oncology Group Survivorship Guidelines
• Passport for Care

Blog post based on Med-Peds Forum talk by Melinda Delaney, MP Core Faculty