The Journal of Pediatrics
Volume 150, Issue 4 , Pages 332-334, April 2007

Childhood Cancer Cures: The Ongoing Consequences of Successful Treatments

  • Sharon E. Oberfield, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Sharon E. Oberfield, MD, Division of Pediatric Endocrinology, Columbia University, 630 W 168th St, PH 5 East, Room 522, New York, NY 10032.

Division of Pediatric Endocrinology, Columbia University, New York, NY

Article Outline

Abbreviations: ALL, Acute lymphoblastic leukaemia, BMI, Body mass index, CCSS, Childhood Cancer Survivor Study, CNS, Central nervous system, GH, Growth hormone, RT, Radiation therapy

 

In 1979, with colleagues in hematology/oncology and neurology at Memorial Sloan-Kettering Cancer Center, New York, we began a Late Effects Endocrine Clinic. Patients were only a few months post-treatment, and most of the patients were survivors of childhood brain tumors. Our treatment options were limited, little was known about long-term disease survival, risks of endocrine therapy, or the development of secondary malignancies. We published our preliminary findings on a small cohort of patients and noted marked impairment of statural growth and the development of primary hypothyroidism.1 Over the past more than 25 years, multiple studies have documented the development of endocrinopathies that impact normal growth and development. Indeed, some of these analyses have resulted in the modification of treatment protocols.2, 3, 4, 5

See related article, p 370

Today, there are close to 270,000 survivors of childhood cancer, and nearly 1 in 640 persons between the ages of 20 and 39 years has had some form of childhood malignancy.2 Long-term consequences—now close to 30 years after diagnosis and treatment—include “early death, secondary neoplasm, organ dysfunction … reduced growth and development, decreased fertility, impaired intellectual function, difficulties obtaining employment and insurance, and overall reduced quality of life.”6 The good news is that most survivors do not experience serious untoward effects as a direct consequence of their cancer or its treatment.5 However, ongoing vigilance is crucial, as was recently shown by Oeffinger et al,7 who evaluated chronic health conditions in adult survivors of childhood cancer by using data from the Childhood Cancer Survivor Study (CCSS). The CCSS is a retrospective cohort of 5-year survivors of childhood cancers in whom a diagnosis was made before the age of 21 years between 1970 and 1986, with 26 sites contributing data from the United States and Canada. This study also compares results with those of siblings (>20,000 initially enrolled, with approximately 5000 siblings amassed). Cancer diagnoses include leukemia, central nervous system (CNS) tumors (excluding craniopharyngiomas), Hodgkin’s disease, non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, and sarcoma and bone tumors. This study determined the prevalence of chronic conditions in survivors and siblings with a grading scale for untoward outcomes (grade 1, mild, through grade 4, life-threatening or disabling) and assessed whether a person had ≥2 health conditions. Chronic conditions included replacement of joints, congestive heart failure, second malignancy, severe cognitive dysfunction, coronary artery disease, cerebrovascular accident, renal failure or dialysis, loss of hearing or eyesight, and ovarian failure in female patients. Sixty-two percent of survivors, compared with 37% of siblings, reported having at least 1 chronic health condition, but only 28% reported a grade 3 or 4 condition. Twenty-five percent of survivors (compared with 5% of siblings) reported having ≥3 conditions. The cancer survivors were 8 times more likely than their siblings to have a severe or life-threatening chronic health condition; persons at highest risk were survivors of bone tumors, CNS tumors, or Hodgkin’s disease. Furthermore, severe life-threatening conditions were increased when cancer treatment included chest, abdominal, or pelvic radiation therapy (RT). Sex differences also were noted; female survivor were at greater risk than male survivors for growth hormone (GH) deficiency and obesity.7

Previous papers from the CCSS also have assessed the risk in survivors of childhood brain cancers for reduced final height, alterations in body mass index (BMI), use of GH treatment, and related outcomes of GH treatment and risk of secondary malignancy.8, 9, 10 It appears that although GH therapy does not increase the risk of recurrence of the primary disease, secondary malignancies are 2.15 times more likely (5%-95% CI, 1.3-3.5) to develop in survivors treated with GH, with meningiomas being the most common tumor reported in the group treated with GH.10

Perhaps the most worrisome late effect in survivors of childhood cancer and acute lymphoblastic leukemia (ALL), specifically, is the onset of obesity and associated co-morbidities. In another, recent CCSS study by Oeffinger,11 1765 adult survivors were compared with 2565 siblings. The risk of obesity was greatest in female survivors in whom ALL was diagnosed before the age of 4 years who were treated with cranial RT doses ≥20 Gy (RR 3.81), whereas no increased risk was seen when treatment involved only chemotherapy or lower doses of cranial irradiation. Most recently, a study from Australia12 compared the prevalence of overweight/obesity, abdominal adiposity, hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in 248 survivors of childhood cancers. Although in this study the prevalence of overweight/obesity was not increased, the incidence of abdominal adiposity in both prepubertal and pubertal children was nearly doubled. Body RT, untreated hypogonadism, and abdominal adiposity were found to be independent risk factors for the development of hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus. A total of 116 patients had ALL, at a mean age of 3.8 years, followed to a mean age of 20.4 years; 21 patients underwent bone marrow transplants, 13 patients underwent total body RT, and 92 patients underwent pituitary RT. Of the 39 subjects in whom hyperinsulinemia and impaired glucose tolerance were diagnosed, 15 had ALL, 10 of whom had undergone bone marrow transplants, 8 of whom had undergone total body RT, and 6 of whom underwent pituitary RT at doses >30 Gy. Sixteen adult patients with ALL who had undergone bone marrow transplants, compared with the 82 who did not, had a >25-fold risk for the development of hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus. Because of the worldwide epidemic of obesity, children with ALL would seem to benefit from ongoing nutritional counseling and prudent dietary intake.

In this issue of The Journal, the paper by Chow et al adds to the current body of knowledge on the long-term consequences of cancer treatment for ALL. It also addresses the need for future outcome analysis in ALL, specifically for the use of various chemotherapeutic agents, without CNS radiation.13 Earlier reports on growth in survivors of ALL have shown loss of height after RT doses >24 Gy, but consistent patterns of growth are not well defined for treatment with chemotherapy alone.14, 15, 16 In a cross-sectional study by Chow et al, adult height was determined in 2434 survivors of ALL who participated in the CCSS and was compared with that of 3009 siblings, of whom 818 were actual siblings of survivors of ALL. The mean age of the survivors was 27 years, and the mean age of the siblings was 31 years.

Exposure and outcome assessment reviewed cumulative chemotherapy doses for anthracyclines, epipodophyllotoxins, and methotrexate (given intravenously, intramuscularly, or intrathecally). Cumulative scores were created to define the overall intensity of treatment. CNS irradiation doses were assessed, and 95% of the survivors received between 15 and 29 Gy to the spine. Height was determined either with self-report or proxy-reported points. Although self-reporting of heights may overestimate true height by at most 2 cm, these findings still revealed a significant height deficiency in the cancer cohort. Data also were analyzed as to whether the patient was prepubertal or pubertal at the time of initial treatment. The authors state that year of diagnosis or date of birth did not affect statistical models, so these were not included for additional analysis. This study is unique because, to date, it reports on the largest group of survivors of ALL who were evaluated for true adult height, and it allows for evaluation of final height in a number of patients with ALL who were exposed to chemotherapy alone.

This paper reports that patients with ALL, irrespective of treatment exposure (chemotherapy alone or in combination with cranial or craniospinal RT), have decreased adult heights and are at a 12.5-fold risk of decreased final height (height >2 SD below that of siblings). Furthermore, even with chemotherapy alone, there was a >3-fold increased risk of decreased stature. Patients who were prepubertal at the time of diagnosis and received ≥20 Gy, compared with <20 Gy, or who had any spinal RT or were female had the greatest risk (12.5% versus 5.5%).

The greatest impact on height occurred in male survivors who had received craniospinal RT ≥20 Gy plus chemotherapy; their mean adult height was 168.5 ± 10 cm or 5′6″, compared with 180.1 cm or 5′11″ in male siblings. For female survivors, the lowest mean final height also was in this group and was reported as 155.7 cm or 5′″, compared with 165.5 cm or 5′5-″ for female siblings. None of the patients received GH. The mean final heights were still within 2 SDs for sex and height for >18 years of age, although the data demonstrated a loss of –0.69 SD for male survivors and –0.74 SD for female survivors compared with sibling control groups.

These findings are important, particularly because the most recent studies suggest that the overall risk of a secondary neoplasm developing in survivors of childhood cancer is 2.15 higher for those who have undergone GH treatment than for those who did not, although the risk appears to be decreasing with time of follow-up.10 Patients who had leukemia and received GH had a 2.3 greater relative risk of a second malignancy developing than patients who did not receive GH. These second malignancies included osteosarcoma of bone and lower extremity, astrocyoma, and glioma.10 Because many of these children also are known to have early onset or rapid pubertal progress, treatment of these children with growth augmenting therapies, such as GH or agents designed to halt pubertal progress (gonadotropin releasing hormone agonists) still needs to determined on a case-by-case basis.

Chow et al provide yet another reminder that the treatment of childhood cancers is no longer simply within the realm of a few pediatric endocrinologists and oncologists. Optimal outcome for these young adults will result from continued review of long-term multicenter outcome studies and aggressive vigilance. Early supportive care and intervention should allow, ultimately, for appropriate modification of treatment regimens, anticipation of co-morbidities, and further reduction of severe, untoward effects.

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References 

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PII: S0022-3476(07)00009-1

doi:10.1016/j.jpeds.2006.12.049

Refers to article:

  • Decreased Adult Height in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

    Eric J. Chow, Debra L. Friedman, Yutaka Yasui, John A. Whitton, Marilyn Stovall, Leslie L. Robison, Charles A. Sklar
    The Journal of Pediatrics April 2007 (Vol. 150, Issue 4, Pages 370-375.e1)

The Journal of Pediatrics
Volume 150, Issue 4 , Pages 332-334, April 2007

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