Journal of the National Cancer Institute Advance Access originally published online on July 31, 2009
JNCI Journal of the National Cancer Institute 2009 101(16):1105-1107; doi:10.1093/jnci/djp238
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Published by Oxford University Press 2009.
EDITORIALS |
The Legacy of Cancer Therapy in Children
Affiliations of authors: Pediatric Oncology Branch (EF) and Radiation Oncology Branch (DC), Center for Cancer Research, National Cancer Institute, Bethesda, MD; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA (FMB)
Correspondence to: Elizabeth Fox, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 10-CRC, 1-5750, 10 Center Dr, Bethesda, MD 20892 (e-mail: foxb{at}mail.nih.gov).
Multimodality treatment approaches integrating surgery, radiation, and combination chemotherapy have had a substantial impact on the survival of children with cancer. The 5-year relative survival rate for children younger than 15 years of age who were diagnosed in 1996–2004 was 80% for all types of childhood cancer compared with 28% for children diagnosed in 1960–1963 (1). Most of those who survived are cured of their cancer. Although childhood cancers are rare diseases, this high survival rate combined with the potentially long life span of children surviving cancer has translated into a growing population of adult survivors of childhood cancer (approximately one in 900 adults in the United States). These childhood cancer survivors are at risk for late effects from cancer therapy.
The Childhood Cancer Survivor Study (CCSS) is systematically and quantitatively characterizing a broad range of late effects in a cohort of more than 14 000 childhood cancer survivors who were diagnosed between 1970 and 1986 (2,3). This issue of the Journal includes a report, Laverdière et al. (4), on the subset of 954 survivors who had neuroblastoma. When the characteristics of the neuroblastoma survivors, who account for 6.7% of the CCSS cohort, were compared with the remainder of the CCSS cohort, neuroblastoma survivors were younger at diagnosis, accounting for 54% of subjects who were younger than 1 year of age at diagnosis in the CCSS cohort (Table 1). Therefore, the late outcomes of this small subset substantially influence the findings of the entire CCSS cohort regarding children who were very young at diagnosis. In addition, compared with other childhood cancer survivors, a smaller fraction of the neuroblastoma survivors received chemotherapy and radiation, which cause most of the late effects. Fifty-nine percent of neuroblastoma survivors received some form of chemotherapy and 49% received some form of radiation compared with 80% and 68%, respectively, for non-neuroblastoma survivors in the cohort. In the neuroblastoma subset, survivors who received multimodality therapy were at twofold higher risk of late effects compared with those who had only surgical resection.
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The characteristics of the neuroblastoma survivor subset reflect the enrichment for younger patients with low-stage tumors, which may have required only surgical resection for a cure, and thus likely underestimates the late effects of current treatment approaches in patients with intermediate- and high-risk neuroblastoma. In the 1970s, 50%–60% of children with neuroblastoma had metastatic disease (stage IV, Evans staging system) at presentation and fewer than 20% of these patients survived for at least 5 years (5). Patients with stage I and II neuroblastoma accounted for 30%–40% of the population at diagnosis, and 5-year survival was 100% and 85% for stage I and II, respectively (5). Therefore, in the 1970s, 75% of 5-year survivors of neuroblastoma had survived stage I or II disease and fewer than 15% had survived stage IV disease (Figure 1).
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Compared with a sibling control population, the neuroblastoma survivors reported a higher incidence of second cancers and musculoskeletal, endocrine, and neurological late effects, and they had a higher death rate, primarily related to late recurrence of neuroblastoma (4). Radiation therapy was statistically associated with the development of second cancers, scoliosis, growth hormone deficiency, ovarian failure, deafness, and blindness.
Late effects may be caused by the cancer or the treatment. Cancer-related late effects are often from primary or metastatic tumors that arise in or impinge on the brain or spinal cord and cause permanent neurological deficits. Most late effects in childhood cancer survivors represent cumulative, irreversible, drug-specific toxicities, such as the ototoxic effect of cisplatin, cardiotoxic effect of doxorubicin, or site-specific toxic effects from radiation. In the case of chemotherapy, dose and treatment schedule have been primarily determined by acute reversible toxic effects, such as myelosuppression, and generally have not been influenced by consideration of late effects. With respect to late effects, safe cumulative doses of most anticancer drugs have not been defined in children, by contrast to the well-defined tissue-specific cumulative dose limits for radiation.
Certain developing organs, such as growth plates, are more susceptible to radiation toxicity in children than in adults. In other tissues, such as kidney and lung, the risk of toxicity is proportional to the tissue volume exposed to a threshold dose of irradiation, which may be large because of the size of the tumor and the small habitus of children with neuroblastoma. Organ or tissue susceptibility to the late effects of radiation also depends on age and developmental status. For example, the effects of brain radiotherapy on cognition are more pronounced in younger patients, whereas the risk of breast cancer after chest radiotherapy is thought to be highest in pubertal girls. The fact that even very low doses of radiation present a risk of second cancers remains a major concern for any child receiving definitive radiotherapy because of his or her potentially long life span.
The CCSS comprehensive late effects studies benefit current adult cancer survivors, children undergoing treatment, and future patients by:
- demonstrating the need for long-term follow-up of survivors of cancer
- focusing follow-up evaluations by identifying organ systems at highest risk for late effects
- helping to define safe cumulative doses of chemotherapy and radiation using the detailed treatment profiles from chart reviews
- guiding the design of future treatment regimens to minimize or prevent late effects.
During the observation period for the neuroblastoma subset of the CCSS cohort, both the assessment of prognosis (risk classification) and the treatment of neuroblastoma have evolved. Therapy for high-risk neuroblastoma has become more intensive and may now include topotecan (6), retinoic acid (7,8), and immunotherapy (anti-GD2 antibody) (9). Some patients receive substantially more alkylating agents than they did previously during induction (>4000 mg/m2 for intermediate-risk neuroblastoma and 12 400 mg/m2 for high-risk neuroblastoma), in addition to platinum analogs and etoposide, which are also associated with late effects. In addition, many high-risk patients undergo single or tandem myeloablative autologous stem cell transplants. Although this intensification of treatment has resulted in an incremental improvement in the survival of high-risk patients, the survivors are likely to be at considerably higher risk of late effects from therapy. Advancements in imaging and radiation treatment planning now allow more homogeneous doses of radiotherapy to be delivered with improved accuracy and maximal exclusion of organs at risk. In addition, use of radiolabeled metaiodobenzylguanidine (131I-MIBG) (10,11) may provide better targeting of radiation to the tumor, resulting in an improved therapeutic ratio.
The introduction of more selective and less toxic molecularly targeted drugs holds the promise of substantially altering the acute and long-term toxic effects of cancer therapy. These agents are in the early phase of clinical testing in children, and several of the drug targets, such as the insulin-like growth factor-1 receptor or anaplastic lymphoma kinase play important roles in the pathogenesis of childhood cancers. Unfortunately, many of the pathways that are critical to the pathogenesis of cancers and are targeted by these new agents, for example angiogenesis, are also important to normal growth and development. The potential requirement for extended treatment with these drugs may have a substantial impact on a child's development and will require careful study of late effects, similar to the ongoing efforts of the CCSS.
NOTES
The authors report no conflicts of interest.
REFERENCES
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9. Yu A, Gilman AL, Ozkaynak MF, et al. A phase III randomized trial of the chimeric anti-GD2 antibody ch14.18 with GM-CSF and IL2 as immunotherapy following dose intensive chemotherapy for high-risk neuroblastoma: Children's Oncology Group (COG) study ANBL0032. J Clin Oncol (2009) 27(15S). Abstract 10067z.
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