Cancer Survivors, Growth Hormone Treatment and Second Neoplasms

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Ergun-Longmire and colleagues conducted a statistical analysis of the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study of 5-year survivors of childhood cancer diagnosed before 21 years of age, which assessed the risk of developing a second neoplasm (SN) in the 14 108 respondents. Specifically, they examined the relationship between risk and the presence or absence of growth hormone (GH) treatment. A previous report¹ by these authors indicated a 3-fold increase in the risk of developing an SN in cancer survivors who were treated with GH compared to those who did not receive GH. In the present study, the authors reassessed that risk in their initial cohort of 361 GH-treated survivors after an additional 32-month follow-up. Details of their GH exposure, including start and stop dates, dose, and height data, were obtained from their physicians.

The relationship between GH therapy and the time to development of a SN, and death, were examined using a time-dependent Cox regression model. The investigators adjusted for age, sex, chemotherapy, alkylating agent score, and radiation as potential confounding factors. After adjusting for these variables, the model revealed an increased risk (rate ratio; [RR]) of GH-treated survivors developing a SN of 2.15 (95% confidence interval [CI], 1.33-3.47; p = 0.002) compared with non GH-treated survivors. When the survivors were stratified by original cancer diagnosis, the difference between survivors who did and those who did not receive GH did not reach statistical significance for any of the diagnostic groups. There was no association found between dose and duration of GH therapy and the risk of developing a SN. In the GH-treated survivors, meningiomas were the most common SN (9 of 20). All GH-treated survivors who developed a meningioma had received radiation to the brain/head. The latency period for developing a meningioma in the GH-treated group was 12.2 years compared with 19.0 years in the survivors not treated with GH (p=0.01). The percentage of deaths due to a SN was statistically similar for survivors treated with GH compared with those not treated (25% vs. 13%).

The authors concluded that the risk of developing a SN in childhood cancer survivors treated with GH remains elevated compared with the risk seen in survivors not treated with GH. Findings suggested the risk appears to diminish with increasing length of follow-up (ie, RR 2.15 vs. RR 3.21). They also found that within the GH-treated group, meningiomas were the most common SN and all had received radiation to the brain as part of the treatment for primary cancer. Because of the asymptomatic nature of meningiomas, possible surveillance/detection bias needs to be considered when interpreting results. If GH-treated survivors participated in more consistent and frequent medical surveillance compared with non GH-treated survivors, the results could have demonstrated an overestimated risk.

Ergun-Longmire B, Mertens AC, Mitby P, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab. 2006;91:3494-8.

Editor’s Comment

Increased survival rates of those diagnosed with childhood cancer is encouraging for patients, families, and medical professionals; it also means that we increasingly need to consider long-term quality of life issues. Given that GH deficiency is a common condition that affects childhood cancer survivors, some survivors have received GH treatment. This, however, is not without controversy. Both this report and its predecessor suggested an increased risk of SNs among those treated with GH compared to those who were not treated. Further research is needed to address unresolved methodological issues: it may be that GH treatment by itself increases the incidence of SNs, perhaps increased monitoring secondary to GH treatment resulted in earlier detections of SNs, perhaps those parents and patients who elected GH treatment differ from those who did not in a way that is associated with either susceptibility to SNs or earlier detection of SNs.

Oeffinger et al conducted a study to determine the type of outpatient medical care reported by young adult survivors of childhood cancer—that speaks to the detection/surveillance issues.² Results showed 71.4% of participants had contact with a general physician and 41.9% attended a cancer-related visit, but only 19.2% visited a cancer center. They also reported medical contact decreased significantly as the survivor aged or the time from cancer diagnosis increased. Considering the majority of the survivors were seen only by their primary care physicians, it is important to maintain communication between these physicians and childhood cancer centers to enhance risk-based care and to correct growth hormone and other hormone deficiencies. The prevalence of GH deficiency and neuropsychological alterations in cancer survivors is discussed in the review, “ Leukemia Survivors: GH Deficiency, Quality of Life, and Neuropsychological Function” in this issue of GGH.³

We now have reason to suspect that GH treatment may be associated with an increased risk of a SN among childhood cancer survivors; however, we don’t know “why.” Neither do the patients nor their parents. When the child’s GH deficiency is a consequence of either the malignancy itself or a result of its treatment, how then, do we help patients and their parents make informed decisions about the risks and benefits of GH treatment?

David E. Sandberg, PhD

References - (linked to )

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Last Updated: 04/30/2008