The study raises concern for possible new cancer development in patients treated with human growth hormone, while already having a history of treated malignancy. There was also a trend for Hodgkin lymphoma, bone and bladder cancer in individuals without prior history of carcinoma. About 25,000 patient data were analyzed, including initial hGH users from 1984. Further research is needed to confirm or identify the mechanism of causality.
J C E M
Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited.
To examine cancer risks in relation to GH treatment. Cohort study. Population-based.
Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics.
Cancer incidence and cancer mortality.
Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease.
Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer.
Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001).
Hodgkin lymphoma incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer).
Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and Hodgkin lymphoma risks, need further investigation.
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Growth hormone (GH) has been prescribed since 1957 to treat GH deficiency and short stature due to other causes. The hormone used was initially extracted from human pituitaries (p-hGH), but after an outbreak of Creutzfeldt–Jakob disease consequent on prion infection from these pituitaries, this was discontinued in 1985 and all subsequent treatment has been with recombinant human growth hormone (r-hGH).
GH raises serum concentrations of insulin-like growth factor (IGF)-1, which is mitogenic and antiapoptotic in vitro, and adult levels of which have been associated in most studies with risks of subsequent breast, colorectal, and prostate cancers and in some studies with other cancers. Furthermore, cohort studies of patients with endogenously raised GH concentrations, acromegaly, have found raised risks of several cancers, most consistently colorectal. Potential effects on leukemia and other malignancy risks have been suggested, and second primary malignancy risk has been shown raised in patients receiving GH after childhood cancer. Although these data give suspicion that there might be carcinogenic effects, no risks have been shown consistently or established.
Our cohort showed a significant raised bone cancer incidence in GH-treated patients, both those with and without an initial cancer diagnosis. Bone cancer has been one of the most common second primaries in previous childhood GH-treated cohorts.
Bladder cancer risk was greatly and significantly raised in patients without previous cancer, but based on small numbers. There appear to be no previous data about this and until such data are available, little weight can be put upon it.
We found significant excesses of incidence and mortality from cancers of the soft tissue, kidney, CNS, and thyroid, and of incidence of melanoma and cancer of the ovary and mortality from non-HL, all restricted to patients with cancer as the reason for GH treatment. Mainly, these are cancer sites for which raised risk of second cancer after radiotherapy and/or chemotherapy is well known, although this does not preclude GH raising the risks further. Melanoma, however, is not a tumor usually raised after radiotherapy and chemotherapy, although it has been in at least one instance.
Overall, our study, with much larger numbers of GH-treated patients followed long-term than previously, does not suggest that GH treatment affects the risk of cancer incidence or mortality for the outcomes and durations of follow-up for which our analyses have substantial data. The lack of increased risk with greater cumulative dose or duration of treatment, key variables for which data have not been published previously, makes a causal relation less likely.
There was also no clear raised risk in patients with isolated growth failure. These factors argue against a major risk of cancer overall within the length of follow-up currently available. Nevertheless, continued vigilance during follow-up is desirable, both because of the lack of data for longer follow-up than in our study and because of the presence of some significant raised risks in the results. The rising cancer mortality with greater daily dose in cancer patients, however, leaves open the possibility of an effect on cancer survival. Also, the raised risks of bone and bladder cancers in patients with initial noncancer diagnoses and the rising risk of HL with longer follow-up in such patients leave possibilities of effects on site-specific cancer causation for which further data are needed.