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Previous cancer affects future cancer incidence, mortality risk with pediatric GH therapy
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In patients with previous cancers treated with recombinant human growth hormone therapy as children, researchers observed increased risks for both cancer incidence and mortality during long-term follow-up, but no clear cancer-related risk was observed in patients with growth failure without other major disease, according to findings from a population-based European study.
“GH therapy is widely used and a range of biological data suggest that hormone levels in the GH–[insulin-like growth factor I] axis may affect cancer risks,” Anthony J. Swerdlow, DSc, head of the epidemiology section at the Institute of Cancer Research and an honorary consultant in epidemiology at The Royal Marsden NHS Foundation Trust, and colleagues wrote. “It is therefore important clinically to determine whether cancer risks are raised by GH treatment. Information on this has been very limited, however. Generally, the larger studies have had short follow-up, and the studies with long follow-up have been small.”
Swerdlow and colleagues analyzed data from 23,984 patients from eight European countries who were treated with recombinant human GH as children since the treatment was first available in 1984. Researchers followed the cohort for mortality and cancer incidence using population-based registries in Belgium, the Netherlands, Sweden and the United Kingdom, and by other methods in France, Germany, Italy and Switzerland, where cohorts were smaller and clinic-based. Approximately half the cohort received GH treatment from age 10 to 14 years; about half received GH for isolated growth failure, according to researchers. Patients treated with GH therapy with certain rare conditions that predispose them to cancer, such as neurofibromatosis, were excluded from analysis.
Researchers calculated person-years at risk for cancer incidence and mortality, and they used these with national population rates to calculate standardized mortality ratios (SMR), standardized incidence ratios (SIR), absolute excess rates (AER) and trends in risk. The mean follow-up for mortality was 16.5 years; mean follow-up for cancer incidence was 14.8 years. Within the cohort, 251 cancer deaths occurred; there were 137 incident cancers in countries where incidence risk was analyzed.
In the overall cohort, cancer mortality was raised more than 13-fold, according to researchers, whereas cancer incidence risk doubled. The AER for cancer mortality was 5.9 (95% CI, 5.1-6.7); the AER for cancer incidence was 4.8 (95% CI, 3.4-6.4).
However, in patients with an initial diagnosis of isolated growth failure without other major disease, overall cancer risk was not raised, the researchers found. Among patients with an initial diagnosis that was not isolated growth failure or cancer, there were increased risks for cancer incidence (SIR = 1.4; 95% CI, 1.1-1.9) and mortality (SMR = 2.2; 95% CI, 1.3-3.7), as well as specific risks for bone cancer (SIR = 4.1; 95% CI, 1.3-12.6) and bladder cancer incidence (SIR = 27.8; 95% CI, 7-111.3).
For patients treated with GH therapy without a cancer diagnosis, neither cancer mortality nor incidence was related to duration or dose of therapy. For patients treated after previous cancer, risk for cancer mortality increased with increasing daily dose (P for trend < .001).
In examining site-specific cancer risks, researchers found that incidence of Hodgkin lymphoma increased with longer follow-up for patients overall (P for trend = .001) and for patients without previous cancer (P for trend = .002).
“Overall, our study, with much larger numbers of GH-treated patients followed longer-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 researchers wrote. “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.”
The researchers noted that the rising cancer mortality with greater daily GH dose in cancer patients raises the possibility of an effect of GH therapy on cancer survival.
“Also, the raised risks of bone and bladder cancers in patients with initial non-cancer diagnoses, and the rising risk of Hodgkin lymphoma with longer follow-up in such patients, leave possibilities of effects on site-specific cancer causation for which further data are needed.” – by Regina Schaffer
Disclosure: Swerdlow reports no relevant financial disclosures. Please see the full study for the other authors’ relevant financial disclosures.
Perspective
Back to TopOverall, the researchers noticed that in patients with a previous history of cancer treated with GH during childhood, cancer mortality risk and cancer incidence risk were higher than general population risk, whereas they did not see the same increased risk in non-cancer patients treated with GH.
So, do we think this study answered the million dollar question: Is GH therapy safe to be used in children with cancer history? Of course not. The authors themselves acknowledge the limitations of the study and the need for further probing before we can close the chapter on this topic. We know that childhood cancer survivors in general have a higher risk for subsequent neoplasm, and this study does not address the key question as to whether GH treatment increases that risk as it did not include a control group of cancer survivors who did not need or receive GH therapy. Also, given that this is a population-based study, we have no information on confounders, such as radiation therapy, obesity, smoking, family history of cancer, etc, that also would increase cancer risk. The analysis on different types of cancer incidence and mortality is difficult to interpret given the low incidence of each type.
Recent literature from the Childhood Cancer Survivor Study cohort in the United States lets us ease our concerns a little bit on GH therapy and subsequent neoplasm risk in childhood cancer survivors. And yes, this study would and should raise our awareness and alertness that GH therapy is still not completely cleared of causing potential long-term harm in these patients. Maybe it is time for clinicians and researchers to finally invest their time, money and effort in creating a quality long-term prospective follow-up study on childhood cancer survivors with and without GH therapy.
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