A possible correlation between GH therapy and increased risk of leukemia was reported in Japan16); however, the investigators carried out a follow-up analysis of the cohort and could not find a close association between GH therapy and leukemia when subjects with known risk factors for leukemia were excluded17). The United States' National Hormone Pituitary Program found 3 cases of leukemia in 59,736 patient-years of GH treatment between 1963 and 1985. The rate was not significantly higher than the 1.6 cases expected for an age, ethnicity, and sex-matched population18). Genentech's National Cooperative Growth Study (NCGS), which enrolled more than 40,000 GH recipients during 20 years of follow-up, showed that the leukemia risk was comparable to that of the general population when subjects with known risk factors for leukemia were excluded19). Another study from the NCGS reported 3 cases of de novo leukemia compared with the 5.6 cases expected in a theoretical, age-matched general population20).

There has been concern that elevated endogenous levels of GH and IGF-I might be associated with an increased risk of certain solid tumors. Swerdlow et al.21) studied cancer incidence and mortality in 1,848 patients in the UK who were treated with human pituitary GH during childhood and early adulthood between 1959 and 1985. The incidence and mortality of colorectal cancer and the mortality of Hodgkin's disease initially increased after patients with an otherwise high risk of cancer were excluded. Since then, however, the validity of the results have been debated, because the current GH therapy regimen differs from what was used at the time8). All patients received standard GH doses given 2 or 3 times a week, and serum IGF-I levels were not monitored.

Tyden et al.22) reported 2 cases of de novo development of cancer in living kidney transplant recipients, although de novo development of cancer in renal transplants might be rare. According to the analysis from the Kabi International Growth Study (KIGS) and NCGS databases, however, only 2 cases of renal cell carcinoma in those who did not have renal disease were found among the 43,000 patients in the NCGS registry and 42,000 in the KIGS registry23). The number of malignancies seemed disproportionately high for the relatively small number of children who had chronic renal failure and who were receiving GH treatment8,23).

Tuffli et al.24) reported that the number of extracranial, nonleukemic neoplasms from 12,209 individuals who were treated with the recombinant GH was no greater than expected cases. Although 10 new cases of malignancies were noted, it was not a greater value than predicted, indicating that GH was not implicated in the occurrence of solid tumors. Another report from NCGS showed no evidence of an increase in the incidence of de novo intracranial tumors in children treated with GH25). Bell et al.20) reported, from a recent analysis of the NCGS registry, that de novo intracranial and extracranial malignancies were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected). One of the most recent reports from the KIGS compared the incidence of cancer in the cohort to that in the general population by using the standardized incidence ratio (SIR)26). A total of 32 new malignant neoplasms were reported in 58,603 patients, versus the 25.3 expected (SIR, 1.26; 95% confidence interval [CI], 0.86-1.78). Again, patients treated with GH showed no statistically significant difference in cancer incidence compared with the expected number of cases in this study.

Survivors of childhood leukemia are at risk of developing complications, including growth failure, which may require GH treatment8). Patients with GH deficiency are particularly common because total body irradiation increases risk of growth failure, although GH deficiency can also result from solely chemotherapeutic regimens27). There has been concern that children treated with GH after therapy against leukemia may be at a higher risk of leukemia recurrence.

Leung et al.28) studied 47 patients who had received GH replacement therapy among 910 patients treated for acute lymphoblastic leukemia and examined recurrence rates at 7 years and 11 years after continuous hematologic remission. There was no statistical evidence that GH therapy was associated with leukemia relapse or development of a second malignancy.

The NCGS has monitored the safety of recombinant human GH since 1985. There have been 3 new cases of leukemia in children without known risk factors for developing leukemia and 5 cases in children with known risk factors; however, there was no evidence of an increased recurrence of leukemia29). Follow-up reports showed no evidence of increased incidence of leukemia among patients without previous risk factors30). Another investigator analyzed 47,000 patients representing 165,000 patient-years from the NCGS and found reassuring evidence that leukemia (de novo or relapse), extracranial nonleukemic neoplasms, and central nervous system (CNS) tumor recurrence were not associated with GH therapy31).

Sklar et al.32) investigated 122 acute leukemia survivors from among 13,539 subjects enrolled in the Childhood Cancer Survivor Study (CCSS), a cohort of 5-year survivors of childhood cancer. They found that the relative risk of recurrence was not increased compared to 4,545 children not treated with GH.

GH deficiency is a common disease in patients with hypothalamic-pituitary tumors. The deficiency is caused either by the mass itself or by surgical or irradiation therapy to hypothalamopituitary axis9). Deficiency can also develop in those who have tumors far from the hypothalamopituitary axis, because cerebrospinal irradiation is often needed to treat these tumors33).

In 1985, Arslanian et al.34) reported the outcome of GH therapy in 34 children with brain tumors who developed hypopituitarism. Of the 34 patients with brain tumors and hypopituitarism, 24 received GH therapy. Eight of the 24 (33%) experienced tumor recurrence, compared with 3 of the 10 (30%) who did not receive GH. Clayton et al.35) reported similar results, namely that the late relapse rate of medulloblastoma and glioma was not altered by GH therapy, and the therapy might not increase the relapse rate of brain tumors.

Medulloblastoma is one of the most malignant childhood brain tumors. Survivors of medulloblastoma are, however, increasing as progress has been made in the treatment of the tumor36). From a retrospective analysis of 34 children treated with GH for medulloblastoma over 3 years, Chae et al.37) reported no cases of recurrence. Another retrospective review included 545 children with medulloblastoma, of whom 170 patients were treated with GH38). This review found that while GH treatment was underutilized in survivors of medulloblastoma, it was not associated with disease relapse.

Craniopharyngioma is a relatively common brain tumor derived from pituitary gland embryonic tissue in children39). Due to the morbidities associated with damage to the pituitary and hypothalamus from surgical removal and irradiation against craniopharyngioma, GH treatment is commonly needed after therapy to treat this tumor40). The recurrence rate of craniopharyngioma was 0.045/treatment year in 488 patients who were enrolled in the KIGS from 1988 to 1996, and the investigators concluded that GH treatment might be safe and effective in children with craniopharyngioma41). In the NCGS report, children receiving GH after treatment for craniopharyngioma had a recurrence rate of 6.4%, considerably lower than the estimates of 20%-25% in another report25,42).

Swerdlow et al.43) investigated 180 children with brain tumors treated with GH, and 891 children not treated with GH during 1965-1996. The relative risk of first recurrence in GH-treated patients decreased after adjusting for potentially confounding prognostic variables (0.6; 95% CI, 0.4-0.9). The relative risk of mortality also decreased (0.5; 95% CI, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since GH treatment started. Another study showed, using surveillance imaging, that hypothalamopituitary tumor recurrence in GH-treated patients was as low as in non-GH-treated patients44). Only 1 patient among 100 consecutive patients showed evidence of slight intrasellar tissue enlargement using pituitary imaging at 6 months. GH replacement was continued, and there was no further change between 6 and 12 months, though the follow-up duration was short and may not be conclusive evidence against recurrence.