Growth hormone treatment and risk of malignancy

Article information

Korean J Pediatr. 2015;58(2):41-46

Publication date (electronic) : 2015 February 28

doi : https://doi.org/10.3345/kjp.2015.58.2.41

Hyun-Wook Chae, MD ¹, Duk-Hee Kim, MD, PhD ², Ho-Seong Kim, MD, PhD ¹

¹Department of Pediatrics, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.

²Sowha Children's Hospital, Seoul, Korea.

Corresponding author: Ho-Seong Kim, MD, PhD. Department of Pediatrics, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: +82-2-2228-2069, Fax: +82-2-393-9118, kimho@yuhs.ac

Received 2014 August 25; Accepted 2014 November 06.

Abstract

Growth hormone (GH) treatment has been increasingly widely used for children with GH deficiencies as the survival rate of pediatric patients with malignancies has increased. Both GH and insulin-like growth factor-I have mitogenic and antiapoptotic activity, prompting concern that GH treatment may be associated with tumor development. In this review, the authors examined the relationship between GH treatment and cancer risk in terms of de novo malignancy, recurrence, and secondary neoplasm. Although the results from numerous studies were not entirely consistent, this review of various clinical and epidemiological studies demonstrated that there is no clear evidence of a causal relationship between GH treatment and tumor development. Nonetheless, a small number of studies reported that childhood cancer survivors who receive GH treatment have a small increased risk of developing de novo cancer and secondary malignant neoplasm. Therefore, regular follow-ups and careful examination for development of cancer should be required in children who receive GH treatment. Continued surveillance for an extended period is essential for monitoring long-term safety.

Keywords: Growth hormone; Neoplasms; Recurrence; Malignancy insulin-like growth factor-I

Introduction

Growth hormone (GH) has been administered to children with GH deficiency since the late 1950s, initially using extracts from human pituitary glands1). Since the 1980s, GH has been produced by recombinant DNA technology and prescribed for a wide variety of disorders. As the use of synthetic human recombinant GH has increased over the past several decades, there has been a concurrent increase in awareness of the potential safety issues accompanying the treatment2). Recently, Carel et al.3) analyzed a French population-based registry of 6,928 children who started GH treatment between 1985 and 1996. The researchers reported that mortality rates increased in children treated with recombinant GH; however, all types of cancer-related mortality did not increase, and most of the increased mortality was due to bone tumors or cerebral hemorrhage. This exemplifies the controversy associated with GH treatment and risk of malignancy.

Survival rates of pediatric patients with malignancies are increasing due to improved treatment modalities, and interest in improved, long-term quality of life is increasing in tandem, including optimizing the final height of a patient with GH deficiency after cancer treatment4). For patients with GH deficiency after completing antitumor therapy, GH is often recommended to increase height velocity and improve quality of life5).

On its own, however, GH has mitogenic activity6). There have been theoretical and clinical concerns that GH may play a part in tumor recurrence7,8). GH treatment may increase an individual's risk of developing cancer, particularly in the case of cancer survivors, by increasing the risk of recurrence or secondary malignancy9). Controversies and debates are currently ongoing regarding GH treatment's possible causal relationship with tumor recurrence.

It is known from in vitro and in vivo studies that GH and insulin-like growth factor-I (IGF-I) have mitogenic and antiapoptotic activity, and it is possible that GH treatment may be associated with tumor development7,8). Higher serum levels of IGF-I may also be associated with increased cancer risk, and concern has been raised regarding its potential role as a carcinogen after GH treatment10). Some epidemiological studies have shown a correlation between high serum levels of IGF-I and occurrence of certain cancers, including carcinomas of the prostate, lung, breast, and colon11,12). GH receptors have been expressed on normal and transformed human white blood cells, and in vitro studies have shown that GH may cause transformation of normal cells and proliferation of leukemic cells9,13). Most of IGF-I's physical effects are mediated through the type 1 IGF receptor, which is overexpressed in many different types of cancers14). Although the results of all studies are not completely consistent, a high concentration of IGF-I may be linked to an increased risk of cancer development15).

As with IGF-I, there is a concern that GH treatment may be associated with tumor development. Although GH treatment has been shown to be generally safe, it is important to investigate the relationship between GH treatment and cancer risk. The authors reviewed clinical and epidemiological studies that examined cancer risk in patients treated with GH with a focus on de novo malignancy, recurrence, and secondary neoplasm.

GH treatment and de novo malignancy

1. Leukemia

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).

2. Solid tumors

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.

GH treatment and recurrence of malignancy

1. Leukemia

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.

2. Brain tumors

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.

GH treatment and risk of secondary malignancy

Childhood cancer survivors might be at increased risk for secondary malignancies compared with the general population45). Assessing their risk of second and subsequent malignancies during long term follow-up is thus very important.

Meadows et al.46) investigated 14,358 cohort members in the CCSS and analyzed SIRs for occurrences of a second malignant neoplasm. The 30-year cumulative incidence of second malignant neoplasm was 9.3%, and the risk of subsequent neoplasms remained elevated for more than 20 years of follow-up for all diagnoses of primary childhood cancer. Another report from the CCSS showed that the risk of sarcoma was more than 9 folds greater among childhood cancer survivors than among the general population47). Ergun-Longmire et al.48) analyzed the cohort and reported that the rate of GH-treated survivors developing secondary neoplasms was 2.1 folds greater compared with non-GH-treated survivors; however, the risk appeared to decrease as follow-up time extended. Using large cohort follow-up studies, Carel and Butler49) suggested that children treated with GH following childhood cancer treatment might not have a greater number of relapses, but that there might be a higher incidence of secondary tumors in the early years of GH therapy.

There are, however, some more reassuring data. Neglia et al.50) analyzed 13,581 children from a retrospective cohort drawn from US and Canadian institutions who were diagnosed with common cancers before the age of 21 and survived at least 5 years. Twenty years after the childhood cancer diagnosis, the estimated cumulative incidence of second malignancy was 3.2%, and only 1.88 excess malignancies occurred during follow-up. Sklar et al.32) studied 172 brain tumor survivors from among 13,539 survivors enrolled in the CCSS. The relative risk of disease recurrence was 0.83 (95% CI, 0.37-1.86) for survivors who had been treated with GH, and risk was not increased for any of the major cancer diagnoses.

Most recently, Patterson et al.51) analyzed 12,098 pediatric cancer survivors from the CCSS and reported the incidence of meningioma, glioma, and other solid CNS tumors. The adjusted rate of CNS tumor development in patients treated with GH compared with untreated survivors was 1.0 (95% CI, 0.6-1.8). Overall, there was no statistically significant increase in risk of the occurrence of solid CNS tumors associated with GH exposure. Major recent studies of growth hormone treatment and malignancy risk from large data registries were summarized in Table 1.

Table 1

Major recent studies of growth hormone treatment and malignancy risk (large data registries)

Levels of circulating IGF-I might be associated with an increased risk of common cancers, although the association remains unclear52), as there have been few large cohort studies studying the relationship between GH dosage, IGF-I levels, and risk of tumor recurrence. A meta-analysis and systematic review showed that high concentrations of IGF-I were associated with an increased risk of prostate cancer and premenopausal breast cancer, but the associations were modest52). Nonetheless, monitoring and maintaining IGF-I levels within a normal range might be important, and titrating GH doses to target IGF-I levels (IGF-I based dosing) could be a reasonable approach in this high risk GH-treated group49).

Conclusions

The benefits of GH treatment for growth and metabolism in children with GH deficiency are well defined, and replacement therapy with GH is recommended53). Despite theoretical concerns about the effect of GH on tumor development, this review of various clinical and epidemiological studies demonstrated that there is no clear evidence of a causal relationship between GH treatment in patients with GH deficiency and tumor development. Nonetheless, a small number of studies have reported that childhood cancer survivors who have received GH treatment have a small increased risk of de novo cancer and second malignant neoplasm. Therefore, regular follow-ups and careful examination for the development of cancer should be required in those who receive GH treatment. Continued surveillance for an extended period is essential to monitor further potential changes.

Notes

No potential conflict of interest relevant to this article was reported.

References

1. Blizzard RM. History of growth hormone therapy. Indian J Pediatr 2012;79:87–91. 22081428.

2. Laron Z. Growth hormone therapy: emerging dilemmas. Pediatr Endocrinol Rev 2011;8:364–373. 21972776.

3. Carel JC, Ecosse E, Landier F, Meguellati-Hakkas D, Kaguelidou F, Rey G, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab 2012;97:416–425. 22238382.

4. Noorda EM, Somers R, van Leeuwen FE, Vulsma T, Behrendt H. Dutch Late Effects Study Group. Adult height and age at menarche in childhood cancer survivors. Eur J Cancer 2001;37:605–612. 11290436.

5. Adan L, Sainte-Rose C, Souberbielle JC, Zucker JM, Kalifa C, Brauner R. Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation. Med Pediatr Oncol 2000;34:14–19. 10611579.

6. Wabitsch M, Braun S, Hauner H, Heinze E, Ilondo MM, Shymko R, et al. Mitogenic and antiadipogenic properties of human growth hormone in differentiating human adipocyte precursor cells in primary culture. Pediatr Res 1996;40:450–456. 8865283.

7. Ogilvy-Stuart AL, Gleeson H. Cancer risk following growth hormone use in childhood: implications for current practice. Drug Saf 2004;27:369–382. 15144231.

8. Banerjee I, Clayton PE. Growth hormone treatment and cancer risk. Endocrinol Metab Clin North Am 2007;36:247–263. 17336744.

9. Sklar CA. Growth hormone treatment: cancer risk. Horm Res 2004;62(Suppl 3):30–34. 15539796.

10. Pekic S, Popovic V. GH therapy and cancer risk in hypopituitarism: what we know from human studies. Eur J Endocrinol 2013;169:R89–R97. 23935131.

11. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000;21:215–244. 10857553.

12. Furstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol 2002;3:298–302. 12067807.

13. Mercola KE, Cline MJ, Golde DW. Growth hormone stimulation of normal and leukemic human T-lymphocyte proliferation in vitro. Blood 1981;58:337–340. 6972789.

14. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer 2003;107:873–877. 14601044.

15. Cohen P, Clemmons DR, Rosenfeld RG. Does the GH-IGF axis play a role in cancer pathogenesis? Growth Horm IGF Res 2000;10:297–305. 11161960.

16. Watanabe S, Tsunematsu Y, Fujimoto J, Komiyama A. Leukemia in patients treated with growth-hormone. Lancet 1988;1:1159–1160. 2896972.

17. Nishi Y, Tanaka T, Takano K, Fujieda K, Igarashi Y, Hanew K, et al. GH Treatment Study Committee of the Foundation for Growth Science, Japan. Recent status in the occurrence of leukemia in growth hormone-treated patients in Japan. J Clin Endocrinol Metab 1999;84:1961–1965. 10372694.

18. Fradkin JE, Mills JL, Schonberger LB, Wysowski DK, Thomson R, Durako SJ, et al. Risk of leukemia after treatment with pituitary growth hormone. JAMA 1993;270:2829–2832. 8133622.

19. Allen DB, Rundle AC, Graves DA, Blethen SL. Risk of leukemia in children treated with human growth hormone: review and reanalysis. J Pediatr 1997;131(1 Pt 2):S32–S36. 9255225.

20. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab 2010;95:167–177. 19906787.

21. Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 2002;360:273–277. 12147369.

22. Tyden G, Wernersson A, Sandberg J, Berg U. Development of renal cell carcinoma in living donor kidney grafts. Transplantation 2000;70:1650–1656. 11152228.

23. Mehls O, Wilton P, Lilien M, Berg U, Broyer M, Rizzoni G, et al. Does growth hormone treatment affect the risk of post-transplant renal cancer? Pediatr Nephrol 2002;17:984–989. 12520324.

24. Tuffli GA, Johanson A, Rundle AC, Allen DB. Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone. J Clin Endocrinol Metab 1995;80:1416–1422. 7714117.

25. Moshang T Jr, Rundle AC, Graves DA, Nickas J, Johanson A, Meadows A. Brain tumor recurrence in children treated with growth hormone: the National Cooperative Growth Study experience. J Pediatr 1996;128(5 Pt 2):S4–S7. 8627468.

26. Wilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr 2010;157:265–270. 20400105.

27. Haddy TB, Mosher RB, Nunez SB, Reaman GH. Growth hormone deficiency after chemotherapy for acute lymphoblastic leukemia in children who have not received cranial radiation. Pediatr Blood Cancer 2006;46:258–261. 16369923.

28. Leung W, Rose SR, Zhou Y, Hancock ML, Burstein S, Schriock EA, et al. Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2002;20:2959–2964. 12089225.

29. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab 1996;81:1704–1710. 8626820.

30. Maneatis T, Baptista J, Connelly K, Blethen S. Growth hormone safety update from the National Cooperative Growth Study. J Pediatr Endocrinol Metab 2000;13(Suppl 2):1035–1044. 11086659.

31. Wyatt D. Lessons from the national cooperative growth study. Eur J Endocrinol 2004;151(Suppl 1):S55–S59. 15339245.

32. Sklar CA, Mertens AC, Mitby P, Occhiogrosso G, Qin J, Heller G, et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 2002;87:3136–3141. 12107213.

33. Bernier V. Technical aspects in cerebrospinal irradiation. Pediatr Blood Cancer 2004;42:447–451. 15049018.

34. Arslanian SA, Becker DJ, Lee PA, Drash AL, Foley TP Jr. Growth hormone therapy and tumor recurrence. Findings in children with brain neoplasms and hypopituitarism. Am J Dis Child 1985;139:347–350. 3976624.

35. Clayton PE, Shalet SM, Gattamaneni HR, Price DA. Does growth hormone cause relapse of brain tumours? Lancet 1987;1:711–713. 2882131.

36. Ranke MB, Price DA, Lindberg A, Wilton P, Darendeliler F, Reiter EO. Final height in children with medulloblastoma treated with growth hormone. Horm Res 2005;64:28–34. 16103682.

37. Chae HW, Park YS, Kim DS, Kwon AR, Kim HS, Kim DH. Final height and insulin-like growth factor-1 in children with medulloblastoma treated with growth hormone. Childs Nerv Syst 2013;29:1859–1863. 23775040.

38. Packer RJ, Boyett JM, Janss AJ, Stavrou T, Kun L, Wisoff J, et al. Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol 2001;19:480–487. 11208842.

39. Price DA, Jonsson P. Effect of growth hormone treatment in children with craniopharyngioma with reference to the KIGS (Kabi International Growth Study) database. Acta Paediatr Suppl 1996;417:83–85. 9055921.

40. Hogeveen M, Noordam C, Otten B, Wit JM, Massa G. Growth before and during growth hormone treatment in children operated for craniopharyngioma. Horm Res 1997;48:258–262. 9402242.

41. Price DA, Wilton P, Jonsson P, Albertsson-Wikland K, Chatelain P, Cutfield W, et al. Efficacy and safety of growth hormone treatment in children with prior craniopharyngioma: an analysis of the Pharmacia and Upjohn International Growth Database (KIGS) from 1988 to 1996. Horm Res 1998;49:91–97. 9485178.

42. Weiss M, Sutton L, Marcial V, Fowble B, Packer R, Zimmerman R, et al. The role of radiation therapy in the management of childhood craniopharyngioma. Int J Radiat Oncol Biol Phys 1989;17:1313–1321. 2689398.

43. Swerdlow AJ, Reddingius RE, Higgins CD, Spoudeas HA, Phipps K, Qiao Z, et al. Growth hormone treatment of children with brain tumors and risk of tumor recurrence. J Clin Endocrinol Metab 2000;85:4444–4449. 11134091.

44. Frajese G, Drake WM, Loureiro RA, Evanson J, Coyte D, Wood DF, et al. Hypothalamo-pituitary surveillance imaging in hypopituitary patients receiving long-term GH replacement therapy. J Clin Endocrinol Metab 2001;86:5172–5175. 11701673.

45. Henderson TO, Rajaraman P, Stovall M, Constine LS, Olive A, Smith SA, et al. Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 2012;84:224–230. 22795729.

46. Meadows AT, Friedman DL, Neglia JP, Mertens AC, Donaldson SS, Stovall M, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 2009;27:2356–2362. 19255307.

47. Henderson TO, Whitton J, Stovall M, Mertens AC, Mitby P, Friedman D, et al. Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2007;99:300–308. 17312307.

48. Ergun-Longmire B, Mertens AC, Mitby P, Qin J, Heller G, Shi W, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab 2006;91:3494–3498. 16822820.

49. Carel JC, Butler G. Safety of recombinant human growth hormone. Endocr Dev 2010;18:40–54. 20523016.

50. Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M, et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 2001;93:618–629. 11309438.

51. Patterson BC, Chen Y, Sklar CA, Neglia J, Yasui Y, Mertens A, et al. Growth hormone exposure as a risk factor for the development of subsequent neoplasms of the central nervous system: a report from the childhood cancer survivor study. J Clin Endocrinol Metab 2014;99:2030–2037. 24606096.

52. Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004;363:1346–1353. 15110491.

53. Kelnar CJ. Which children should receive growth hormone treatment. Cost-benefit analysis is the key. Arch Dis Child 2000;83:176–178. 10950748.

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