Growth hormone deficiency after chemotherapy for acute lymphoblastic leukemia in children who have not received cranial radiation

Abstract

Chemotherapy-related growth failure is a significant problem in children with acute lymphoblastic leukemia (ALL) and other childhood cancers. Growth impairment after cranial radiation (CR) can result in diminished adult height, but growth failure following chemotherapy without CR is usually followed by catch-up growth and normal adult height.1 A retrospective review of 347 ALL survivors registered in our Long Term Follow Up (LTFU) Clinic, since 1997 revealed that 109 had received CR; 3, total body irradiation (TBI); and 235, neither CR nor TBI. For patients whose growth velocity slowed, growth hormone (GH) levels and pediatric endocrinology referrals were obtained. Among the 112 ALL survivors who had received some form of CR, 5 had significant growth failure with growth hormone deficiency (GHD). Among the 235 ALL survivors treated with chemotherapy without CR, 2 were diagnosed with growth failure and GHD. We report the two survivors of childhood ALL treated with chemotherapy without CR who required GH replacement due to absence of catch-up growth. A 15-year-old boy and a 12-year-old girl, off therapy for 9 and 6 years, respectively, were evaluated for decreased growth velocity and failure of catch-up growth. Peak GH responses to stimulation using arginine and clonidine were 3.4 and 3.0 ng/ml, respectively (normal >10 ng/ml). Other causes of growth failure were ruled out, and GH replacement therapy was instituted. Their chemotherapy had included methotrexate, 6 mercaptopurine, vincristine, adriamycin, cyclophosphamide, L-asparaginase, dexamethasone, cytarabine, 6 thioguanine, and intrathecal methotrexate. The growth of all children treated with intensive chemotherapy, regardless of whether CR was administered, should be closely monitored with measurement of standing height at 6 months intervals until growth is complete.

Height Deficit and Impairment of the GH/IGF-1 Axis in Patients Treated for Acute Lymphoblastic Leukemia during Childhood

“…Patients treated with the same dose of cranial irradiation but with a more intensive chemotherapeutic protocol have been regarded by some authors as having a significantly higher deficit in their final height when compared to those with a less intensive protocol [29]. Our patients had received a relatively intensive chemotherapy regimen and a statistically significant growth deficit was found among those treated with chemotherapy alone, as found by others [23,30], although the deficit was significantly larger in the irradiated group, as observed in our previous study with a smaller sample [7] and by others [10]. Nevertheless, others [8,31] could not find any detrimental effect on final height for patients treated with chemotherapy alone.…”

Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

“…18 Previously, administration of Eto or Cyc in young rats was shown to reduce growth plate thickness, [20][21] produce bone growth arrest in long bones, [19][20][21] and induce osteopenia. 21 However, how these two drugs affect the bone growth mechanisms has been largely unclear.…”

“…17 Alkylating agent cyclophosphamide is a common component of intensive chemotherapy for acute lymphoblastic leukemia in children who often suffer from growth failure during the chemotherapy. 18 Some skeletal side effects of cyclophosphamide have also been documented in experimental animals, including reduced thickness of growth plate, disturbed cell differentiation and maturation, decreased femoral growth and metaphyseal bending strength. [19][20] Topoisomerase is an enzyme required for DNA synthesis and toplogy alteration, and etoposide (Eto), the most commonly used topoisomerase inhibitor, binds to topoisomerase II and DNA, inducing DNA damage and causing arrest in S-or G 2 -phase.…”

Late Effects of Childhood Leukemia Therapy

“…During high-demand periods of growth such as puberty, the system has limited reserve to increase GH production, and the result is apparent GHD and growth failure. Recent reports suggest that GHD can also be seen in patients treated with chemotherapy alone [92]. High doses of prednisone or dexamethasone used during the leukemia treatment also affect growth, although most children demonstrate good catch-up growth in the first few years of follow-up after treatment [93].…”