Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia.

Davies, Helena; Didcock, E; Didi, Mohammed; Ogilvy-Stuart, Amanda; Wales, J.; Shalet, Stephen M

doi:10.1136/adc.70.6.472

Cited by 75 publications

(49 citation statements)

References 14 publications

(4 reference statements)

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“…Those who received any form of spinal radiotherapy had the shortest adult heights among all survivor groups. Prior studies had not been consistent in finding differences in final height between survivors treated with 18 Gy versus 24 Gy cranial radiotherapy (3)(4)(5)7,12,(15)(16)(17), or between 18 Gy and treatment with chemotherapy alone (3,6,14). These studies had relatively few subjects who reached adult height (N <200), limiting their statistical power to detect differences.…”

Section: Discussionmentioning

confidence: 99%

“…Growth deficits have been reported consistently following doses of ≥24 Gy cranial radiotherapy, but the data are less consistent for doses <20 Gy (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The effect on loss of stature was greater in children who also received radiotherapy to the spine, secondary to direct inhibition of vertebral growth (13).…”

Section: Introductionmentioning

confidence: 89%

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Decreased Adult Height in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

Chow

Friedman

Yasui

et al. 2007

The Journal of Pediatrics

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Objectives-To determine risk factors associated with reduced adult height in survivors of childhood acute lymphoblastic leukemia (ALL).Study design-Cross-sectional study. Attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study, a cohort of five-year survivors of common pediatric cancers diagnosed from [1970][1971][1972][1973][1974][1975][1976][1977][1978][1979][1980][1981][1982][1983][1984][1985][1986], and compared with 3,009 siblings.Results-All survivor treatment exposure groups (chemotherapy alone, chemotherapy with cranial or craniospinal radiotherapy) had decreased adult heights and an increased risk of adult short stature (height standard deviation score < −2) compared with siblings (p<0.001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (OR 3.4, 95% CI 1.9, 6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL prior to puberty, higher dose cranial radiotherapy (≥20 Gy versus <20 Gy), any radiotherapy to the spine, and female sex.Conclusions-Survivors of childhood ALL are at increased risk of adult short stature, including those treated with chemotherapy alone. Risk is highest for those treated with cranial and craniospinal radiotherapy at a young age. PO Box 19024, Seattle, WA 98109-1024. Phone (206) 667-7724, Fax (206) 667-5948, email: ericchow@u.washington.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The authors disclose no potential conflicts of interest. Cranial and craniospinal radiotherapy were commonly used in the 1970s and early 1980s to treat as well as to prevent the spread of acute lymphoblastic leukemia (ALL) to the central nervous system (CNS) in children. While radiotherapy was effective, it was associated with adverse endocrine and neurocognitive outcomes(1). As a result, over the past three decades, radiotherapy doses have been reduced or eliminated in an attempt to decrease these adverse long-term outcomes, and have been replaced by more intensive chemotherapy.Several studies have examined growth in ALL survivors. Growth deficits have been reported consistently following doses of ≥24 Gy cranial radiotherapy, but the data are less consistent for doses <20 Gy(2-17). The effect on loss of stature was greater in children who also received radiotherapy to the spine, secondary to direct inhibition of vertebral growth(13). For most studies in which the impact of chemotherapy without radiotherapy was examined, growth suppression during treatment was followed by catch-up growth (...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Decreased Adult Height in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

Chow

Friedman

Yasui

et al. 2007

The Journal of Pediatrics

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“…Growth retardation following treatment has been demonstrated in several studies (Olshan et al 1992, Ogilvy-Stuart & Shalet 1995 and there is radiological evidence that the epiphyseal growth plate is damaged in children with acute lymphoblastic leukaemia (ALL) who have received sustained and intensive chemotherapy (Wollner et al 1980). This is further supported by a large collaborative study between the Manchester, Nottingham and Sheffield paediatric oncology centres (Davies et al 1994) in which the effects of combination chemotherapy and cranial irradiation on final height and body proportions were examined in a cohort of 142 children treated for ALL. Of the children in the study for whom sitting height measurements were available, 81% had relatively shorter backs than legs and it was suggested that this disproportion might be due to effects of the chemotherapy on the large numbers of epiphyses that are found in the spine.…”

Section: Introductionmentioning

confidence: 90%

Chemotherapeutic agents used in the treatment of childhood malignancies have direct effects on growth plate chondrocyte proliferation

Robson

Anderson²,

Eden³

et al. 1998

Journal of Endocrinology

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Short stature is one of the most well recorded long term sequelae for adult survivors of childhood malignancies. It has become increasingly apparent that cytotoxic chemotherapy, as well as craniospinal irradiation, has a major impact on growth, but there are virtually no studies which explore the mechanisms by which these cytotoxic drugs affect growth. We have used an in vitro system to investigate the direct effects of a range of chemotherapeutic agents on the proliferative responses of rat tibial growth plate chondrocytes, both in suspension and monolayer culture.The glucocorticoids and purine anti-metabolites reduced chondrocyte proliferation both in monolayer and suspension cultures and this resulted from an increase in cell doubling times with a concomittant reduction in the numbers of S phase cells. DNA damaging agents (e.g. actinomycin-D) were also able to reduce chondrocyte proliferation, both in monolayer and suspension culture. This, however, was the result of a cell cycle arrest and subsequent cell death. In our studies, methotrexate had no significant effect on the proliferative responses of the chondrocytes either in monolayer or suspension culture.These results indicate direct effects of a range of chemotherapeutic agents on the proliferative responses of growth plate chondrocytes. Both cytostatic and cytotoxic effects were observed although the impact of either the potential loss of cells from the proliferative pool during chondrocyte differentiation, or the reduction in the rate of chondrocyte turnover on long bone growth remains to be elucidated.

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“…The drugs can cause precocious toxic effects, but the late effects are mainly due to RT [9][10][11] . Children who were very young at the time of irradiation tend to develop sequelae such as growth impairment and early puberty 12,13 . Only one 3-yearold girl among the 5 patients of the group A showed low levels of GH and a reduction in predicted final height.…”

Section: Discussionmentioning

confidence: 99%

Growth and puberty after treatment for acute lymphoblastic leukemia

et al. 2004

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Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment. PATIENTS AND METHOD:The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy), and group C underwent chemotherapy plus radiotherapy (24 Gy). Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging. RESULTS: Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau) between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy). The final predicted height (Bayley-Pinneau) was significantly less (P = 0.0071) in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis. CONCLUSION: Radiotherapy was been responsible for late side effects, especially related to growth and puberty.KEY WORDS: Endocrine dysfunction in lymphoblastic leukemia. Growth and acute leukemia. Puberty in lymphoblastic leukemia.

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Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia.

Cited by 75 publications

References 14 publications

Decreased Adult Height in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

Decreased Adult Height in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

Chemotherapeutic agents used in the treatment of childhood malignancies have direct effects on growth plate chondrocyte proliferation

Growth and puberty after treatment for acute lymphoblastic leukemia

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