A Systematic Review of Selected Musculoskeletal Late Effects in Survivors of Childhood Cancer

Abstract

Survivors of childhood cancer are at risk for treatment-related musculoskeletal late effects. Early detection and orthopedic intervention can help ameliorate musculoskeletal late effects and prevent subsequent complications. This systematic review summarizes the literature describing associations between cancer, its treatment, and musculoskeletal late effects. We searched PubMed and Web of Science for English language articles published between January 1970 and December 2012. The search was limited to investigations with at least 15 participants and conducted at least 2 years after completion of therapy for childhood, adolescent, or young adult cancer. Some late skeletal effects, including low bone mineral density, osteonecrosis, slipped capital femoral epiphyses, oncogenic rickets, and hormone-related growth disturbances have been previously reviewed and were excluded, as were outcomes following amputation and limb-salvage procedures. Of 2347 references identified, 30 met inclusion criteria and were retained. An additional 54 studies that met inclusion criteria were found in reference lists of retained studies. Of 84 studies, 60 focused on associations between radiotherapy, six between chemotherapy, and 18 between surgery and musculoskeletal late effects. We found that younger age, higher radiation dosage, and asymmetric or partial bone radiation volume influences the effects of radiation on the musculoskeletal system. Methotrexate and vincristine are associated with long-term muscular strength and flexibility deficits. Laminectomy and chest wall resection are associated with spinal malalignment, and enucleation is associated with orbital deformities among survivors. Radiotherapy, chemotherapy, and surgery are associated with musculoskeletal late effects independently and additively. Associations are additionally influenced by host and treatment characteristics.

INTRODUCTION

The 5-year survival rate among children with malignancies is over 80%. As of January 1, 2010, there were nearly 380,000 survivors of childhood cancer in the United States (1). This growing population is the result of progress in cancer treatment and supportive care. However, survivors remain at risk for significant treatment-related late effects (2, 3), including musculoskeletal complications (4).

Late musculoskeletal effects such as low bone mineral density (BMD) (5), osteonecrosis (6), slipped capital femoral epiphyses (7), oncogenic rickets (8), hormone-related growth disturbances (9), and limb salvage and amputation-related outcomes (10), have been comprehensively reviewed. However, the current state of knowledge about other, equally important, musculoskeletal late effects has not been systematically evaluated. Clinicians providing care to survivors should anticipate musculoskeletal late effects such as muscular atrophy, fibrosis, skeletal hypoplasia, and craniofacial and spinal deformity. Although these late effects influence physical functioning and quality of life of survivors (11–13), they have not been rigorously studied compared to the aforementioned well-reviewed late effects. Early detection and orthopedic intervention can help ameliorate musculoskeletal late effects and prevent subsequent complications.

To aid clinicians in the provision of individualized care through the identification of at-risk survivors and provision of timely intervention, we systematically review and summarize the existing knowledge about musculoskeletal late effects of childhood cancer treatment.

METHODS

Data Sources

We searched the PubMed and Web of Science database (Limits: English, human, dates: 01/01/1970 to 12/31/2012) for clinical trials, observational studies, case series, and reviews using the search terms “musculoskeletal abnormalities”, “adverse effects”, “infant”, “child”, “adolescent”, “adult, young”, “neoplasms”, “survivors”. Studies were selected after reviewing the abstracts for relevance. This search was augmented with selected publications from reference lists of studies retrieved from databases.

Study Selection

The systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (14). Reports were limited to studies with at least 15 participants that discussed late musculoskeletal effects among childhood cancer survivors evaluated a minimum of 2 years after completion of therapy. Previous literature reviews were excluded. Specific musculoskeletal effects, including low BMD (5), osteonecrosis (6), slipped capital femoral epiphyses (7), limb salvage and amputation related late effects (10), oncogenic rickets (8), and hormone-related growth complications after cranial radiation (9) were excluded because comprehensive reviews have been published. Primary outcomes were defined as the occurrence of musculoskeletal complications at least 2 years after completion of cancer therapy.

Data Extraction and Synthesis

One reviewer (P.L.G.) screened all titles and abstracts for relevance and validity. The methodological quality of the selected studies was independently evaluated by two reviewers (P.L.G. and K.K.N.) (15). Criteria used to determine the quality of the studies included comparability of subjects, clear definition of exposure or intervention, standard outcome measurement and appropriate statistical analysis. Discrepancies in assessment of validity and quality of studies were resolved by discussion between reviewers. We extracted information about sample size, age at diagnosis, type of diagnosis, follow-up period, type and details of treatment and musculoskeletal late effects from the selected studies.

RESULTS

Search Results

Our initial search of PubMed database identified 2347 studies; 30 were retained as relevant. An additional 54 studies that met inclusion criteria were found in reference lists of initially retained studies. No additional studies were identified in the Web of Science database. The 84 studies selected were evaluated according to the predominant anticancer therapy exposure (radiotherapy [n = 60], chemotherapy [n = 6], or surgery [n = 18]) associated with the late musculoskeletal effects (Figure 1).

Figure 1.

Flow of studies through review.

Study Quality and Risk of Bias

Studies included in this review had clearly defined exposure and outcome measures. Most of the studies were cross-sectional, retrospective in design, from single institutions, and did not mention the eligible source population. Although we excluded studies with fewer than 15 participants, several studies included were conducted among small convenience cohorts because data from larger cohorts documenting musculoskeletal late effects were not available. These study designs may have either excluded patients with the most severe musculoskeletal effects because of death or inability to participate in follow-up testing, or oversampled them because of their concerns regarding late effects. Longitudinal studies included in this review were likely subject to selection bias due to attrition.

Muscular Late Effects of Radiotherapy (Table 1)

Table 1.

Summary of 60 reports of radiation-associated musculoskeletal late effects in long-term survivors of childhood cancer

First Author (Year)	Sample Size (n)	Age at Diagnosis	Diagnosis	Time since Diagnosis	Surgery/ HCT	Chemotherapy Agents	Radiotherapy (RT) and Dose	Late Effects															Risk Factors
								Muscular				Skeletal											Younger age at RT	Growth spurt	RT dosage	RT field size	RT asymmetry	Epiphyses in RT field	Orthovoltage	Accompanied chemo	Accompanied surgery	Longer follow-up
								Atrophy	Fibrosis	Hypoplasia	Myalgia	Scoliosis	Kyphosis	Lordosis	Spinal growth retarded	Vertebral asymmetry	Hypoplasia	LLD	Craniofacial deformity	Orbital deformity	Chest wall deformity	Osteochondroma
Probert(58) 1973	22	< 15 y	HL (n=16) MB (n=2) ALL (n=4)	9 mo–10.5 y	NA	MOPP (HL) VCR, PRED, MP, MTX, CPM (ALL)	Spinal RT (MeV) > 40 Gy (n=18) < 25 Gy (n=4)								✓									✓
Probert(44) 1975	44 plus 15000 controls	< 15 y	HL (n=28) MB (n=3) ALL (n=13)	3.5 y (> 35 Gy) 1.7 y (< 25 Gy)	NA	MOPP (HL) VCR, PRED, 6-MP, MTX, CPM (ALL)	Spinal RT (MeV) > 35 Gy (n=29) < 25 Gy (n=15)					✓			✓									✓	✓
Riseborough (23) 1976	81	0–13 y (mean 3.1 y)	WT	6.6–21.6 y (mean 11.9 y)	All had nephrectomy	AMD (n=71)	31 Gy (n=74; OV) 28 Gy (n=7; Co-60)	✓				✓	✓			✓	✓					✓	✓		✓
Oliver(21) 1978	21	5 mo–9 y	WT	3.5–35 y	All had nephrectomy	AMD (n=20)	All had RT 20–45 Gy	✓				✓	✓			✓	✓								✓
Heaston(43) 1979	25	1 mo–9.3 y (mean 3.5 y)	WT	4–18 y (mean 9.83 y)	All had nephrectomy	All had chemo	35 Gy (n=20; Co-60) 35 Gy (n=5; OV)					✓				✓								✓					✓
Jentzsch(26) 1981	22	4–29 y	ES	> 2 y	NA	Protocol S1–S4	All had RT mean 50 Gy	✓	✓		✓							✓					✓		✓
Libshitz(119) 1981	44	< 16 y	HL, NHL, ES, RMS	≥ 3 y	NA	Chemo (n=14)	All had RT 30–55.5 Gy															✓			✓					✓
Mayfield(34) 1981	74	0–10.4 y (mean 1.5 y)	NB	5–31 y (mean 12.9 y)	Resection (n=6), laminec tomy (n=7)	Resection and chemo (n=6)	27.5 Gy (n=67; OV) 23.5 Gy (n=1; MeV) 49.9 Gy (n=1;High RT)					✓	✓	✓										✓	✓		✓				✓	✓
Pastore(55) 1982	86	< 1 y	Various cancers	5–29 y (median 12 y)	NA	Chemo (n=78)	4.5–40 Gy (n=60; OV) mean 21 Gy		✓	✓		✓	✓				✓				✓	✓
Smith(45) 1982	22	0.75–9 y (median 2.5 y)	WT	1–22.5 y (median 10.5 y)	NA	Chemo (n=16) AMD, VCR, ADR, CPM	22–35 Gy (n=7 for OV & n=15 for MeV)					✓	✓			✓	✓							✓					✓			✓
Guyuron(72) 1983	41	1–17 y (mean 4.8 y)	Facial tumors	7–25 y (mean 15.1 y)	NA	NA	Craniofacial RT 4–85.1 Gy												✓				✓		✓
Kajanti(27) 1983	32	0–12.9 y	NB	3–24.5 y (mean 13.6 y)	Resection (n=29)	Chemo (n=25) CPM and VCR	RT (n=25) MeV (n=19)/X-rays	✓	✓														✓		✓		✓				✓	✓
Thomas(46) 1983	26	0–133 mo	WT	60–226 mo (median153 mo)	Nephrectomy (n=25)	VCR, AMD CPM (n=24)	All had RT 3–44 Gy					✓	✓		✓		✓					✓		✓
Carli (67) 1986	70	0–15 y (median 6 y)	RMS	NA	NA	Chemo (n=69)	RT (n=48) 16–84 Gy		✓			✓	✓		✓		✓
Fromm (77) 1986	20	7 mo–13 y (median 6 y)	Soft-tissue sarcoma	2–10 y (median 5.5 y)	NA	All had Chemo ADR VCR, AMD, CPM	40–60 Gy (median 50 Gy)		✓								✓		✓				✓
Heyn (78) 1986	50	0–20 y	RMS	3 y	Resection (n=40)	All had Chemo	All had RT 50–60 Gy										✓		✓	✓
Brown (70) 1987a	67	0.3–33 y (median 11 y)	ES	NA	Surgery (n=7) & RT (n=24)	VCR, CPM, AMD, DOXO, MELPH,	RT (n=60; MeV) 25–65 Gy											✓							✓			✓			✓
Shalet (59) 1987	79	1–15 y	Brain tumors	16–30 ya	All had surgery	NA	All had RT 27–35 Gy								✓								✓
Dahllöf (120) 1989	17 plus 85 controls	1–12.9 y	Hematolo gical (14) Aplastic (3)	1.9–5.9 y (median 3.9 y)	All had HCT	High dose CPM 50–60 mg/kg	10 Gy TBI (n=12) 8 Gy TBI (n=2) 24 Gy CRT (n= 3)												✓				✓
Butler (47) 1990	143	0.1–12.9 y (mean 8.3 y)	Various cancers	2–18 y (mean 9.9 y)	Surgery (n=119)	Chemo (n=131)	All had RT 19.5–50 Gy				✓	✓	✓					✓			✓				✓		✓
Larson (33) 1990	50	2 mo–16 y (median 5 y)	Various cancers	6–27 y (median 13 y)	NA	Chemo (n=41)	All had RT	✓									✓								✓
Sonis (81) 1990	97	< 10 y	ALL	≥ 5 y	NA	All had chemo	CRT (n=78; MeV) 18 Gy (27) 24 Gy (51)												✓				✓		✓
Wallace (42) 1990	30	0.3–11.3 y (median 2.4 y)	WT	15.2–39.4 y (median 21 y)a	All had nephrectomy	NA	All had RT 20–30 Gy					✓			✓		✓						✓	✓
Silber (62) 1990	49	0.3–16.7 y (mean 7.3 y)	Various cancers	3.3–15.4 y (median 8.9 y)	Laminectomy (n=1)	Chemo (n=46)	RT (n=36)								✓								✓		✓	✓		✓
Evans (24) 1991	680	NA	WT	> 5 y 7416 person-y	NA	AMD, VCR or ADR	RT (n=486)	✓				✓										✓					✓
Crooks (48) 1991	89	9 d–13.2 y (median 3.7 y)	ALL, WT, MB, others	4–23 y (mean 10.8 y)	NA	All ALL patients had intrathecal MTX	All had RT					✓			✓	✓	✓					✓			✓
Rate (49) 1991	31	0.08–13.4 y (median 4.8 y)	WT	4–18 y (median13 y)	All had nephrectomy	All had chemo	28.9 Gy (n=10; OV) 34.5 Gy (n=21; MeV)					✓	✓				✓	✓							✓	✓			✓
Meadows (121) 1992	400	< 2 y (n=93) > 2 y (n=318)	Various cancers	> 5 y	NA	NA	39 of 93 had RT 71 of 318 had RT								✓										✓
Makipernaa (30) 1993	44	3 mo–14.7 y (median 2.6 y)	WT, NB and others	10.8–27.7 y (median 18.9 y)	All had resection	Chemo (n=38)	13–49 Gy (WT) 17.7–43 Gy (Others)	✓		✓		✓	✓	✓											✓
Mameghan (32) 1993	49	3–33 y (median 16 y)	ES	2–24 y (mean 12.3 y)	Amputation/resection(n=5)	Chemo (n=44)	RT (n=41) median 50 Gy	✓										✓
Dahllöf (35) 1994	19 plus 19 cont.	6.2–19.9 y (mean 14.2 y)	ALL, AML Gaucher’s	> 3 y	All had HCT	NA	All had TBI		✓		✓								✓
Willman (57) 1994	124	< 16 y (boys) < 14 y (girls)	HL	≥ 2 y	NA	Chemo (n=77)	All had spinal RT ≥ 33 Gy or < 33 Gy									✓							✓			✓
Imhof (82) 1996	68	0.5–53 mo (mean 11 mo)	RB (52 B/L and 16 U/L)	95–97 mo	Enucleation (n=43)	NA	RT only (n=77), RT & enucleation (n=43)													✓			✓
Taylor (66) 1997	138	NA	WT	Median 127 m	All had surgery	UKW1 protocol;	Abdominal RT 20–30 Gy									✓	✓				✓
Denys (74) 1998	26	2–18 y (median 13 y)	RMS (6 y), NPC (17 y)	1–20 y (median 4 y)	NA	All had chemo	50.2 Gy (RMS) 56.8 Gy (NPC)												✓	✓			✓
Hale (50) 1999	73	0–18.3 y (median 9.2 y)	GCT	5.1–26.5 y (median 11.3 y)	All had resection	Chemo (n=48)	RT (n=29) 20–30 Gy					✓	✓	✓			✓						✓								✓
Hovi (122) 1999	31	TBI (3 y) Chemo (3 y)	NB poor-risk	TBI (4.7 y) Chemo (7.7 y)	All had HCT	VP-16, MELPH, CP L/CSPL, Thiotepa	10–12 Gy (n=16; TBI) 4–24 Gy (n=6; chemo)								✓											✓
Paulino (28) 2000a	42	0.5–10.5 y (median 4 y)	WT	5–25.5 y (median 15 y)	NA	All had chemo AMD, VCR, ADR	All had RT 10–40 Gy			✓		✓	✓				✓	✓							✓							✓
Paulino (75) 2000b	17	2.2–11.6 y (median 5.7 y)	Head and neck RMS	7.5–33 y (median 20 y)	NA	Chemo (n=15)	All had RT 41.4–65 Gy (MeV)										✓		✓	✓					✓
Hogeboom (61) 2001	2778	Median 2 y 11 mo	WT (94%) Other (6%)	Median 6 y 2 mo	All had nephrectomy	NWTS-1, NWTS-2 and NWTS-3	RT (n=1323) 10–40 Gy								✓								✓		✓	✓
Karsila- Tenovuo (73) 2001	40 plus 40 cont.	Median 13.4 y	Craniofacial tumors	Median 6 y	NA	CRT+Chemo (n=18) Chemo only (n=11)	CRT (n=18) 19.5–59.6 Gy												✓
Trobs (22) 2001	49	NA	WT	NA	All had nephrectomy	SIOP No.9/GPO SIOP 93-01/GPO	RT (n=48)	✓				✓	✓								✓
Oberlin (86) 2001	306	< 1–17 y (median 6.8 y)	Orbital RMS	25–204 mo (median 82 mo)	Resection (n=9)	All had chemo	RT (n=245) 6–64 Gy										✓
Paulino (51) 2002	53	0–1 y	NB	2–41 y (median 13.1 y)	Resection (n=38)	Chemo (n=22) CPM and/or DOXO	12–31 Gy (n=20)					✓	✓				✓					✓	✓		✓							✓
Fuchs (123) 2003a	41	5–51 y (mean 16.8 y)	ES	20–36 y (mean 25 y)	Surgery (n=20)	Chemo (n=32) VCR, CPM or AMD	RT (n=37)											✓														✓
Pinter (36) 2003	79	< 1 y	Solid tumors	16–25 y (mean 20 y)	Surgery (n=79)	Chemo (n=64)	RT (n=23) always with surgery & chemo	✓				✓	✓																	✓
Merchant (87) 2004	15	5.1–18.9 y (median 13.3 y)	HL	Median 39.6 mo	NA	Vinblastine, DOXO MTX and PRED	All had asymmetric mantle RT to clavicle			✓							✓						✓		✓	✓	✓					✓
Paulino (25) 2004	15	3.5–20 y (median 13 y)	Extremity sarcomas	6–36 y (median 20 y)	Excision (n=7)	Chemo (n=10) VCR, CPM/DOXO	45–66 Gy (n=9) 41.4–66.4 Gy (n=6)	✓	✓									✓														✓
Taitz (88) 2004	58	< 15 y	NB IV & others	≥ 30 mo	All had HCT	NA	All had TBI															✓	✓
Ness (4) 2005	11481 plus3839 siblings	0–20 y	Various cancers	8–47 y (median 23 y)	Surgery only (7.7%)	Surgery, Chemo & RT (54%)	RT with or without surgery (12.4%)					✓						✓
Paulino (52) 2005	58	2 wk–15 y (median 6 y)	NB	5–46 y (median 10 y)	Laminectomy (n=5)	Chemo (n=33) CPM, DOXO/VCR	3–39 Gy (n=27; median 20 Gy)					✓													✓						✓
Escobar (124) 2006	52	Mean 29.1 ± 31.7 mo	NB stage IV	12.4 ± 8.3 ya	Surgery (n=51)	CCG protocol (n=50)	RT (n=17)					✓
Calaminus(125) 2007	36 plus 319 cont.	1–16 y	Various cancers	1–10 y (median 5 y)	NA	Intrathecal MTX (n=15)	12–54 Gy (n=15; median 18 Gy)		✓
Mansky (126) 2007	32 plus 22 cont.	7.1–34.2 y (median 15 y)	Sarcoma	2.9–32.6 y (median 17.3 y)	Surgery (n=19)	DOXO, CPM, Ifos- famide, Etoposide	3–63 Gy (n=28)
								Locoregional functional limitations
Trahair (53) 2007	40	0–10.8 y (median 2.7 y)	NB high risk	0.6–17.8 y (median 4.6 y)	All had HCT	Chemo only conditioning (n=6)	18 Gy (local) 12 Gy (n=34; TBI)					✓	✓		✓			✓				✓				✓
Hartley (63) 2008	61	3–13 y (median 7 y)	MB and PNET	13.8–74.9 mo (median 44 mo)	NA	All had chemo CPM, VCR, CSPL	36–39.6 Gy (n=26) 23.4 Gy (n=35); CSRT								✓								x		✓
Choi (68) 2010	32 orbits	2–65 mo (median 7 mo)	RB	55–249 m (median150 mo)	Enucleation (n=14 orbits)	NA	Orbital RT (n=28) 35–54.9 Gy										✓			✓
Van Dijk (29) 2010	185	0.3–16.5 y (median 3.7 y)	WT	5–36.7 y (median 18.9 y)	All had nephrectomy	Chemo (n=182) SIOP protocol	RT (n=85) 13–41.1 Gy			✓		✓	✓		✓			✓					✓				✓
Barrena (54) 2011	188	Not reported	NB/GN, PNET/Askin	2.5 y 3.4 y	Surgical removal	SIOP guidelines	Spinal RT					✓	✓																		✓
Rombi (127) 2012	30	1.8–21 y (median 10 y)	ES	Median 38.4 mo	Resection (n=13)	AEWS 0031 and POG protocol	All had proton RT median 54 Gy					✓	✓					✓													✓

^a= age at study;

✓ = reported late effect or risk factor;

^x= older age at RT and male sex associated with growth retardation

Abbreviations: AEWS: Trial for Chemotherapy Intensification Through Interval Compression in Ewing’s Sarcoma; ALL: Acute Lymphoblastic Leukemia; ADR: Adriamycin; AMD: Actinomycin-D; B/L: Bilateral; CCG: Children’s Cancer Group; Chemo: Chemotherapy; Co-60: Cobalt-60; cont.: controls; CPL: Carboplatin; CPM: Cyclophosphamide; CML; Chronic Myeloid Leukemia; CRT: Cranial Radiotherapy; CSPL: Cisplatin; CSRT: Craniospinal Radiotherapy; DOXO: doxorubicin; EORTC: European Organization for Research and Treatment of Cancer; ES: Ewing’s Sarcoma; GCT: Germ Cell Tumor; GN: Ganglioneuroma; Gy: Gray; HL: Hodgkin lymphoma; HCT: Hematopoietic Cell Transplant; LLD: limb length discrepancy; mo: months; MB: Medulloblastoma; MELPH: Melphalan; MeV: Megavoltage; MOPP: Mechlorethamine, Vincristine, Procarbazine and Prednisone; MP: Mercaptopurine; MTX: Methotrexate; NA: Not applicable; NB: Neuroblastoma; NHL: non-Hodgkin Lymphoma; NWTS: National Wilms Tumor Study; NPC: Nasopharyngeal carcinoma; OB: Osteoblastoma; OV: Orthovoltage; PNET: Primitive Neuroectodermal Tumor; POG: Pediatric Oncology Group; PRED: Prednisone; RB: Retinoblastoma; RMS: Rhabdomyosarcoma; RT: Radiotherapy; SIOP: International Society of Pediatric Oncology; TBI: Total Body Irradiation; UKW1: United Kingdom Children’s Cancer Study Group First Wilms Tumor Study; U/L: Unilateral; VCR: Vincristine; VP-16: Etoposide; WT: Wilms tumor; y: years.

The underlying pathophysiology linking radiation to muscular late effects is unclear. However, acutely, radiation prevents mitosis of progenitor myosatellite cells (16), disrupts cell membrane permeability and lipid fluidity, and can result in sodium-potassium pump failure at the neuromuscular junction (17). Additionally, in the long-term, post-radiation inflammation, mediated by the transforming growth factor-β family, may prevent muscle growth (18), radiation-induced vascular and parenchymal damage may interfere with muscle nutrition (19), and mantle radiation may result in nemaline myopathy (20), potentially contributing to muscular atrophy (21–26), fibrosis (25–27), and hypoplasia (28).

Younger age and radiation doses ≥ 20 Gy influence the impact of radiation on muscle (28, 29). Thus, muscular late effects are most common among survivors of dysontogenetic tumors such as Wilms tumor (21–24, 29, 30) and neuroblastoma (27, 30) because these tumors typically present in early childhood and require radiation in cases of advanced disease (31). In contrast, while sarcomas (25, 26, 32) present across a wider age spectrum, survivors of these tumors are vulnerable to muscular late effects, not exclusively because of young age at exposure but because high doses of radiation (> 30 Gy) are required to achieve local control if complete surgical resection is not feasible.

All but two studies (24, 29) describing associations between radiotherapy and muscular late effects had small sample sizes (21–23, 25–28, 30, 32–36). Among 185 survivors of Wilms tumor treated at a median age of 3.7 and followed for a median of 18.9 years, Van Dijk et al. (29) reported an increased risk of tissue hypoplasia with increased dose of chest (Odds Ratio [OR]: 1.10 Gy ⁻¹; 95% Confidence Interval [CI]: 1.03–1.18) and flank/abdominal (OR: 1.17 Gy ⁻¹; 95% CI: 1.10–1.24) radiation. The authors also observed that female sex, younger age at diagnosis, and treatment with anthracyclines increased risk of tissue hypoplasia. A National Wilms Tumor Study (NWTS) analysis (n = 680) reported a higher prevalence of muscular atrophy five years after radiotherapy among survivors of Wilms tumor diagnosed between 1969 and 1979 who received radiation (30.2%) than among those who did not (1%) (24). Post-radiation muscular atrophy is uncommon for survivors of Wilms tumor treated after 1980 because unlike the historical age-adjusted 18–40 Gy radiotherapy, contemporary Wilms tumor patients are treated with 10.8 Gy (31).

Skeletal Late Effects of Radiotherapy (Table 1)

Acutely, radiation damages DNA in osteocytes by causing single or double strand breaks, sugar damage, base damage, by creating protein crosslinks, or by producing free hydroxyl radicals (37, 38). Animal and clinical evidence suggests that radiation may affect bone formation by: 1) arresting chondrogenesis at the epiphyseal growth plate, 2) inducing absorption failure of calcified cartilage and bone at the metaphysis, and 3) altering diaphyseal periosteal activity (39–41). Flat bones grow primarily by membranous ossification may present with diminished or asymmetrical growth after irradiation (Figure 2) (33).

Figure 2.

Effect of radiation on striated muscles and bones in childhood cancer patients

Spinal Malalignment

One reported effect of radiotherapy is alteration in axial alignment, often presenting long after treatment as scoliosis or kyphosis (Supplementary figure). In this review, the prevalence of post-radiotherapy scoliosis ranged from 10–80% (42, 43) and kyphosis from 2–48% (23, 43). In a cohort of 123 Wilms tumor survivors followed for a median of 18.9 years, the authors reported a 36.6% prevalence of scoliosis or kyphosis. Most cases (93.3%) were among survivors with a history of radiation (29). An NWTS analysis (n = 680) also reported a higher prevalence of scoliosis or kyphosis among survivors who had received radiation (51.4%) compared to those who had not (4.1%) (24). The evidence for the association between radiotherapy and spinal malalignment is strengthened by other studies (4, 21–23, 27, 28, 30, 34, 36, 42–55).

The effect of radiation on spinal malalignment is influenced by younger age, higher doses, and asymmetric radiation. Differential effects of radiation are reported based on age cutoffs of six months (51), one year (45), five years (23), or six years (44), depending on the population being studied. Similarly, varied thresholds for radiation dose are reported to increase risk for spinal malalignment including, > 20 Gy (34), > 23 Gy (52), > 24 Gy (28), and > 26 Gy (23). Asymmetric radiation increases the risk of spinal deformity in two ways (27, 34, 47). It is possible that radiation impairs the vertebral growth plate more on one side than the other. However, because vertebral bodies are small, it is likely difficult to impair only a portion of a vertebra. Two authors have speculated that spinal deformity is the result of tethering in atrophied paraspinal muscles (23, 34). Butler et al. (47) found that the prevalence of scoliosis after an average follow-up of 9.9 years after diagnosis was higher among survivors of Wilms tumor (63%) and neuroblastoma (83%), who had received asymmetric radiation, than among Hodgkin lymphoma survivors (39%), who received symmetric radiation. High rates of post-irradiation spinal deformity have gradually declined with refinement in radiotherapy techniques for solid tumors and with the use of lower radiation doses (31).

Spinal Growth Retardation

Although growth retardation is reported as an indirect result of growth hormone deficiency after cranial radiation (56), there is also evidence to suggest an association between spine directed radiation and abnormal vertebral growth. Survivors with this impairment are not only shorter in stature but are also cosmetically challenged as their trunk length is not congruent with normal length arms and legs. In a study of 124 Hodgkin lymphoma survivors treated when younger than 16 years of age, those treated before puberty with ≥ 33 Gy radiation to the entire spine and evaluated 2 years later had both standing (7.7%) and sitting height (8.2%) deficits (57). Other studies support the association between spinal radiation and growth retardation (42, 44, 58–61).

Both younger age (42, 58–61) and higher radiation doses (61–63) are associated with spinal growth retardation. Age-related effects of radiotherapy on spinal growth are described with age cutoffs of one year (59), three years (42), six years (58), and before the onset of puberty (60). Hartley et al. (63) found impaired vertebral growth among survivors of medulloblastoma and supratentorial primitive neuroectodermal tumor (median follow-up: 44 months) who received 36–39.6 Gy craniospinal irradiation (n = 26) than among those who received 23.4 Gy (n = 35).

Vertebral Asymmetry

Among cohorts of Wilms tumor survivors treated before 1980, spinal radiotherapy is associated with anterior beaking of vertebrae (23, 43, 45, 46), which results in progressive spinal deformity, typically kyphosis, later in life (64, 65). Riseborough et al. (23) reported beaking of vertebral bodies among 16 of 81 Wilms tumor survivors followed a median of 12 years; 74 had received 31 Gy orthovoltage radiation.

Skeletal Hypoplasia

The inhibitory effect of radiation on osteogenesis commonly manifests as hypoplasia of bones among survivors of childhood cancer (45, 48, 50, 51, 55, 66), reported especially in flat bones (21, 33, 42, 45–47, 50, 66–69). In a study of 89 survivors of various childhood cancers treated at a median age of 3.8 years and followed for an average of 10.8 years, Crooks et al. (48) observed a higher prevalence of skeletal hypoplasia among survivors treated with > 25 Gy than among those treated with ≤ 25 Gy radiation (9/16 vs. 0/8).

Limb Length Discrepancy

Limb length discrepancy may develop in survivors treated with extremity radiation for Ewing sarcoma (25, 26, 32, 70) or abdominal radiation for Wilms tumor when the hemipelvis is included in the radiation field (28, 29, 49). Because the proximal femoral epiphysis accounts for only 30% of growth (71), most of the discrepancy observed among Wilms tumor survivors is likely due to the tilt resulting from iliac wing hypoplasia. Jentzsch et al. (26) observed limb length differences of > 1.5 cm among 9 of 22 lower extremity Ewing sarcoma survivors 2 years after treatment with a median dose of 50 Gy. Among 42 Wilms tumor survivors treated with abdominal radiation of 10–40 Gy (28), five survivors developed limb length differences ranging from 0.8 to 2.5 cm. Although cutoff criteria for defining limb length discrepancy varies across studies, the prevalence is higher among Ewing sarcoma (25, 26, 47) than among Wilms tumor survivors (29, 49). The severity of limb length discrepancy is influenced by younger age at radiation (25, 26). In a study of extremity sarcoma survivors followed for a median of 13 years, those radiated when younger than 10 years had greater limb length discrepancy than those radiated when older than 10 years of age (median: 4.4 vs. 1.2 cm) (25).

Craniofacial Deformities

Craniofacial deformities are reported after radiotherapy for head and neck tumors (72–74) including retinoblastoma (68) and rhabdomyosarcoma (69, 75–80). In a recent study, all of 25 retinoblastoma survivors treated with 35–54.9 Gy and followed for 5 to 21 years presented with midfacial hypoplasia (68). Another study reported facial deformity in 73% of survivors of head and neck rhabdomyosarcoma exposed to 41.4–65.0 Gy and followed for a median of 20 years (75).

The impact of radiation on craniofacial structure is age (73, 74, 77, 81) and dose dependent (72, 81). Younger age at diagnosis (2–9 vs. 11–13 years) was associated with a higher prevalence of craniofacial deformities (16/16 vs. 0/4) in survivors of head and neck sarcoma (77). Craniofacial deformity assessed using cephalometric analysis of lateral radiographs was present among 18 of 20 ALL survivors treated when younger than 5 years of age with 24 Gy but not among those treated when older than 5 years of age or those treated with < 24 Gy cranial irradiation (81).

Orbital Deformities

Several observational studies (68, 75, 78, 82–86) have reported associations between radiotherapy and orbital hypoplasia. This association is also influenced by younger age at radiation (82). Imhof et al. (82) examined 68 retinoblastoma survivors (120 affected orbits) diagnosed at a mean age of 11 months, treated with 42 Gy radiation, and followed for 96 months. Among 16 unilateral retinoblastoma survivors treated with radiotherapy alone, the mean orbital width, height, and edge-tragus distance were shorter in irradiated orbits when compared to contralateral non-irradiated orbits. Mean orbital widths, heights, and edge-tragus distances of irradiated orbits improved with increasing age at radiation (82).

Chest Wall Deformities

Although usually reported as a late effect of surgery, chest wall deformities may result from radiotherapy (22, 47, 55, 66, 87). These deformities are not only important cosmetically but also impact risk for scoliosis and restrictive lung disease. Among 143 survivors treated with 19.5–50 Gy spinal and/or extremity radiation at a mean age of 8 years and followed for an average of 10 years, Butler et al. (47) observed chest and rib deformities in 36%. A higher prevalence of chest and rib deformities (63%) was observed in a subsample of 30 Wilms tumor survivors following asymmetric radiation (median dose 20 Gy) that included caudal ribs (47). Among 15 early-stage Hodgkin lymphoma survivors treated with 15 Gy asymmetric mantle radiation at a median age of 13 years (median follow-up of 39.6 months), Merchant et al. (87) observed impaired growth in fully versus partially irradiated clavicles (1.3 ± 1.1 vs. 1.8 ± 1.2 cm).

Osteochondroma

Osteochondromas are observed after exposure to TBI (53, 88) or local radiotherapy (23, 24, 28, 43, 45, 46, 51, 55), with a suggested higher prevalence reported following TBI. Assessments of TBI-exposed survivors reported osteochondroma among 9% (88) to 42% (53). Evans et al. (24) noted osteochondroma in 3.5% Wilms tumor survivors treated with local radiation, and Pastore et al. (55) observed osteochondroma in 8% survivors treated with an average of 21 Gy radiation. Although most osteochondromas do not require any treatment, some may require intervention if the tumor becomes abnormally large or symptomatic (89) or undergoes malignant transformation to secondary chondrosarcomas (90).

Muscular Late Effects of Chemotherapy (Table 2)

Table 2.

Summary of 6 reports of chemotherapy-associated musculoskeletal late effects in long-term survivors of childhood cancer

First Author (Year)	Sample Size (n)	Age at Diagnosis	Diagnosis	Time since Diagnosis	Surgery	Chemotherapy Agents	Radiotherapy (RT) and Dose	Late Effects				Risk Factors
								Loss of muscle strength	Spinal growth retardation	Nephrotoxicity	Rickets	Younger age at treatment	Accompanied RT	Vincristine & Methotrexate	Ifosfamide	L-asparaginase
Olshan (96) 1992	38	1.3–11.3 y (mean 6.8 y)	MB	4 consecutive years follow-up	All had surgery	Chemo (n=23), VCR, lomustine and CSPL	CSRT 38.1 Gy and 36.3 Gy with chemo		✓				✓
Hovi (91) 1993	43 plus 69 controls	2–14 y (mean 7 y)	ALL	1–19 y (mean 8 y)	NA	All had Scandinavian protocol	24 Gy (n=32; CRT) 10–12 Gy (n=6; TBI)	✓	✓							✓
Loebstein (97) 1999	174	0.4–21.2 y (median 8 y)	Various cancers	5 y	NA	All had IF and Mesna CSPL (n=123)	NA			✓	✓	✓			✓
Chow (60) 2007	2434 plus 3009 siblings	0–18 y	ALL	≥ 5 y	NA	All had chemo	RT (65.1%) CRT and CSRT		✓				✓
Hartman (93) 2008	92 plus 155 cont.	Mean 4.3 ± 2.0 y	ALL, WT, NHL, others	1–7.5 y (mean 3.3 y)	NA	Dutch Childhood Oncology Protocol	RT (n=9)	✓
Ness (92) 2012	415	0.2–18.8 y (median 4.8 y)	ALL	13.7–46.5 y (median 29.9 y)	NA	VCR (n=415) MTX (n=385)	CRT (n=305)	✓						✓

✓ = reported late effect or risk factor

Abbreviations: ALL: Acute Lymphoblastic Leukemia; ADR: Adriamycin; CRT: Cranial Radiotherapy; CSPL: Cisplatin; Gy: Gray; IF: Ifosfamide; MB: Medulloblastoma; MTX: Methotrexate; NA: Not applicable; NHL: non-Hodgkin Lymphoma; TBI: Total Body Irradiation; VCR: Vincristine; WT: Wilms tumor; y: years.

Recent studies have reported muscular late effects of chemotherapeutic agents including L-asparaginase, methotrexate, and vincristine that commonly present as loss of muscular strength (91–93) and/or flexibility (92). The inhibitory effect of L-asparaginase on protein synthesis (94) and the neurotoxicity (95) of methotrexate and vincristine may be responsible for these long-term muscular late-effects. In a study of 43 female survivors of ALL (mean follow-up: 8 years), Hovi et al. (91), even after accounting for physical activity levels, reported an association between L-asparaginase exposure and muscle weakness (effect sizes: 0.83–1.01). A more recent study of 415 survivors of ALL (median follow-up: 29.9 years) observed that survivors treated with cumulative dose of intrathecal methotrexate ≥ 215 mg/m² were at a higher risk for impaired strength, walking efficiency, and ankle range of motion than those not treated with methotrexate (92). Restricted ankle range of motion was also associated with a cumulative dose of vincristine ≥ 39 mg/m² (92).

Skeletal Late Effects of Chemotherapy (Table 2)

The skeletal late effects of chemotherapy have been observed as a result of additive effect with radiotherapy (96) or as an independent effect due to renal injury (97). Medulloblastoma survivors treated with both chemotherapy and craniospinal irradiation had lower growth velocities than those who received craniospinal irradiation alone (SDS: −3.57 vs. −0.88) when assessed for four consecutive years after treatment (96). However, the mechanism of this additive effect is unclear. Ifosfamide induces proximal tubular injury to the kidneys, presenting as loss of glucose, proteins, phosphate and bicarbonates (98), and is associated with rickets after an average of 5 years follow-up (97).

Skeletal Late Effects of Surgery (Table 3)

Table 3.

Summary of 18 reports of musculoskeletal late effects associated with surgery in long-term survivors of childhood cancer

First Author (Year)	Sample Size (n)	Age at Diagnosis	Diagnosis	Time since Diagnosis	Surgery	Chemotherapy Agents	Radiotherapy (RT) and Dose	Late Effects							Risk Factors
								Scoliosis	Kyphosis	Paraparesis/motor deficit	Tibial torsion/contractures	Orbital growth retardation	Orbital asymmetry	Orbital implant migration	Younger age at treatment	Laminectomy	Thoracotomy	Number of ribs resected	No orbital implant	Small orbital implant	Accompanied RT	Follow-up time
Osborne (109) 1974	65	0–13+ y	NA	1–11+ y	Enucleation (31 with implant and 34 without implant)	NA	NA					✓			✓				✓			✓
King (103) 1975	16	0–15 y	NB intraspinal	≥ 2 y	Resection; complete (n=11), partial (n=5)	Chemo (n=3) CPM	All had RT	✓	✓		✓
Ameniya (83) 1977	17	Mean 1.6 y	RB U/L	Mean 8.8 y	Enucleation	NA	RT (n=12)					✓									✓
Kumar (107) 1977	22	3.5–25 y (median 10 y)	ES, RMS, NB, OS.	7–175 mo	Resection (n=11)	Chemo (n=21)	23.0–56.1 Gy (n=17; Co-60)	✓													✓
Kennedy (110) 1992	42	0–15 y (median 4 y)	Tumors & trauma	22 mo–40 y (mean 11.25 y)	Enucleation (29 with implant and 13 without)	NA	NA					✓			✓				✓
Plantaz (104) 1996	42	1 d–14 y (median 8 mo)	NB intraspinal	0–66 mo	Resection (n=40) Neurosurgery (n=17)	Chemo (n=32)	RT (n=3)	✓	✓							✓
Kaste (85) 1997	54 (82 orbits)	0–6.9 y (median 13 mo)	RB	4.9–25.8 y (median 7.5 y)	Enucleation (n=51) with RT (n=26)	NA	22.5–44 Gy (n=29)					✓	✓	✓	✓					✓	✓
Hoover (105) 1999	26	4 d–6.5 y (median 0.9 y)	NB intraspinal	2–29 y (median 10.1 y)	Laminectomy (n=15)	Chemo (n=17)	RT (n=4)	✓	✓		✓					✓
De Bernardi (100) 2001	54	0–15 y (median 16 mo)	NB intraspinal	4–209 mo (median 139 mo)	Laminectomy (n=32)	Chemo (n=33)	RT (n=11)	✓		✓						✓
Katzenstein (106) 2001	73	0–13 y 2m (median 10 mo)	NB Intraspinal	0–10 y	Laminectomy (n=27) Resection (n=31)	Chemo (n=66)	RT (n=8)	✓								✓
Nahum (112) 2001	21 (28 orbits)	Median 24 mo	RB	Median 12 y	Enucleation (n=21)	Chemo (n=8)	RT (n=21)					✓	✓								✓
Peylan-Ramu (84) 2001	28 (45 orbits plus 45 control orbits)	Mean 13.3 mo	RB	7.2–246 mo (median 50 mo)	Enucleation only (n=9) Enucleation with RT (10)	Chemo (n=17)	RT only (n=26) 44–54 Gy					✓	✓
de Jonge (99) 2005	76	2 mo–16 y (mean 4 y 7 mo)		9 mo–20.2 y (mean 6 y 7 mo)	Laminectomy (n=45) or Laminoplasty (n=10)	NA	35–45 Gy (n=43)	✓	✓							✓						✓
Lyle (111) 2007	33	1–82 mo (mean 21.4 mo)	RB 33 U/L	31–251 mo (mean 141.2 mo)	Enucleation with implants	NA	NA					✓
Laverdiere (101) 2009	954 plus 3899 siblings	0–20.7 y (median 0.9 y)	NB	5.7–45.2 ya (median 23.3 y)	All except 16 had surgery	Chemo (n=484)	RT (n=400)	✓								✓	✓				✓
Angelini (108) 2011	98	0–150 mo (median 8 mo)	NB	2–23 y (median 7.3 y)	Neurosurgery (n=46)	Chemo (n=89)	RT (n=16)	✓	✓	✓					✓						✓
Lin (114) 2011	18	Mean 29 ± 23 mo	RB	Mean 49 ± 31 mo	Enucleation with implants	NA	NA					✓			✓
Shildkrot (113) 2011	133 (135 orbits)	0.2–9 y (median 2.2 y)	RB (128) others (6)	0.1–9.3 y (median 3.6 y)	All had Enucleation and implants	Chemo (69) Chemo only (49) Chemo+ RT (20)	RT (n=21)							✓				✓			✓

^a= age at study; ✓ = reported late effect or risk factor

ADR: Adriamycin; AMD: Actinomycin-D; CPM: Cyclophosphamide; Co-60: Cobalt-60; CRT: Cranial Radiotherapy; ES: Ewing’s Sarcoma; Gy: Gray; mo: months; NB: Neuroblastoma; OS: Osteosarcoma; NA: Not applicable; POG: Pediatric Oncology Group; RMS: Rhabdomyosarcoma; U/L: Unilateral; VCR: Vincristine; y: year

Spinal Malalignment

Surgeries such as laminectomy for any type of spinal tumor (99), neuroblastoma (52, 100–102) or intraspinal neuroblastoma (103–106), and chest wall resection (107) are associated with spinal malalignment. A study of 954 neuroblastoma survivors treated primarily with surgery reported a 20-year cumulative incidence of 5.8% for scoliosis requiring surgical correction (101). The authors also found that neuroblastoma survivors were 27 times (95% CI: 13.6–53.4) more likely to develop severe scoliosis than their siblings. Laminectomy (Relative Risk [RR]: 11.0; 95% CI: 5.8–21.1), spinal radiotherapy (RR: 5.6; 95% CI: 1.7–18.4) and thoracotomy (RR: 3.1; 95% CI: 1.6–6.1) were independently associated with severe scoliosis (101). In a study of 26 intraspinal neuroblastoma survivors followed for a median of 10 years, Hoover et al. (105) reported scoliosis among 66.7% of those treated with, compared to 36.4% among those treated without, laminectomy.

Follow-up time (52, 99) and concomitant radiotherapy (107, 108) influence the effects of surgery on spinal malalignment. In a study of neuroblastoma survivors, Paulino et al. (52) observed that those treated with laminectomy developed scoliosis after a median of 23 months, and those treated with radiotherapy developed scoliosis after a median of 68.5 months. Among 98 neuroblastoma survivors with symptomatic epidural compression, the prevalence of spinal deformity among those who had chemotherapy, radiotherapy and surgery was 62.5% compared to those who had chemotherapy and surgery (30%) or surgery alone (50%) (108).

Orbital Deformities

Orbital hypoplasia (84, 85, 109–112) and orbital asymmetry (84, 85, 112) occur in retinoblastoma survivors after enucleation. Among 65 retinoblastoma survivors treated with unilateral enucleation, Osborne et al. (109) observed a higher mean percent difference in orbital volume (enucleated – contralateral) among those enucleated at 0–2 years (10.4%) and 3–12 years (9.6%) than those enucleated when older than 13 years of age (3.6%). In a cohort of 54 retinoblastoma survivors treated at a median age of 13 months and followed for a median of 7.5 years, Kaste et al. (85) observed that orbital volume of survivors treated with enucleation alone were smaller than the contralateral orbits (median volume difference = 1.5 cm³; p = 0.01)

There is consistent evidence suggesting that concomitant radiation (83, 112, 113), younger age at enucleation (110, 114), and use of appropriate orbital implants (85, 109–111) impact the effect of enucleation on orbital deformities. Ameniya et al. (83) reported greater differences in size between enucleated and contralateral orbits after an average of 8.8 years of follow-up among 12 retinoblastoma survivors treated with both radiation and enucleation compared to 5 survivors treated with enucleation alone. Another study of 18 unilateral retinoblastoma survivors noted that children younger than 1 year of age at enucleation had higher mean orbital volume differences compared to those treated when older than 1 year of age (1.8 ± 1.5 vs. 0.6 ± 0.6 cm³) (114). Kaste et al. (85) also observed that survivors treated with smaller orbital implants (12–14 mm) had higher prevalence (70%) of orbits with smaller volume than survivors treated with larger orbital implants (16 mm: 60% and 18–22 mm: 50%).

CONCLUSION AND FUTURE DIRECTION

This systematic review summarizes the evidence that describes treatment-related musculoskeletal late effects in childhood cancer survivors. It includes information about both well-established musculoskeletal toxicities and novel musculoskeletal toxicities identified in recent studies. This information provides a foundation for providers who care for these children. Providers can identify children most at risk for adverse musculoskeletal outcomes so that they can target surveillance for outcomes amenable to early intervention (e.g. limb length differences, muscle weakness), or counsel those children and families who will require intervention when they reach skeletal maturity (e.g. mid-facial hypoplasia).

There has been a gradual refinement in therapeutic approaches to reduce late effects (31, 115) and several studies included in this review were instrumental in this process. Identification of adverse musculoskeletal effects after asymmetric and high-dose radiation among children treated for Wilms tumor led to the use of symmetric administration and lowering of radiation dose and restriction of radiation to only those with advanced stage tumor (31). Despite the gradual refinement in therapeutic approaches, many contemporary protocols include the same chemotherapeutic agents used in the past and may also include high-dose radiotherapy for advanced stage disease and radiotherapy for younger patients (31).

Very few studies have evaluated the musculoskeletal late effects of contemporary protocols and most of the studies in our review were conducted in small convenience cohorts. Therefore, continued work is needed to document musculoskeletal outcomes among those treated with newer radiotherapy delivery methods (116), personalized chemotherapy (117), and modern surgical management (118) so that risk factors can be updated for survivors treated on contemporary protocols. Continued observational research will help clinicians identify survivors at high risk of developing musculoskeletal late effects with improved precision and perhaps facilitate the design of interventions structured to ameliorate musculoskeletal late effects.

Abbreviations

ALL

Acute lymphoblastic leukemia

BMD

Bone mineral density

CI

Confidence interval

DNA

Deoxyribonucleic acid

Gy

Gray

HCT

Hematopoietic cell transplant

NHL

non-Hodgkin lymphoma

NWTS

National Wilms Tumor Study

RR

Relative risk

SDS

Standard deviation score

TBI

Total body irradiation