Introduction
Methods
Results
General characteristics of studies
Cardiac outcomes
Author | Country |
N
| Sex (% male) | Diagnosesa | Age (Dx) | Age (follow-up) | Follow-up time | Treatment modality | Outcome assessments | Prevalence/result | Risk factors | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Chemo | Rad | HCST | |||||||||||
Hamada [80] | Japan | 26 | 73% | Mixed | NR | 13.5 [6–22] | 5.6 [1.2–10.7] post-tx | ✓ (NR) | NR | NR | Dobutamine stress ECG | • Group who received higher dose of anthracyclines had lower cardiac function at rest than other groups with lower doses. • Subclinical cardiotoxicity found even in groups with ≥ 200 mg/m2 | • Anthracycline cumulative dose ≥ 200 mg/m2 |
Cheung [79] | HK | 36 | 54% | Leukemia | NR | 15.6 ± 5.5 | 7.0 [3.1–24.3] post-tx | ✓ (100%) | NR | NR | Left ventricular twisting and untwisting motion | • Impairment of LV twisting NR and untwisting motion evident even in those with normal LV ejection | |
Shimomura [78] | Japan | 61 | 49% | Leukemia | 5.7 ± 3.5 | 14.7 ± 3.5 [7.6–25.7] | 8.1 [1.7–12.5] post-tx | ✓ (100%) | ✓ (NR) | NR | ECG, echocardiogram, serum BNP | • Ventricular premature contraction (3.3%) • Reduced exercise tolerance (12.2%) • Abnormal BNP levels (10%) | • Pirarubicin dose ≥ 300 mg/m2 |
Cheung [77] | HK | 100 | 57% | Leukemia | 8.0 [3–13] | 24.1 ± 4.2 | 15.3 ± 5.8 post-tx | ✓ (100%) | ✓ (13%) | ✓ (15%) | Plasma high sensitivity troponin T, conventional, 3D and speckle tracking echocardiogram | • Elevated troponin T (19%) • Worse LV myocardial deformation in survivors than controls | • Cumulative anthracycline dose • Cardiac radiation • Leukemic relapse • Stem cell transplant • CYBA rs4673 polymorphism |
Yu [76] | HK | 32 | 66% | Mixed | NR | 19.3 ± 5.4 | 6.9 [2.2–14.4] post-tx | ✓ (100%) | NR | NR | 3D and 2D speckle tracking echocardiogram | • Impairment of subendocardial circumferential deformation and apical rotation in survivors than controls. | • Cumulative anthracyclines dose |
Yu [75] | HK | 53 | 70% | Mixed | NR | 18.6 ± 5.1 | 7.2 [2.4–16.4] post-tx | ✓ (100%) | NR | NR | 3D speckle tracking echocardiogram | • Lower LV global 3D strain, twist and torsion, and LV regional deformation in survivors than controls | • Cumulative anthracyclines dose |
Cheung [74] | HK | 58 | 57% | Leukemia | 7.6 ± 4.7 | 24.5 ± 4.4 | 16.6 ± 5.8 post-tx | ✓ (100%) | ✓ (14%) | ✓ (14%) | Cardiac MRI, Tissue Doppler Imaging | • Subnormal LV ejection fraction (9%) • Abnormal and subnormal RV ejection fraction in 12% and 34%, respectively • LV fibrosis (9%) • RV fibrosis (38%) | • Cumulative anthracyclines dose |
Li [73] | HK | 94 | 56% | Leukemia | 12.9 ± 6.8 | 22.2 ± 5.5 | 14.9 ± 6.2 | ✓ (100%) | ✓ (12%) | ✓ (12%) | Calibrated integrated backscatter, M-mode, Doppler and speckle tracking echocardiography | • Lower LV diastolic wall strain and stiffer LV myocardium in survivors than controls | • Older age at follow-up |
Li [72] | HK | 49 | 53% | Mixed | 8.1 ± 4.5 | 22.9 ± 5.8 | 14.2 ± 5.4 post-tx | ✓ (100%) | ✓ (2%) | ✓ (2%) | Calibrated integrated backscatter, M-mode, Doppler and speckle tracking echocardiography, plasma proANP | • Left atrial remodeling as characterized by contractile dysfunction and increased fibrosis in survivors than controls. | NR |
Endocrine, metabolic, and fertility outcomes
Author | Country |
N
| Sex (% male) | Diagnosesa | Age (Dx) | Age (follow-up) | Follow-up time | Treatment modality | Outcome assessments | Prevalence/result | Risk factors | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Chemo | Rad | HCST | |||||||||||
Yamashita [71] | Japan | 21 | 71% | Leukemia | [1.3–14.6] | 10.5–22.9 | [1.3–12.5] post-tx | ✓ (100%) | ✓ (100%) | ✓ (24%) | Linear growth, endocrinological analysis, BMD and metabolic bone markers | • Growth at post-treatment was negatively correlated with changes in height Z scores during therapy in pubertal survivors who had received chemotherapy and cranial radiation. • L2-L4 BMD less than the mean (81%) | • Changes in height Z scores during therapy |
Jaruratanas-irikul [70] | Thailand | 85 | 60% | Leukemia | 5.8 ± 3.6 | NR | Up to 6 years post-tx | ✓ (43.5%) | ✓ (37.6%) | NR | Auxological data | • Significant decrease of height trajectory, resulting in a reduction of final height of about one standard deviation or 5 cm from their genetic potential. | • Male sex (decreased height) • Female sex (overweight) |
Ishiguro [69] | Japan | 30 | 100% | Mixed | 10.5 [0.9–15.8] at BMT | 21.9 [15.8–29.6] | 13.3 [7.6–21.2] post-BMT | ✓ (100%) | ✓ (83.3%) | ✓ (100%) | Pubertal development, testicular Leydig cell function and germinal epithelium damage | • Puberty started spontaneously in all (100%) patients. • Normal testosterone levels but elevated luteinizing hormone level (indicating partial Leydig cell dysfunction) in 87% • One survivor (3%) fathered a child after reaching spontaneous puberty. | • Radiation without gonadal shield |
Miyoshi [68] | Japan | 122 | 51% | Mixed | 6.4 [0–15] | 17.3 [4–36] | 8.8 [2–30] post-tx | ✓ (95%) | ✓ (59%) | ✓ (53%) | Anthropometric measurements, BMD, hormone assays | • Endocrine abnormalities detected in 67% • Gonadal dysfunction (49%) • Growth retardation (32%) • Thyroid dysfunction (21%) • Obesity (16%) • Leanness (8%) • Central diabetes insipidus (9%) • Adrenocortical dysfunction (7%) • Low BMD (42%) • Osteoporosis (11%) | NR |
Adachi [67] | Japan | 23 | 48% | CNS tumor | NR (indicated “childhood cancer survivors”) | 14.1 [4.7–22.8] | NR | ✓ (NR) | ✓ (NR) | ✓ (4.34%) Autologous peripheral stem cell transplant | Anthropometric measurements, lipid profile | • BMI above 90th percentile (52%) • Hypercholesterolemia (17%) • Elevated fasting triglycerides (30%) • Hypoadiponectinemia (61%) | • Higher BMI |
Surapolchai [66] | Thailand | 131 | 59% | Leukemia | 4 [1–15] | 10 [4–20] | 1.8 [0.6–6.9] post-tx | ✓ (100%) | ✓ (5%) | No | Anthropometric measurements, oral glucose-tolerance test, genotyping | • Impaired glucose tolerance detected in 7.6% and persisted one year after initial tests • Insulin resistance (31%) | • Older age at screening, obesity at follow-up • PAX4 variant (R129H) |
Lusawat [65] | Thailand | 19 | 74% | CNS tumor | 9.9 ± 4.6 [2.3–14.9] | [8.5–21.1] | 5.8 ± 2.2 post-dx | ✓ (32%) | ✓ (84.2%) | No | Anthropometric measurements, GH stimulation test, ACTH stimulation test, thyroid function test | • Low peak GH (74%) • Cortisol deficiency (35%) • Central hypothyroidism (53%) • Delayed puberty (42%) | • Brain tumor location with direct HP axis involvement |
Tomita [64] | Japan | 51 | 59% | Mixed | 10.5 [0.9–15.9] at HSCT | 26.6 [19.4–34.3] | 15.0 [6.7–27.7] post-HSCT | ✓ (100%) | ✓ (90%) | ✓ (100%) | Anthropometric measurements, glucose and lipid metabolism profiles, abdominal CT and ultrasound, endocrine function, hormones assay | • Obesity (4%) • Underweight (male 30%; female 71%) • Fatty liver (male 37%; female 48%) | • Received cranial radiation before HSCT |
Nishi [63] | Japan | 6 | 33% | Leukemia | 5 [2.7–10.2] | 29.5 [21–40] | 22.4 [15.5–33.9] post-dx | ✓ (100%) | ✓ (100%) | ✓ (50%) | MRI of pituitary gland, endocrinological panel | • Hypogonadism (66.7%) • Primary hypothyroidism (16.7%) | NR |
Sohn [62] | Korea | 98 | 62% | Mixed | 5.9 ± 4.9 | 11.2 ± 4.9 | 5.3 ± 2.9 post-dx 3.9 ± 2.6 post-tx | ✓ (100%) | ✓ (64%) | ✓ (63.3%) | Anthropometric measurements; GH stimulation test, glucose and lipid metabolism profiles | • Overweight or obese (17%) • Metabolic syndrome (19%). • Median body fat percentage was 31.5% • At least one abnormal lipid value (62%) • Hypercholesterolemia (21%) • Hypertriglyceridemia (58%) • Hypertension (27%) | • Cranial radiation |
Hyodo [61] | Japan | 34 | 100% | Mixed | 10.0 [0.7–15.8] at HSCT | 25.1 [18.0–36.0] | 16.3 [6.7–27.7] post-tx | ✓ (100%) | ✓ (100%) | ✓ (100%) | Anthropometric measures, liver ultrasound, glucose and lipid metabolism profiles, hormones assay | • BMI < 18.5 kg/m2 in 32% • Fatty liver in 44% Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. | • Cranial radiation |
Kang [60] | Korea | 28 | 46% | CNS tumor (Germ cell) | 11.5 ± 2.4 | 23.1 ± 4.4 | 11.6 ± 5.0 post-dx 10.9 ± 5.2 post-tx | ✓ (67.9%) | ✓ (96.4%) | No | DEXA, anthropometric measurements, calcium, phosphate, alkaline phosphate activity, sex hormones assay | • Osteoporosis and osteopenia detected in 25% and 42.9%, respectively. • Deficiencies in growth hormone (82%), gonadotrophic hormone (68%), adrenocorticotropic hormone (64%), thyroid hormone (75%), and antidiuretic hormone (68%) | • Lower BMI • Later starting age of adult growth hormone replacement • Male sex • Low lean mass |
Miyoshi [59] | Japan | 53 | 0% | Mixed | 6.3 [0–12.9] | 17.4 [4.0–29.6] | 8.8 [2.3–26.1] post-tx | ✓ (100%) | ✓ (57%) | ✓ (43%) | Anti-Mullerian hormone assay, FSH assay, pubertal development | • Decreased anti-Mullerian hormone level (53%) • Increased FSH level (30%) • Abnormal breast development (17%) •No spontaneous menstruation (26%) | • Total body irradiation • Spinal radiation • Radiation of pelvis or its vicinity |
Choi [58] | Korea | 78 | 44% | Leukemia | Male: 7.2 ± 3.8 Female: 7.7 ± 3.9 | Male: 11.6 ± 3.4 Female: 13.0 ± 3.3 | Male: 4.4 ± 2.5 post-dx Female: 5.4 ± 3.2 post-dx | ✓ (100%) | ✓ (62%) | ✓ (64%) | DEXA, hormones assay, anthropometric measurements | • Lumbar BMD standard deviation scores less than −2 (74%) | • Longer duration of glucocorticoid treatment for GVHD • HSCT • Chronic GVHD • Reduced BMI |
Kojima [57] | Japan | 49 | 55.1% | Mixed | 5.1 [0.2–14.2] | 10.7 [6.0–25.3] | 5.1 [3.0–14.6] post-tx | ✓ (100%) | ✓ (22.5%) | ✓ (32.7%) | Anthropometric measures, glucose and lipid metabolism profiles | • Metabolic syndrome in 6%. At least one and more than two components of metabolic syndrome in 37% and 20%, respectively • Hypertriglyceridemia (57%) • Hypertension (54%) • High fasting blood sugar (18%) | • Female sex |
Han [56] | Korea | 108 | 67% | Mixed | 8.9 ± 4.7 | 20.3 ± 3.0 | 9.2 ± 5.2 post-tx | ✓ (98%) | ✓ (56%) | ✓ (17%) | DEXA | • Severe BMD deficits (16%) • Moderate BMD deficits in at least one bone region (36%) | • Endocrine dysfunction • Shorter duration after treatment completion |
Lee [55] | Korea | 92 out of 423 (overall cohort) | 66% | Mixed | 4.0 [1.8–8.1] | 14.4 [10.8–19.2] | 4.0 [2.2–5.8] post-tx | ✓ (99%) | ✓ (52%) | ✓ (47%) | Thyroid function | • Subclinical hypothyroidism in 24.6% of the overall cohort • Among survivors with subclinical hypothyroidism, 34% had persistent subclinical hypothyroidism | • Radiation treatment to head > 1800 cGy • Radiation to neck and spine • Lymphoma • Brain/ nasopharyngeal tumor |
Adachi [54] | Japan | 65 | 45% | Mixed | 4.8 [1.0–14.3] at HSCT | 15.3 ± 5.1 [6.6–27.9] | With Lipodystrophy: 18.3 [10.8–24.6] post-HSCT Without Lipodystrophy: 8.2 [3.3–26.2] post-HSCT | ✓ (NR) | ✓ (85%) | ✓ (100%) | Liver ultrasound or CT | • Partial lipodystrophy and fatty liver disease in 9.2%, of which half of them had overt diabetes | • Older age • Longer elapsed time following HSCT • Recurrence of underlying malignant disease • History of multiple HSCT • Total body irradiation |
Yoon [53] | Korea | 105 | 54% | Mixed | 13.3 [0.9–22.6] | 19.7 [15.0–26.5] | 6.5 [2.2–22.9] post-dx | ✓ (100%) | ✓ (37%) | ✓ (14%) | Anti-Mullerian hormone assay, FSH assay | • Sex hormone replacement required in 27.1% of female survivors • Decreased Anti-Mullerian hormone level in 51% of female survivors • Hypogonadism (decreased testosterone) in 8.8% of male survivors • Azoospermia and oligospermia in 37.5% and 12.5% of male survivors, respectively. | • High cyclophosphamide equivalent dose in male survivors |
Neurologic and neurocognitive outcomes
Author | Country |
N
| Sex (% male) | Diagnosesa | Age (Dx) | Age (follow-up) | Follow-up time | Treatment modality | Outcome assessments | Prevalence/result | Risk factors | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Chemo | Rad | HCST | |||||||||||
Chan [82] | HK | 37 | 67.6% | Leukemia | [0.8–13] | [12–27] | [5.6–19] | ✓ (100%) | ✓ (100%) | No | Brain MRI, H-MRS | • Leukoencephalopathy (10.8%), infarct (2.7%), hemosiderin (59.4%) • Lower Cho/Cr and NAA/Cr observed in brains with hemosiderin | NA |
Khong [52] | HK | 9 | NR | CNS tumor | 7.8 [3–14] at tx | 10.8 [3–19] | 3.6 [1–6] post-tx | ✓ (100%) | ✓ (100%) | No | Brain MRI with DTI | • White matter at posterior fossa and supratentorial were reduced by 14.6% and 18.4%, respectively, as compared to controls. | • Younger age at treatment (< 5 years) • Longer interval since treatment (> 5 years) |
Khong [51] | HK | 20 | 70% | CNS tumor | 8.6 ± 4.2 [2.9–17.4] | 11.0 ± 4.6 [5.2–18.6] | 2.4 [0.2–5.8] post-tx | ✓ (100%) | ✓ (100%) | No | Brain MRI with DTI | • Correlations found between white matter integrity and age at cranialspinal radiation and dose | • Younger age at radiation |
Chan [81] | HK | 64 | 65% | Leukemia and other solid extracranial neoplasms (mixed) | ALL: 5.2 ± 2.9 [1.2–13.7] Others: 5.9 ± 4.0 [0.5–13.0] | ALL: 17.4 ± 4.6 [6.9–27.6] Others: 15.4 ± 5.5 [7.2–31.8] | ALL: 12.2 ± 3.6 [5.0–18.8] Others: 9.5 ± 4.2 [5.6–20.4] | ✓ (100%) | ✓ (95.2% of ALL) | No | Brain MRI | • 62 lesions consistent with old hemorrhages in 55% of ALL patients • White matter abnormalities (4.8%) • Old infarcts (10.0%) | • Radiation dose • Time since diagnosis |
Khong [50] | HK | 30 | 66.7% | Mixed | ALL without RT: 6.68 ± 6.32 ALL with RT: 6.47 ± 4.35 CNS tumor: 8.52 ± 3.57 | 13.1 [6–22.1] | ALL without RT: 6.38 ± 4.29 ALL with RT: 8.39 ± 4.74 CNS tumor: 3.25 ± 2.26 | ✓ (100%) | ✓ (70%) | NR | Brain MRI with DTI, Neurocognitive tests | • Impaired overall (17%), verbal (10%) and perceptual (20%) IQ • Impaired performance on at least one IQ subtest (53%) | • Radiation dose • Younger age at treatment |
Akira [49] | Japan | 6 out of 1846 (overall cohort) | 66% | Leukemia | [1–15] for the overall cohort [2.1–14.1] for survivors with moyamoya | [3.2–20.9] for survivors with moyamoya | 8.7 years post-dx for the overall cohort [1.5–6.8] post-dx for survivors with moyamoya | ✓ (100%) | ✓ (100%) | NR | Brain CT, MRI and cerebral angiography | • Cumulative incidence of moyamoya was 0.46% ± 0.02% at 8 years post-dx | • Cranial radiation |
Chiou [48] | Taiwan | 32 | 53% | Leukemia | 4.4 ± 2.2 [0.8–10.8] | 13.2 ± 2.5 [8.9–18.9] | 8.74 ± 2.3 [5.3–13.9] post-dx | ✓ (100%) | ✓ (19%) | No | Neurocognitive tests for IQ, memory, executive function, visual spatial, attention, information processing speed and motor skills | • Impaired IQ (15.6%) • Impairment in one or more cognitive domains (27.8%) | NR |
Liang [47] | Taiwan | 56 | 77% | CNS tumor (germ cell) | 11.9 [3.2–19.9] | 17.7 [8.9–29.1] | 6.9 [1.7–17.9] post-tx | ✓ (48%) | ✓ (96%) | No | Neurocognitive tests for IQ, memory, verbal and visual constructional memory, attention, executive function and visual organization | • Patients with tumors in the basal ganglia region had lower IQ than those with tumors in the pineal or suprasellar regions. | • Tumors in the basal ganglia region • Extensive irradiation field • High irradiation dosage |
Kim [46] | Korea | 42 | 60% | Leukemia | 3.8 ± 2.3 | 10.5 ± 2.4 | 6.6 ± 1.3 post-dx | ✓ (100%) | ✓ (43%) | No | Neurocognitive tests for IQ, executive function and attention | • Lower but non-significant IQ in survivors than healthy controls • Worse attention and executive function in survivors than healthy controls. | • Cranial radiation • Male • Younger age at diagnosis |
Yamasaki [45] | Japan | 25 | 52% | CNS tumor | [2.3–15.8] | NR | 7.5 [1.3–24.2] post-dx | ✓ (NR) | ✓ (100%) | No | Brain MRI | • Multiple cavernous angioma (52%) | • Radiation therapy at age younger than 6 years • PNET • Pineoblastoma |
Tay [44] | Malaysia | 101 | 66% | Leukemia | 5.3 ± 3.2 [0.4–12.9] | 11.8 ± 3.8 [4.8–18.0] | 4.1 ± 2.1 [2.0–10.2] post-tx | ✓ (100%) | No | NR | Electrophysiological nerve conduction studies, gross and fine motor function, VIPN | • Both clinical and electrophysiological neuropathy abnormalities (15.8%) | • Intermediate or high-risk stratification treatment arms |
Yamasaki [43] | Japan | 41 | 63% | CNS tumor | 9 [3.3–15.7] | NR | 7.2 [1.2–15.8] months post-dx | ✓ (NR) | ✓ (100%) | No | Brain MRI | • Cystic malacia detected in 26.8% at a median of 30.8 months [14.9–59.3 months] • White matter changes (46%) | • Younger age at radiation • Supratentorial location of tumors |
Secondary malignant neoplasms
Author | Country |
N
| Sex (% male) | Diagnosesa | Age (Dx) | Age (follow-up) | Follow-up time | Treatment modality | Outcome assessments | Prevalence/result | Risk factors | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Chemo | Rad | HCST | |||||||||||
Araki [42] | Japan | 744 | 51% | Retinoblastoma | < 1 year: 48% ≥ 1 year: 52% | NR | SMN: 8.5 [2–36.5] post-dx No SMN: 9.1 [0–49.5] post-dx | ✓ (NS) | ✓ (56%) | No | Records of SMN | • Twenty-one cases (2.8%) developed 23 SMN • Most frequent SMN were osseous or soft tissue sarcomas | • Younger age at diagnosis • Hereditary • Focal therapy • Focal chemotherapy • Systemic chemotherapy • External beam irradiation |
Sun [41] | HK | 1233 | 43% | Mixed | 6.3 [0–20.1] | NR | 5.3 [0–26.1] post-dx | ✓ (NR) | ✓ (NR) | ✓ (NR) | Pathological reports of suspected SMN | • Twelve cases developed SMN with 10-year and 20-year cumulative incidence of 1.3% and 2.9%, respectively. • Most frequent SMN were acute leukemia or myelodysplastic syndrome and central nervous system tumor. • Median interval between diagnosis of primary and SMN was 7.4 [2.1–13.3] years | • Radiotherapy in patients with acute lymphoblastic leukemia |
Ishida [40] | Japan | 1716 | NR | Mixed | [1–15] | NR | Every 2 years | ✓ (100%) | ✓ (NR) | ✓ (NR) | Records of SMN | • Thirty-seven cases of SMN (2%) • Most frequent SMN were AML, MDS, non-Hodgkin lymphoma and CNS tumors • Median latency period from ALL diagnosis to secondary • Cancers was 6 years (range 1–23 years) | • Cranial radiation, especially moderate and high doses • Age at ALL diagnosis > 7 years • Inclusion in more recent protocols |
Fujiwara [39] | Japan | 857 | NR | Retinoblastoma | 0.3 [0.1–1.7] for the 10 patients who developed SMN | NR | 10.3 [7–24.1] post-dx for the 10 patients who developed SMN | ✓ (NR) | ✓ (NR) | No | Secondary osteosarcoma | • Ten cases (1.1%) developed second primary osteosarcoma • The latent period from diagnosis of retinoblastoma until the diagnosis of second primary osteosarcoma was 10.3 [7 to 24.1] years. | NR |
Ishida [38] | Japan | 5387 (5-year survivors) | 57% | Mixed | 5.4 ± 4.5 | 17.9 ± 7.1 | 11.2 [5.0–30.0] post-dx | ✓ (91%) | ✓ (40%) | ✓ (55%) | Records of SMN | • Cumulative incidence of SMN is 1.2% at 10 years and 3.2% at 20 years from the time of primary cancer diagnosis | • Retinoblastoma bone/soft tissue sarcomas allogeneic SCT • Older age at primary diagnosis (> 7 years) • Attained age < 9 years |
Koh [37] | Korea | 102 | 55% | Mixed | 6.6 [0–19.7] | 12.7 [2.5–29.4] | 8.6 [1.2–27.5] | ✓ (NR) | ✓ (NR) | ✓ (NR) | Records of SMN | • Median interval between primary cancer diagnosis and SMN is 4.9 [0.5–18.5], with the shortest interval for AML and MDS | NR |
Lim [36] | Singapore | 1124 | 60% | Mixed | 5.4 [0–20.7] | NR | 3.5 [0–24.1] | ✓ (NR) | ✓ (NR) | ✓ (NR) | Pathological reports of suspected SMN | • Fifteen cases developed SMN (1.3%) • Overall 20-year cumulative incidence of SMNs was 5.3% • Median interval between primary cancer diagnosis and SMN was 3.4 [0.2 to 18.3] years | • Topoisomerase II inhibitor • Osteosarcoma |