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Review Article

Late Toxicity After 3-Dimensional External Beam Radiotherapy Among Children With Cancer: A Systematic Review

Beijer, Josien G.M. MSc*; Teepen, Jop C. PhD*; Streefkerk, Nina MD*; Heijnen, Richard M. BSc*; Janssens, Geert O. MD, PhD*,†; Kremer, Leontien C.M. MD, PhD*,‡; van Dalen, Elvira C. MD, PhD*; Ronckers, Cécile M. PhD*,§

Author Information
Journal of Pediatric Hematology/Oncology: May 2022 - Volume 44 - Issue 4 - p 117-134
doi: 10.1097/MPH.0000000000002445

Abstract

The survival rate after childhood cancer increases steadily.1 At present, the average 5-year survival rate in high income countries is ∼80%.2,3 As more patients are cured, the number of long-term childhood cancer survivors (CCSs) increases.4 Most children receive extensive multimodal treatments.5 Tissue damage caused by, among others, radiation and chemotherapeutic agents, is shown to result in health problems even decades after the initial treatment in a large number of CCSs.6,7

Current knowledge on the extent and impact of tumor-related and treatment-related side effects among CCSs mainly stems from large-scale epidemiologic and clinical studies on patients treated 3 or more decades ago.6–11 These studies included CCSs whose radiotherapy typically was planned based on radiographs and delivered in 2 opposing directions (hereafter referred to as 2-dimensional conventional radiotherapy [2D-RT]), before the large-scale application of computed tomography–based treatment planning.5,12

Such so-called 3-dimensional planned radiotherapy (3D-RT) multibeam treatment planning results in an improved dose delivery to the irregularly shaped tumor. Therefore, a smaller volume of normal tissue receives a high dose.5 As a result, risks of late toxicities are expected to be lower in survivors treated with 3D-RT compared with 2D-RT.13,14 Randomized controlled trails contrasting 2D-RT and 3D-RT are nonexistent for children and rare for adults; of 2 trials among prostate cancer patients15 one showed a lower rate of side effects for 3D-RT16 whereas the other did not.17 On theoretical grounds, concern has been raised about the increased volume of healthy tissue receiving a relatively low dose in 3D-RT techniques, especially intensity-modulated radiotherapy (IMRT), compared with 2D-RT, in view of subsequent tumor risk.18,19 Direct empirical evidence was not available at the time.

Knowledge on the potential late effects in children after 3D-RT is needed. Here, we systematically reviewed the current scientific literature on somatic late toxicity after 3D-RT in children with cancer, to derive a global overview of available evidence.

MATERIALS AND METHODS

Search Strategy and Selection Criteria

We performed a literature search in MEDLINE/PudMed covering January 1, 2000, to April 16, 2019 to identify studies on somatic late toxicity among children after external beam 3D-RT. Searches for radiotherapy, cancer, children,20 late (side) effects and toxicity were combined (Table, Supplemental Digital Content 1, https://links.lww.com/JPHO/A517).

The following inclusion criteria were used: (1) patients were treated for malignant tumors before age 21 (at least 90% of the study population) and survived at least 90 days either from cancer diagnosis or end of treatment; (2) treatment was started in 1995 or later; (3) all included patients were treated with some type of 3-dimensional planned external beam radiotherapy with curative intent (including, eg, IMRT, helical tomotherapy, volumetric arc therapy or 4-dimensional radiotherapy); (4) the authors report on somatic health outcomes that occurred at least 90 days after treatment; (5) study type was randomized controlled trial, cohort study or case series; (6) study population of at least 5 eligible survivors (if a study also included ineligible participants separate results should have been presented for the eligible survivors); (7) original studies (conference proceedings were not eligible); (8) published in English, German, French, Dutch or Spanish language; (9) published from 2000 onwards.

Title/abstract screening of studies identified in the search and full-text screening was performed by 2 independent reviewers (J.G.M.B. and [R.M.H. or E.C.v.D. or C.M.R.]). Disagreements were discussed between the 2 reviewers and if the disagreement persisted, a third reviewer (C.M.R. or E.C.v.D.), was consulted.

In addition, the reference lists of included studies were screened for studies of interest that were not included in the initial MEDLINE/PudMed search. Also, experts in the field were consulted to provide additional relevant literature studies.

Data Extraction and Analysis

Data extraction was performed by 2 independent reviewers (J.G.M.B. and [R.M.H. or E.C.v.D.]). In case of disagreement, the study was reviewed again and discussed. If discrepancies remained, a third reviewer (C.M.R.) was consulted. Data on study characteristics, patient characteristics, treatment data, length of follow-up and late toxicities, including subsequent tumors, were systematically abstracted from the included papers.

The proportion of patients with a late adverse effect as reported in the original studies was calculated as the number of patients with a late effect divided by the total number of patients with an outcome assessment. The 95% confidence intervals of the proportion of patients with a late adverse effect were calculated according to the Wilson method using the Epitools software.21 If no cases of a late adverse effect were identified in a study we used the “Rule of Three,” which is developed specifically to calculate the 95% confidence intervals of a proportion of 0%.22,23

If multivariable risk factor analyses including radiotherapy parameters were presented, this information was extracted.

Risk of Bias Assessment

The risk of bias was assessed by 2 independent reviewers (J.G.M.B. and E.C.v.D.). The used criteria, based on previously described checklists according to evidence-based medicine criteria,24,25 are described in Supplemental Digital Content 2 (Table, https://links.lww.com/JPHO/A518). We assessed selection bias, attrition bias, detection bias and, if applicable, confounding. In case of a persisting disagreement a third reviewer (C.M.R.) was consulted.

RESULTS

Selection of Studies

The search yielded 4958 studies. After title/abstract screening, 800 studies were retrieved for full-text evaluation, of which 788 studies were excluded as they did not meet the inclusion criteria.

One additional study was included based on screening reference lists of all included studies. No additional studies were identified by consultation of experts in the field.

In total, 13 original studies, published between 2007 and 2017, were included in this review (Fig. 1).26–38

F1
FIGURE 1:
Flow chart of included studies. RT indicates radiotherapy.

Characteristics of Included Studies

All eligible studies were cohort studies26–38 (Table 1), one of which retrospectively compared outcomes from a group of 2D-RT-treated patients to 3D-RT-treated patients.29 The number of eligible patients in the included studies varied, if reported (38.5% of all included studies), between 5 and 246. Two studies (15.4%) included >50 patients.29,33 The reported median age at radiotherapy ranged between 4.0 and 14.3 years and median follow-up time ranged between 1.3 and 8.8 years. The treatment period of the included studies varied between 1995 and 2014. Seven studies (53.8%) started inclusion before 2001.27,28,31,33–35,37

TABLE 1 - Characteristics of the Included Studies
Study characteristics
 References Lopez Guerra et al26 Casanova et al27 Louis et al28 Qiu et al29
 Country Spain Italy United States China
 Study design Cohort Cohort Cohort Cohort
 Method of data collection Chart review NM, presumambly chart review Chart review NM, presumambly chart review
 Inclusion period 2007-2010 2000-2009 1996-2005 2003-2013
Study population
 Type of childhood cancer Medulloblastoma Nasopharyngeal carcinoma Nasopharyngeal carcinoma Nasopharyngeal carcinoma
 Total number of eligible patients NM NM, but 30 survived at least 24 months 5 102*
 Total number of patients with outcome evaluation NM 26 5 102
 Died during follow-up NM NM 1 6
 Lost to follow-up NM 4 0 0
 Age at RT, median (range) (y) NM NM 14 (10-17)§ NM
 Follow-up from RT, median (range) (y) NM NM 6.3 (2.5-9.8) NM
Treatment characteristics
 RT type HT NM IMRT IMRT
 Received median RT dose/range at primary tumor (Gy) NM NM 61.2-66 68 (62-70)
 Median RT or number of fractions at primary tumor (Gy/d) NM 1.8 NM (1.8-2.0) 28-33
 Tumor region CSI Head and neck region Primary site and upper neck nodes Head and neck region
 Additional RT region NM NM NM NM
 Organ at risk NM NM Cochlea, parotid glands, brainstem, spinal cord, larynx Brainstem, spinal cord, optic nerve, chiasm and temporal lobe, parotid gland
 Chemotherapy All All All n=99 (97.1%)
 Other treatment NM NM NM NM
Study characteristics
 References Tao et al30 Kandula et al31 Nazmy and Khafaga32 Casey et al33
 Country China United States Saudi Arabia United States
 Study design Cohort Cohort Cohort Cohort
 Method of data collection NM, presumambly chart review Chart review Chart review NM, presumambly chart review
 Inclusion period 2003-2010 2000-2010 2008-2010 2000-2014
Study population
 Type of childhood cancer Nasopharyngeal carcinoma Neuroblastoma Neuroblastoma Neuroblastoma
 Total number of eligible patients 34 NM 12 246
 Total number of patients with outcome evaluation 24 NM 11 SMN n=246 Other: NM
 Died during follow-up 4 NM 2 NM
 Lost to follow-up 10 NM 1 SMN: n=0 Other: NM
 Age at RT, median (range) (y) NM NM NM 4.0 (1.2-17.9)
 Follow-up from RT, median (range) (y) NM NM NM 4.6 (0.7-15.6)# 6.4 (1.3-15.6)#**
Treatment characteristics
 RT type SIB-IMRT 3D-CRT  IMRT VMAT  IMRT IMRT: n=85 (34.6%) 3D-planned APPA: n=161 (65.4%)
 Received median RT dose/range at primary tumor (Gy) NM 21.6 (21.0-30.6) NM 21
 Median RT or number of fractions at primary tumor (Gy/d) NM 1.8 (1.5-2.0) NM 1.5 hyperfractionated (2× daily)
 Tumor region Primary tumor and upper neck area above the caudal edge of the cricoid cartilage Abdomen Abdomen Abdomen (94%); thorax/mediastinum (6%)
 Additional RT region NM NM Total body irradiation: n=1 (8.3%) Metastatic sites: n=157 (63.8%) (consolidative)
 Organ at risk Brainstem, spinal cord, optic nerve and chiasm, temporal lobes, pituitary gland Kidneys, liver Kidneys, liver NM
 Chemotherapy NM All All All
 Other treatment NM Surgery: all HSCT: all Immunotherapy/antibody treatment: NM Cis-retinoic acid: NM aHSCT: all Surgery: all Surgery: all HSCT: n=75 (30.5%) Therapeutic MIBG: n=29 (11.8%) 3F8 plus granulocyte-macrophage colony-stimulating factor and isotretinoin: NM
Study characteristics
 References Lockney et al34 McDonald et al35 Pinnix et al36 Casey et al37
 Country United States United States United States United States
 Study design Cohort Cohort Cohort Cohort
 Method of data collection NM, presumambly chart review Chart review Chart review Chart review
 Inclusion period 1999-2014 2000-2007 2006-2010 1998-2009
Study population
 Type of childhood cancer Rhabdomyosarcoma Rhabdomyosarcoma Desmoplastic small round cell tumor Multiple
 Total number of eligible patients 30 20 8 NM
 Total number of patients with outcome evaluation 28-30†† NM 7 242
 Died during follow-up NM 5 3 18
 Lost to follow-up 0-2 NM 1 0
 Age at RT, median (range) (y) 7.4 (1.5-20.8) 8 or 9 (2-19)‡‡ 14.3 (6.0-23) 8.8 (0.6-21.4)
 Follow-up from RT, median (range) (y) 7.7 (1.2-14.4) 2.4 (0.8-7.4) 1.3 (0.3-3.8)§§ 8.8 (5.1-27.6)#** 7.9 (5.0-14.3)**∥∥
Treatment characteristics
 RT type IMRT IMRT (cone-down boost technique (n=14 (70%)) WAP-IMRT IMRT
 Received median RT dose/range at primary tumor (Gy) 50.4 (36-50.4) NM 30 50.4 (9.0-111.6)
 Median RT or number of fractions at primary tumor (Gy/d) 1.8 NM 1.5 NM
 Tumor region Head and neck region: parameningeal: n=24 (80.0%); orbit: n=4 (13.3%); neck: n=1 (3.3%); buccal: n=1 (3.3%) Head and neck region Abdomen pelvis Multiple: CNS, head and neck, thorax, abdomen, pelvis, extremities
 Additional RT region NM NM n=1 (12.5%) liver; n=1 (12.5%) liver, esophageal lymph nodes and skull; n=1 (12.5%) thoracicvertebral body; n=1 (12.5%) mediastinum and supraclavicular fossa) (all recurrent disease) NM
 Organ at risk NM NM Vertebral bodies, pelvic bones, liver, bilateral kidneys and spinal cord NM
 Chemotherapy All All All hyperthermic intraperitoneal chemotherapy: n=7 (87.5%) n=213 (88%)
 Other treatment Surgery: n=6 (20.0%) Surgery: n=5 (25%) Surgery: all NM
Study characteristics
 Reference Peñagarícano et al38
 Country United States
 Study design NM
 Method of data collection NM, presumambly chart review
 Inclusion period >2002
Study population
 Type of childhood cancer Multiple
 Total number of eligible patients NM
 Total number of patients with outcome evaluation 15¶¶
 Died during follow-up 2
 Lost to follow-up 0
 Age at RT, median (range) (y) 13 (2.5-21)¶¶##
 Follow-up from RT, median (range) (y) 1.4 (0.3-4)¶¶##
Treatment characteristics
 RT type HT
 Received median RT dose/range at primary tumor (Gy) 36 (15-40)¶¶##
 Median RT or number of fractions at primary tumor (Gy/d) 1.8 (1.5-2.0)¶¶##
 Tumor region CSI
 Additional RT region NM
 Organ at risk NM
 Chemotherapy n=12 (80%)
 Other treatment Surgery: n=8 (53.3%)
*Seventy-four patients received 2D-RT.
Of subgroup of 30 patients who survived at least 24 months.
n=5 died but unclear if this was before or after 90 days.
§Age at diagnosis.
Not mentioned when characteristic was reported (for instance at diagnosis, at start treatment or at start follow-up).
It is not clear if the dose is the actual received dose or the prescribed dose.
#Follow-up from date of diagnosis.
**For alive/surviving patients.
††Deviating number of patients for the following outcomes: cataract, n=29; central hypothyroidism, n=29; primary hypothyroidism, n=29; thyroid nodule, n=28.
‡‡Both numbers (8 and 9) are mentioned by the authors of the original paper.
§§Follow-up from end of RT.
∥∥Follow-up from initiation of RT.
¶¶Calculated by first author of this paper, based on information reported in the study.
##Malignant and benign tumors are both described, only certain malignant are included (15 of the 18).
2D-RT indicates 2-dimensional conventional radiotherapy; 3D-planned APPA, 3-dimensional planned anterior-posterior-posterior-anterior; 3D-CRT, 3-dimensional conformal radiation therapy; CNS, central nervous system; CSI, craniospinal axis irradiation; HSCT, (autologous) haematopoietic stem cell transplantation; HT, helical tomotherapy; IMRT, intensity-modulated radiation therapy; MIBG, meta-iodobenzylguanidine; NM, not mentioned; RT, radiotherapy; SIB, simultaneous integrated boost; SMN, second malignant neoplasms; VMAT, volumetric modulated arc therapy; WAP, whole abdominopelvic.

Included Patient Group

Most studies included survivors of a specific primary childhood cancer type (n=11, 84.6%),26–36 mostly nasopharyngeal carcinoma (n=4 studies, 30.8%),27–30 followed by neuroblastoma (n=3 studies, 23.1%).31–33 Other studies included rhabdomyosarcoma (n=2, 15.4%),34,35 medulloblastoma (n=1, 7.7%)26 and desmoplastic small round cell tumor (n=1, 7.7%).36 Two studies included several types of tumors (n=2, 15.4%).37,38

Characteristics of Radiotherapy and Other Treatments

The included studies involved patients with radiotherapy to several locations; the head and neck area was represented most often (n=6 studies, 46.2%)27–30,34,35 (Table 1). Radiotherapy was delivered by an IMRT technique only (n=7 studies, 53.8%),28,30,34–37,39 helical tomotherapy only (n=2 studies; 15.4%),26,38 or mixed radiotherapy techniques (n=2 studies; 15.4%).32,33 For one study (7.7%), it was not clear what technique was used.27 The administered target dose and daily doses varied. All studies described multimodal treatments, as expected in current clinical practice, although not all reports explicitly stated the proportion of eligible patients who received treatments other than radiotherapy; for details see Table 1.26–38

Health Outcomes: Definitions and Assessment Methods

Table 2 shows the categories of late toxicity that were reported by the authors of the studies. Seven studies (53.8%) also graded severity of the reported outcomes26,28–31,34,38 (Table 3), either according to the Common Terminology Criteria for Adverse Events (CTCAE) (n=4, 30.8%, different versions)28,29,34,38 or the Radiation Therapy Oncology Group (RTOG) toxicity grading scale (n=3, 23.1%).26,30,31 One study additionally graded facial disfigurement in “mild,” “moderate,” and “severe” according to custom-made classification criteria34 (Table 3).

T2
TABLE 2:
Schematic Overview of the Organ-specific Outcomes Captured in Reports on Side Effects of 3-Dimensional Planned Radiotherapy in Children
TABLE 3 - Reported Late Toxicities
Track References Type of Cancer (Location) No. Patients With an Outcome Assessment Follow-up From RT, Median (Range) (y) Outcome Definition Late Outcome Proportion, % (95% CI) Grade 1-2 Grade 3-5
Any late toxicity Lopez Guerra et al26 Medulloblastoma NM NM RTOG Grade ≥2 late toxicities n=0*
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Any morbidity n=17; 65.4% (46.2%-80.6%)
Pinnix et al36 Desmoplastic round cell carcinoma (abdominopelvic) 7 1.3 (0.3-3.8) NM Toxicity after 3 months (grade 3 or 4) n=0; 0.0% (0.0%-42.9%)
Subsequent tumors Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Any SMN n=0; 0% (0%-12.5%)
Nazmy and Khafaga32 Neuroblastoma (abdominal) 9 NM NM Any SMN n=0; 0% (0%-33.3%)
McDonald et al35 Rhabdomyosarcoma (head and neck) NM 2.4 (0.8-7.4)§ NM Any SMN n=0*
Casey et al37 Multiple 242 8.8 (5.1-27.6) 7.9 (5.0-14.3)# NM Any SMN Solid SMN Hematologic SMN n=6; 2.5% (1.1%-5.3%) n=4; 1.7% (0.6%-4.2%) n=2; 0.8% (0.2%-3.0%)
Casey et al33 Neuroblastoma (abdomen; thorax/mediastinum) 246 4.6 (0.7-15.6) 6.4 (1.3-15.6) NM Any SMN (all hematologic malignancies) Any benign tumor (osteochondroma) n=7; 2.8% (1.4%-5.8%) n=6; 2.4% (1.1%-5.2%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Any SMN (acute myeloid leukemia and myelodysplastic syndrome) n=2; 6.7% (1.8%-21.3%) n=2; 6.7% (1.8%-21.3%)
28 Thyroid nodule (benign) n=1; 3.6% (0.6%-17.7%) n=1; 3.6% (0.6%-17.7%)
30 Schwannoma n=1; 3.3% (0.6%-16.7%) n=1; 3.3% (0.6%-16.7%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Any benign tumor (adrenal gland ganglioneuroma) n=1; 3.8% (0.7%-18.9%)
Gastrointestinal Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Xerostomia n=13; 50% (32.1%-67.9%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Xerostomia n=4; 80% (37.6%-96.4%) n=4; 80% (37.6%-96.4%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Xerostomia n=35; 34.3% (25.8%-44.0%); all grade 2-4
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Xerostomia n=16; 66.7% (46.7%-82.0%) n=16; 66.7% (46.7%-82.0%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Caries n=6; 23.1% (11.0%-42.1%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Caries n=3; 60% (23.1%-88.2%) n=3; 60% (23.1%-88.2%)
McDonald et al35 Rhabdomyosarcoma (head and neck) NM 2.4 (0.8-7.4)§ NM Early dental decay n=1*
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Gingival hyperplasia n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Dental problems n=10; 33.3% (19.2%-51.2%)
Pinnix et al36 Desmoplastic round cell carcinoma (abdominopelvic) 7 1.3 (0.3-3.8) NM Esophageal strictures n=1; 14.3% (2.6%-51.3%)
Casey et al33 Neuroblastoma (abdomen; thorax/mediastinum) NM 4.6 (0.7-15.6) 6.4 (1.3-15.6) NM Chronic diarrhea/RT enteritis n=9*
Musculo skeletal Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Trismus n=9; 35% (19.4%-53.8%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Trismus n=2; 40% (11.8%-76.9%) n=2; 40% (11.8%-76.9%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Trismus n=8; 7.8% (4.0%-14.7%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Trismus n=1; 4.2% (0.7%-20.2%) n=1; 4.2% (0.7%-20.2%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Trismus n=4; 13.3% (5.3%-29.7%) n=4; 13.3% (5.3%-29.7%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Osteonecrosis Left mandibular Left sphenoid and mandible n=2; 40% (11.8%-76.9%) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%) n=2; 40% (11.8%-76.9%) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Osteonecrosis (of the mandible) n=0; 0% (0%-12.5%)
Casey et al33 Neuroblastoma (abdomen; thorax/mediastinum) NM 4.6 (0.7-15.6) 6.4 (1.3-15.6) NM Musculoskeletal abnormalities (eg, short stature, slipped capital femoral epiphysis, scoliosis) n=32*
Nazmy and Khafaga32 Neuroblastoma (abdominal) 11 NM NM Skeletal abnormality n=0; 0% (0%-27.3%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) Categorization in ‘mild’, ‘moderate’ and ‘severe’ Facial disfigurement n=23**; 76.7% (59.1%-88.2%)
Mcdonald et al35 Rhabdomyosarcoma (head and neck) NM 2.4 (0.8-7.4)§ NM Bone hypoplasia (at primary site) n=2*
Ear Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Hearing loss n=7; 27% (13.7%-46.1%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Hearing loss n=23; 22.5% (15.5%-31.6%); all grade 2-4
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Hearing loss n=6; 20% (9.5%-37.3%) n=3**; 10% (3.5%-25.6%) n=3**; 10% (3.5%-25.6%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Hearing loss (bilateral conductive hearing loss) n=2; 40% (11.8%-76.9%) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Hearing loss (bilateral conductive and sensorineural hearing loss) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Ototoxicity n=17; 70.8% (50.8%-85.1%) n=15; 62.5% (42.7%-78.8%) n=2; 8.3%(2.3%-25.0%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Eustachian tube dysfunction with chronic effusions n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Otorrhea n=2; 40% (11.8%-76.9%) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Chronic otitis n=6; 20.0% (9.5%-37.3%) n=3; 10% (3.5%-26.6%) n=3; 10% (3.5%-26.6%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Chronic/recurrent sinusitis and otitis n=5; 19.2% (8.5%-37.9%)
Endocrine Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Growth hormone deficiency n=6; 23.1% (11.0%-42.1%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Growth hormone deficiency n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Growth hormone deficiency n=11††; 36.7% (21.9%-54.5%) n=10; 33.3% (19.2%-51.2%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Growth retardation n=2 (2.0%) (0.5%-6.9%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Hypothyroidism n=14; 53.8% (35.5%-71.2%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Hypothyroidism n=5; 100% (56.6%-100%) n=5; 100% (56.6%-100%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 29 7.7 (1.2-14.4) CTCAE, version 4.03 Central hypothyroidism n=7††; 24.1% (12.2%-42.1%) n=6; 20.7% (9.8%-38.4%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 29 7.7 (1.2-14.4) CTCAE, version 4.03 Primary hypothyroidism n=3; 10.3% (3.6%-26.4%) n=3; 10.3% (3.6%-26.4%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM LH/FSH deficiency n=1; 3.8% (0.7%-18.9%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 LH/FSH deficiency n=4††; 13.3% (5.3%-29.7%) n=3; 10.0% (3.5%-25.6%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 [2.5-9.8)§ CTCAE, version 3.0 LH decreased n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Testosterone deficiency n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Pituitary amenorrhea n=1; 4.2% (0.7%-20.2%) n=1; 4.2% (0.7%-20.2%)
McDonald et al35 Rhabdomyosarcoma (head and neck) NM 2.4 (0.8-7.4)§ NM Pituitary dysfunction n=1*
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 ACTH deficiency n=4††; 13.3% (5.3%-29.7%) n=3; 10.0%†† (3.5%-25.6%)
Hematological Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Anemia n=0*
Cardiac McDonald et al35 Rhabdomyosarcoma (head and neck) NM 2.4 (0.8-7.4)§ NM Dilated cardiomyopathy (believed to be related to chemotherapy) n=2*
Skin and connective tissue Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Neck fibrosis n=10; 38.5% (22.4%-57.5%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Neck fibrosis n=22; 21.6% (14.7%-30.5%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Subcutaneous fibrosis n=5; 20.8% (9.2%-40.5%) n=5; 20.8% (9.2%-40.5%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Skin dystrophy n=30; 29.4% (21.4%-38.9%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Skin dystrophy n=5; 20.8% (9.2%-40.5%) n=5 (20.8%) (9.2%-40.5%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Neck swelling Requiring elective intubation 6 months of intermittent neck swelling n=2; 40% (11.8%-76.9%) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Eye Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Cataract n=0; 0.0% (0%-12.5%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 29 7.7 (1.2-14.4) CTCAE, version 4.03 Cataract n=10; 34.5% (19.9%-52.7%) n=8**; 27.6 (14.7%-45.72%) n=2**; 6.9% (1.9%-22.0%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Myopia n=2; 40% (11.8%-76.9%) n=2; 40% (11.8%-76.9%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Visual disturbance n=6; 20.0% (9.5%-37.3%) n=4; 13.3% (5.3%-29.7%) n=2; 6.7% (1.8%-21.3%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Glaucoma n=1; 3.3% (0.6%-16.7%) n=1; 3.3% (0.6%-16.7%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Amblyopia n=1; 3.3% (0.6%-16.7%) n=1; 3.3% (0.6%-16.7%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Ptosis n=2; 6.7% (1.8%-21.3%) n=2; 6.7% (1.8%-21.3%)
Hepatobiliary Nazmy and Khafaga32 Neuroblastoma (abdominal) 11 NM NM Abnormal liver functions n=2; 18.2% (5.1%-47.7%)
Pinnix et al36 Desmoplastic round cell carcinoma (abdominopelvic) 7 1.3 (0.3-3.8) NM Abnormal liver function (Elevated liver function tests with active hepatic disease) n=1; 14.3% (2.6%-51.3%)
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Late elevation of liver enzymes n=0*
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Signs or symptoms of sinusoidal obstruction syndrome (or venoocclusive disease) n=0*
Nervous system Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Parasthesias below left ear n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Radiation encephalopathy n=4; 3.9% (1.5%-97%)
Qiu et al29 Nasopharyngeal carcinoma 102 NM CTC, version 3.0 Cranial nerve palsy n=4; 3.9% (1.5%-97%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Neuropathy n=0; 0.0% (0%-12.5%)
Tao et al30 Nasopharyngeal carcinoma 24 NM RTOG radiation morbidity scoring criteria Temporal lobe necrosis n=0; 0.0% (0%-12.5%)
Renal Nazmy and Khafaga32 Neuroblastoma (abdominal) 11 NM NM Elevated creatinine n=1; 9.1% (1.6%-37.7%)
Pinnix et al36 Desmoplastic round cell carcinoma (abdominopelvic) 7 1.3 (0.3-3.8) NM Elevated creatinine n=0; 0.0% (0.0%-42.9%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Renal dysfunction n=1; 3.8% (0.7%-18.9%)
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Ipsilateral kidney hypoplasia/atrophy and/or loss of function n=2*
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Contralateral kidney injury n=0*
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Proteinuria n=0*
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Albuminem n=0*
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Hyperfiltration injury n=0*
Nazmy and Khafaga32 Neuroblastoma (abdominal) 11 NM NM Abnormal renal functions n=0; 0% (0%-27.3%)
Nazmy and Khafaga32 Neuroblastoma (abdominal) 11 NM NM Abnormal contrast enhancement evaluation of the kidneys (on CT scan) n=0; 0% (0%-27.3%)
Pinnix et al36 Desmoplastic round cell carcinoma (abdominopelvic) 7 1.3 (0.3-3.8)# NM Blood urea nitrogen n=0; 0% (0%-42.9%)
Respiratory Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Pulmonary fibrosis n=4; 15.4% (6.2%-33.5%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Pulmonary fibrosis (right upper lobe) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Voice changes (with decreased vocal cord motility) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Voice changes n=2; 6.7% (1.8%-21.3%) n=2; 6.7% (1.8%-21.3%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Chronic sinusitis n=2; 40% (11.8%-76.9%) n=2; 40% (11.8%-76.9%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Chronic sinusitis n=7; 23.3% (11.8%-40.9%) n=6; 20.0% (9.5%-37.3%) n=1; 3.3% (0.6%-16.7%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Chronic/recurrent sinusitis and otitis n=5; 19.2% (8.5%-37.9%)
Casanova et al27 Nasopharyngeal carcinoma 26 NM NM Recurrent pneumothorax n=2 (7.7%) (2.1%-24.1%)
Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Recurrent aspiration pneumonia n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Peñagarícano et al38 Multiple types 15‡‡§§ 1.4 (0.3-4)§‡‡§§ CTC, version 3 Symptomatic acute radiation pneumonitis n=0; 0% (0.0%-20.0%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Nasal congestion n=3; 10.0% (3.5%-25.6%) n=3; 10.0% (3.5%-25.6%)
Lockney et al34 Rhabdomyosarcoma (head and neck) 30 7.7 (1.2-14.4) CTCAE, version 4.03 Epistaxis n=4; 13.3% (5.3%-29.7%) n=4; 13.3% (5.3%-29.7%)
Vascular Louis et al28 Nasopharyngeal carcinoma 5 6.3 (2.5-9.8)§ CTCAE, version 3.0 Deep venous thrombosis (left subclavian) n=1; 20% (3.6%-62.4%) n=1; 20% (3.6%-62.4%)
Kandula et al31 Neuroblastoma (abdominal) NM NM RTOG/EORTC Hypertension n=0*
*Number of patients with an outcome assessment is not specified for this outcome, so proportion and confidence interval cannot be calculated.
Number or percentage is calculated by first author of this review.
Follow-up from end of RT.
§Not mentioned when characteristic was reported (for instance at diagnosis, at start treatment or at start follow-up).
Follow-up from date of diagnosis.
For alive/surviving patients.
#Follow-up from initiation of RT.
**Different numbers are mentioned in the study.
††For 1 patient the grade was not reported.
‡‡Calculated by first author of this paper, based on information reported in the study.
§§Malignant and benign tumors are both described, only certain malignant are included (15 of the 18).
ACTH indicates adrenocorticotropic hormone; CI, confidence interval; CT, computed tomography; CTC, Common Toxicity Criteria; CTCAE, Common Terminology Criteria for Adverse Events; EORTC, European Organization for Research and Treatment of Cancer; FSH, follicle-stimulating hormone; LH, luteinizing hormone; NM, not mentioned; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group (RTOG) toxicity grading scale; SMN, subsequent malignant neoplasm.

Frequency of Reported Health Outcomes

As the studies were not comparable with regard to age, sex, follow-up period, treatment, toxicity of interest, including definitions used, data pooling was not possible. Accordingly, results were expressed descriptively, as proportions of affected patients. Medical context needed for a reliable interpretation of the results, like treatment age and detailed descriptions of radiotherapy characteristics, was either not clearly reported, or varied considerably between studies.

Table 3 shows an overview of the findings regarding specific health outcomes for each of the included studies, including findings on overall morbidity/toxicity from 3 studies.26,27,36 Below, we provide a summary of results on health outcomes reported in 2 or more included studies.

Subsequent Tumors

Subsequent tumors were targeted in 7 studies with a median study follow-up, if reported, of 4.6 to 8.8 years.27,30,32–35,37 In 4 of the 7 studies, 1 or more subsequent tumors were identified.27,33,34,37 Six studies reported on subsequent malignant neoplasms (SMNs).30,32–35,37 Six SMNs were observed among 242 survivors of any childhood cancer (2.5% after a median follow-up of 8.8 y from diagnosis) of which 4 were solid tumors (1.7%), all occurring in a prior radiotherapy field, and 2 were hematologic SMNs (0.8%).37 In 2 further reports among neuroblastoma and rhabdomyosarcoma patients, hematological SMNs (proportions of 2.8% and 6.7% after a median follow-up of 4.6 and 7.7 y, respectively) were observed among patients also receiving chemotherapy.33,34 In the 3 remaining small studies (9 to 24 patients), no subsequent tumors were identified during a median follow-up time of, if reported, 2.4 years.30,32,35

Three studies reported on subsequent benign tumors, including 6 osteochondromas in 246 high-risk neuroblastoma patients (2.4%; median follow-up: 4.6 y)33; 2 benign tumors (a schwannoma [3.3%] in the prior radiation field and a thyroid nodule [3.6%]) among 30 head and neck rhabdomyosarcoma patients (median follow-up: 7.7 y),34 and 1 adrenal gland ganglioneuroma among 26 nasopharyngeal carcinoma patients (3.8%; follow-up period unknown).27

Endocrine-related Outcomes

Three studies addressed growth hormone deficiency including 5 to 30 patients with nasopharyngeal carcinoma or rhabdomyosarcoma with a median follow-up, if reported, ranging between 6.3 and 7.7 years,27,28,34 and percentage of affected patients ranging from 20% to 36.7%.27,28,34

Thyroid hormone axis abnormalities were reported in 3 studies27,28,34 including 5 to 29 eligible patients and with a median follow-up, if reported, ranging from 6.3 to 7.7 years. Hypothyroidism was assessed in 2 studies after nasopharyngeal carcinoma and it occurred in 53.8% and 100% of patients,27,28 respectively, while central hypothyroidism (24.1%) and primary hypothyroidism (10.3%) were reported among 29 rhabdomyosarcoma patients.34

Two studies described luteinizing hormone and follicle-stimulating hormone deficiency,27,34 affecting 3.8% of 26 nasopharyngeal carcinoma patients (follow-up period not reported)27 and 13.3% of 30 head and neck rhabdomyosarcoma patients (median follow-up: 7.7 y).34

Outcomes of the Musculoskeletal System, Connective Tissues, and Skin

Trismus was evaluated in 5 studies in head and neck cancer patients, with study size ranging between 5 and 102 patients and a median follow-up of, if reported, 6.3 to 7.7 years. In these studies, the percentage of affected patients ranged between 4.2% and 40%.27–30,34

Osteonecrosis was addressed in 2 studies among 5 and 24 eligible nasopharyngeal carcinoma patients with a median follow-up, if specified, of 6.3 years.28,30 Affected bones in one study28 included the left mandibula, the left sphenoid and the mandible,28 while osteonecrosis of mandible was not reported in the other study (0%).30

Furthermore, of 246 nasopharyngeal carcinoma patients, 32 (13%) had at least 1 musculoskeletal-related abnormality (including short stature, slipped capital femoral epiphysis, or scoliosis) after a median follow-up of 4.6 years,33 while none (0%) of 11 neuroblastoma patients were affected by skeletal abnormalities (follow-up period unknown).32

Three studies assessed fibrosis in 24 to 102 nasopharyngeal carcinoma patients27,29,30 of whom 21.6%29 and 38.5%27 were affected by neck fibrosis and one study described subcutaneous fibrosis in 20.8% of the patients.30 Follow-up periods were not reported.

Skin dystrophy affected 29.4% of 10229 and 20.8% of 2430 nasopharyngeal carcinoma patients (follow-up periods not reported).

Respiratory Outcomes

Two studies among 5 and 26 nasopharyngeal carcinoma patients assessed pulmonary fibrosis reporting affected proportions of 15.4%27 (follow-up period not reported) and 20% after a follow-up 6.3 years, respectively.28

Voice changes, after a follow-up of 6.3 and 7.7 years, were reported among 20% of 5 nasopharyngeal carcinoma patients28 and 6.7% of 30 head and neck rhabdomyosarcoma patients.34 In the same studies, 40.0%28 and 23.3%34 of patients, respectively, were affected by chronic sinusitis.

Gastrointestinal Outcomes

Xerostomia was evaluated in 4 studies and occurred in 34.3% to 80% of 5 to 102 included nasopharyngeal carcinoma patients.27–30 One study reported a follow-up period (6.3 y).28 Caries was assessed in 2 studies, among patients treated with 3D-RT to the head and neck region27,28 and affected 23% of 26 eligible patients; follow-up period not reported27 and 60% of 5 eligible patients with median follow-up of 6.3 years.28

Hepatobiliary and Renal Outcomes

Liver function abnormalities occurred in 18.2% of neuroblastoma patients (follow-up period not reported)32 and among 1 of 7 patients with abdominopelvic desmoplastic small round cell tumor (14.3%) after a median follow-up period of 1.3 years.36

Elevated creatinine levels were assessed in 2 studies after 3D-RT to the abdominal region32,36; in one study also radiotherapy to the pelvic region was administered.36 The proportion of elevated creatinine levels were 0% (in 7 patients after a median follow-up: 1.3 y)36 and 9.1% (in 11 patients), respectively.32

Outcomes Involving the Eye and Ear/Hearing

Cataract was assessed in 2 studies among 29 rhabdomyosarcoma patients (34.5%) and among 24 nasopharyngeal carcinoma patients (0%).30,34 Hearing loss was described in 4 studies among 5 to 102 head and neck cancer patients.27–29,34 The median follow-up ranged, if reported, from 6.3 to 7.7 years. Hearing loss affected 20% to 40% of the patients. Of note, though, ototoxic chemotherapy (cisplatin) was reported as part of the treatment for nearly all eligible patients in 3 studies (97.1%29 to 100%27,28) and the fourth study reported known platinum agent or vincristine administration for 6 of the 7 affected patients.34

Comparison 2D-RT With 3D-RT

Only one paper included a direct comparison of the prevalence of late toxicities after 2D-RT versus those after IMRT, based on 176 patients (IMRT, n=102; 2D-RT, n=74) with nasopharyngeal cancer, though in a nonrandomized manner.29 Both groups of patients were treated between 2003 and 2013 with an overall median follow-up time of 4.3 years (range: 0.3 to 11.3 y). Two outcomes (xerostomia [IMRT: n=35 {34.3%}; 2D-RT: n=39 {52.7%}; P=0.015] and hearing loss [IMRT: n=23 {22.5%}; 2D-RT: n=30 {40.5%}; P=0.010]) were found to occur more frequently among the 2D patients (P=0.05) according to the Pearson χ2 test reported by authors of the original study. Other evaluated toxicities were not significantly different (Table, Supplemental Digital Content 3, for details, https://links.lww.com/JPHO/A519).

Risk of Bias Assessment of the Included Studies

Details on risk of bias assessment are shown in Table 4.

TABLE 4 - Risk of Bias Assessment of the Included Studies
Selection Bias Attrition Bias Detection Bias Confounding
Is the Study Group Representative? Is the Follow-up Adequate? Are the Outcome Assessors Blinded for Important Determinants Related to the Outcome? Are the Analyses Adjusted for Important Confounding Factors?
References Yes/No/Unclear Yes/No/Unclear Yes/No/Unclear Yes/No/Unclear/NA
Lopez Guerra et al26 ? ? ? NA
Casanova et al27 ? + ? NA
Louis et al28 + + ? NA
Qiu et al29 + + ? NA
Tao et al30 + ? NA
Kandula et al31 ? ? ? NA
Nazmy and Khafaga32 + + ? NA
Casey et al33 + Overall ? SMN + ? NA
Lockney et al34 + + ? NA
McDonald et al35 + ? ? NA
Pinnix et al36 + + ? NA
Casey et al37 ? + ? NA
Peñagarícano et al38 ? + ? NA
NA indicates not applicable; SMN, second malignant neoplasms; -, no; +, yes; ?, unclear.

Selection Bias

The study group was representative in 8 studies (61.5%),28–30,32–36 that is, low risk of selection bias. In the remaining 5 studies (38.5%),26,27,31,37,38 the description of the study group and thus the risk of selection bias was unclear.

Attrition Bias

Completeness of follow-up was adequate in 8 studies (61.5%)27–29,32,34,36–38 and for one outcome in one study (7.7%),33 that is, low risk of attrition bias. In one study (7.7%),30 the follow-up was not adequate, that is, high risk of attrition bias. In 4 studies (30.7%),26,31,33,35 the number of patients with an outcome assessment and thus the risk of attrition was unclear.

Detection Bias

No study mentioned whether the outcome assessment was performed by an assessor who was blinded for the important determinants (type of radiotherapy, radiotherapy field, and radiotherapy dose). Therefore, in all 13 studies (100%), the risk of detection bias was considered unclear.26–38

Confounding

None of the studies presented a multivariable risk factor analyses, therefore, this criterion was not applicable for all studies (100%).26–38

DISCUSSION

This systematic review summarized for the first time, the current reported evidence on the proportions of somatic late toxicity, including subsequent tumors, among children with cancer who were treated with 3D-planned radiotherapy. Our results show that a wide variety of late toxicities and proportions of affected survivors are reported on, for instance subsequent tumors, gastrointestinal, musculoskeletal, ear, and endocrine disorders. Of interest, only 3 studies to date provided a comprehensive assessment of any late toxicity among children treated for either medulloblastoma, nasopharyngeal carcinoma, or abdominopelvic desmoplastic round cell carcinoma. Also, only one study included a comparison group not treated with 3D-RT.29 The characteristics reported in the eligible studies are heterogenous (Table 1) so we were unable to pool the data. As a result, the current evidence from studies meeting the inclusion criteria of our review is inconclusive with respect to possible differences in late toxicity between 2D-RT and 3D-RT.

Since the dosage to the healthy tissue is lower in 3D-RT while at the same time the volume of healthy tissue receiving a low dose is higher compared with conventional treatments, a direct comparison of late toxicities among survivors of childhood cancer treated with 3D-RT versus those treated with 2D-RT is of great interest. In one report authors directly compared children treated with 3D-RT versus 2D-RT for nasopharyngeal carcinoma and showed lower frequencies of all late toxicities in 3D-RT; statistical significance was reached for xerostomia and hearing loss only.29 Of concern though, it is not clear from the report on what basis radiotherapy allocation occurred and whether the groups were similar in follow-up time and other potential important factors (eg, chemotherapy regimens or disease stage), each of which may have affected the probability of developing or detection of late toxicities.

The results of our review should be interpreted in light of several additional considerations. The numerical results per organ system are summarized systematically here, to provide an overview of present evidence. Of note, though, the study cohorts were generally small and follow-up times were fairly limited or outright too short for meaningful interpretation of findings. This can partly be explained by clinical reality; specific childhood cancer types for which radiotherapy is indicated typically represent rare diseases. Moreover, 3D-RT was introduced to pediatrics gradually and fairly recently. Since multivariable analyses, accounting for demographic factors and other anti-cancer treatments were not reported on, we were not able to draw firm conclusions. Reported frequencies of late toxicity varied widely. As the included studies were very heterogenous with regard to type of treatment, type of childhood cancer and outcome definitions, a meta-analysis for the crude rates was also precluded.

Of note, not all conditions occurring after radiotherapy are necessarily causally related to radiation exposure because multiple other etiologic factors potentially affect disease risk, including preexisting morbidities, other treatments (including chemotherapy), and genetic and behavioral risk factors.

The majority of included studies described late toxicity after childhood cancer types that are relatively rare in the western world. More specifically, the studies meeting the inclusion criteria for this review (eg, nasopharyngeal carcinoma [4 studies, 30.8%] and desmoplastic round cell tumors [1 study, 7.7%]), reflect only about 20% of the cancer types encountered in current clinical practice,40–42 whereas tumor types typically treated with radiotherapy in contemporary practice, such as central nervous system tumors, rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, Wilms’ tumors, and Hodgkin lymphomas, were underrepresented.43,44 Therefore, results of this review reflect late toxicities in a subgroup of CCSs receiving radiotherapy since 2000 globally, and, therefore, may not be generalizable to the general population of CCSs.

Finally, the initial comprehensive literature search yielded nearly 5000 potentially eligible records, including many case reports, case series and clinical/observational reports on children with specific tumors treated with 3D-RT with details on radiation dose characterization and some information on toxicity. Unfortunately, many such reports did not fit all predefined eligibility criteria for this review, sometimes related to incomplete reporting of study design aspects or relevant patient characteristics required to apply the eligibility criteria. By applying these eligibility criteria, this systematic review derived a global overview of available evidence. Further systematic literature summaries of evidence pertaining to 3D-RT for specific childhood cancer types, and/or radiotherapy techniques used, and health outcomes are highly encouraged. Ideally, based on predefined search methodology and inclusion criteria that are reported transparently, as well as a critical assessment of study methodology, with regard to risk of bias and their impact on the translation of the resulting findings into clinical medicine, according to common practice in systematic reviews.

Radiotherapy remains a rapidly evolving, highly technological field, that continues to hold great promise for continually improving patient outcomes, in terms of balancing tumor control with diminished impact of acute and late side effects, typically based on solid theoretical grounds and evidence from dosimetric studies and projection modeling.45

To get better insight in the differences in potential late effects after various types of radiotherapy methods, including proton therapy,46–48 retrospective and prospective (international) studies are needed by using harmonized protocols for data registration, definition and measurement of radiation exposure (ie, organs at risk) and health outcomes,49,50 as well as applying reporting practices that adhere to common standards, such as STROBE (statement to Strengthening the Reporting of Observational Studies in Epidemiology).51

In conclusion, although children treated with protocols including 3D-RT are at risk of developing a broad variety of late health problems, unfortunately, precise and valid estimates of the frequency and risk factors for late toxicities are unclear to date. It is important to monitor late toxicity with uniform outcome definitions among all children who were treated with new radiotherapy techniques in well-designed studies, with uniform definitions for radiation exposure and health outcomes.

ACKNOWLEDGMENTS

The authors are grateful to the late Edith Leclercq, Information Specialist for Cochrane Childhood Cancer, for her help with developing the search strategy for this systematic review.

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Keywords:

3-dimensional radiotherapy; 2-dimensional conventional radiotherapy; late toxicity; systematic review; childhood cancer

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