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- Paediatr Neonatal Pain
- v.5(1); 2023 Mar
- PMC9997122
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Paediatr Neonatal Pain. 2023 Mar; 5(1): 1–9.
Published online 2023 Feb 2. doi:10.1002/pne2.12094
PMCID: PMC9997122
PMID: 36911786
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Abstract
Radiotherapy is an important aspect of oncological treatment in several childhood cancers. However, radiotherapy is known to have numerous side effects, including detrimental effects on growth, neurocognitive impairment, and the development of secondary malignancies. One less studied long‐term side effect of pediatric radiotherapy treatment is chronic pain. While the short‐term toxicities of radiotherapy resolve over a few weeks to months, the chronic pain caused by radiotherapy‐induced tissue damage can significantly affect children's quality of life. As long‐term childhood cancer survivors age into adulthood, they are typically followed up by a wide variety of doctors, not all of whom may be familiar with radiotherapy‐induced chronic pain and its management. The aim of this review is to discuss the various common manifestations of radiotherapy‐related pain in children, as well as ways to identify and manage these. Common radiotherapy‐related side effects leading to chronic pain symptoms include radiation fibrosis, enteritis, dermatitis, lymphedema, neuropathic pain, and effects on bone development. The pathophysiology, evaluation and management of these are briefly summarized in this review. This is followed by an overview of radiotherapy techniques that allow greater sparing of normal tissue, minimizing future painful side effects. Finally, the assessment of pain in children is described, as well as strategies for management, and red flag symptoms that should prompt urgent specialist referral. In conclusion, a good understanding of the long‐term side effects of radiotherapy treatment in children is essential for the various medical professionals that follow‐up the child in the years after treatment. For young children, the evaluation of pain is in itself a challenge, and effects on growth, development, and learning are crucial. For older children, social and psychological factors become increasingly important. As radiation therapy techniques continue to advance, the spectrum and incidence of chronic pain syndromes may change over time.
Keywords: pediatric oncology, radiotherapy
1. INTRODUCTION
Radiotherapy is an important aspect of oncological treatment in children. While the use of radiotherapy is declining somewhat in the modern era with increasingly effective chemotherapy treatment, radiation remains a mainstay of the treatment protocol for cancers such as neuroblastoma, Wilms' tumors, retinoblastoma, sarcomas, and central nervous system cancers, among others. For instance, based on SEER data, around 53% of Wilms' tumor patients and 25% of neuroblastoma patients received radiotherapy treatment in 2008.1 As prognosis of childhood cancers continues to improve over the years, with the overall 5year survival rate as high as 80%,2 the long‐term side effects of cancer treatment increase in significance. Radiotherapy is known to be toxic to normal tissue, especially at high doses. Sequalae of radiotherapy can range from hormone dysfunction to cardiac and pulmonary toxicity, decreased fertility, and detrimental impact on physical growth and neurocognitive function, as well as secondary cancers.
One less studied long‐term side effect of pediatric radiotherapy treatment is chronic pain. While the short‐term painful effects of radiotherapy, including acute dermatitis or mucositis, are well documented, these tend to resolve over a few weeks to months;3, 4 whereas the chronic pain caused by radiotherapy‐induced tissue damage can significantly affect children's quality of life. Not only can physical function and activities of daily living be affected, chronic pain may have a detrimental impact on young people's ability to learn, form relationships and integrate into society.5 Identification and management of radiotherapy‐induced chronic pain in children is a complex matter, as patients frequently receive other treatment modalities such as chemotherapy and surgery, which may contribute to pain and complicate management.6 As long‐term childhood cancer survivors age into adulthood, they are typically followed up by a wide variety of doctors—for instance neurologists, orthopedic surgeons, general practitioners; not all of whom may be familiar with radiotherapy‐induced chronic pain and its management. The aim of this review is to discuss the various common manifestations of radiotherapy‐related pain in children, as well as ways to identify and manage these. Where possible, this review has incorporated references from pediatric studies; if these were unavailable, relevant literature from publications in adults has been included.
2. ASPECTS OF RADIOTHERAPY‐RELATED CHRONIC PAIN
2.1. Radiation fibrosis
Radiation fibrosis is a process whereby normal tissue components, responding to radiation‐induced inflammation and damage, are replaced by matrix and collagen fibrils, leading to detrimental effects on normal organ function. Damage can incur to organs in or adjacent to the radiation field; for instance skin, lungs, and GI tract can all be susceptible. Radiation fibrosis typically develops after the first 2 weeks of radiotherapy and may persist for years. For areas receiving high doses, incidence of radiation‐induced fibrosis can be as high as 50%.7 While agents such as pentoxifylline and vitamin E have been mooted for the prevention of radiation fibrosis, their use has been mostly limited to adults.8
Radiation fibrosis has wide ranging effects from cosmesis to functional impairment, and chronic pain can often result. For instance, children receiving radiotherapy to the head and neck area may suffer from trismus and dysphagia. Long term side effects of xerostomia, resulting from radiation dose to salivary glands, may cause chronic discomfort in eating and swallowing.9, 10 Meanwhile, in patients receiving radiotherapy to a limb, fibrosis leading to muscle contracture can result, causing chronic pain and decreasing range of movement.11
While physiotherapy, occupational or speech therapy can help with radiation‐induced fibrosis to the head and neck or limbs, fibrosis resulting from radiation to the GI tract is more difficult to manage and may lead to fistula formation as well as stenosis. In extreme cases obstruction may occur.12, 13 Children suffering from the above may experience chronic discomfort while eating, for instance abdominal cramping or nausea and vomiting. This is especially significant for children as it can lead to malabsorption from the GI tract thus contributing to poor growth.
2.2. Dermatitis
Chronic radiation‐induced dermatitis, both in adults and children, is thought to be caused by an influx of cytokines such as TNF‐alpha, IL‐6, and TGF‐B among others.14 The persistent inflammation and endothelial damage causes restricted vascular perfusion and result in a compromised healing process, skin atrophy, and telangectasia. In severe cases, necrosis and ulceration can result. Reviews have shown that up to 95% of patients receiving radiotherapy have some form of skin toxicity.15 RTOG16 and CTCAE17 grading are used to classify these side effects, which are especially significant where a bolus has been used to increase skin dose.
In a group of patients studied 6–16 months after the end of radiotherapy treatment, 45% experienced a feeling of skin induration, 25% experienced dry skin and 25% experienced pain on palpation.18 For young children, the constant sensation of skin irritation and change in texture can be especially disconcerting—parents may have to employ distraction techniques to stop children from frequently touching or scratching the affected area.19 Meanwhile, for adolescents suffering from radiation‐induced dermatitis, there can be additional self‐image issues resulting from poor cosmesis.20 Thus it can be seen that both chronic pain and psychological trauma may occur from this radiation induced side effect of dermatitis, which is especially obvious to outside observers.
2.3. Enteritis
Radiation enteritis is defined as small or large intestinal injury, occurring as acute or delayed side effects of radiotherapy. Initial intestinal changes can be seen as soon as several hours postradiation, for instance apoptosis, acute inflammation of the lamina propria, injury to the crypts and arterioles.21 In the chronic phase, tissue fibrosis and arteriolar endarteritis can occur, leading to symptoms such as cramping, bloating, nausea, vomiting, diarrhea, and malabsorption. Symptoms can typically be further evaluated by imaging and endoscopy, and managed conservatively. More invasive techniques such as argon plasma coagulation are also known to have been successful in radiation‐induced enteritis.22
While radiation enteritis is more common in adults with up to 50% of patients receiving abdominal radiotherapy reporting some form of impact to quality of life,22 this is less‐frequently reported in children with various case series reporting between 1–6 cases each.12, 23, 24 However, due to the nature of some childhood tumors requiring large field abdominal irradiation, for example neuroblastoma or Wilms' tumor, enteritis is an important side effect to consider in children. Indeed, pain‐free feeding is essential for proper growth and development in the pediatric population.
2.4. Lymphedema
The pathophysiology of lymphedema results from a dysfunction of lymphatic drainage causing retention of fluid and swelling of tissues. Range of movement can be affected and susceptibility to infection may be increased. Radiation causes lymphedema by damaging lymphatic vessels, and causing fibrosis of the lymph nodes themselves.25 Patients frequently have surgery to the lymph node basins as well which may exacerbate this. Both upper and lower limbs may be affected.
Radiation‐induced lymphedema often results in chronic discomfort and compromise of limb function. It is burdensome for the pediatric patient to be fully compliant with the long‐term management of lymphedema—for example wearing of compression garments, or attending appointments for lymphatic drainage procedures. Children may thus be at higher risk of infections, which are also a contributory factor for pain and compromised quality of life.26
2.5. Neuropathic pain
Up to a third of patients are reported to have some form of neuropathic pain from radiotherapy.27 Cranial or peripheral nerve damage, for instance brachial plexopathy, have been reported. Pathophysiology is multifold, including directly damaging nerves via demyelination or injury to axons. Alternatively, indirect damage via radiation‐induced tissue fibrosis, resulting in nerve compression or tissue ischemia, may occur.28 Sites that receive higher doses, for example during the radical treatment of head and neck cancer, can be especially susceptible and symptoms can also be potentiated by the damage caused by chemotherapeutic agents.29 Tingling, pain, numbness, temperature sensitivity and decreased somatosensory input have been reported in children.30 In the developing child, neuropathic pain and sequelae may result in balance, coordination and motor skills being affected. Overall, mobility and quality of life may be reduced.31
2.6. Effects on bone development
In young children, radiation can have a significant effect on bone growth and density due to changes in vasculature and chondrocyte populations, leading to side effects such as limb shortening and increased risk of fracture.32 Doses above 30 Gy result in measurable effects—Indelicato et al. reported a 31% rate of fracture among patients with Ewing's sarcoma who received radiotherapy to weight‐bearing bones.33 Osteoradionecrosis, predominantly affecting the mandible in patients receiving RT at doses >60 Gy, has been researched and reported extensively in adults but little data exists regarding this side effect in the pediatric population. While some degree of toxicity to the bone is inevitable, particularly in cases involving young children receiving higher doses of radiotherapy, use of more conformal radiotherapy techniques have reduced the volume of bone at risk and helped to mitigate this side effect.34 Furthermore, it has been recognized that vertebral radiotherapy should be given hom*ogenously, in younger children who have not yet reached puberty, with the vertebral body receiving a consistent dose. This reduces the risk of spinal problems such as scoliosis, kyphosis and lordosis.35
Table1 summarizes the common symptoms, pathophysiology and evaluation of radiation‐induced chronic pain presentations in children.
TABLE 1
Common chronic pain symptoms experienced by childhood cancer survivors receiving previous radiotherapy.
| Symptom | Pathophysiology | Assessment | Treatment |
|---|---|---|---|
| Radiation fibrosis | Normal tissue components are replaced by matrix and collagen fibrils in response to radiation‐induced inflammation. Damage can incur to organs in or adjacent to the radiation field | Organ specific assessments: e.g., CT thorax for pulmonary fibrosis Swallowing assessment for head and neck fibrosis | Physiotherapy—techniques such as myofascial release Occupational therapy Anti‐inflammatory medications for pain relief |
| Dermatitis | Radiation‐induced inflammation and endothelial damage causes restricted vascular perfusion. This results in a compromised healing process, skin atrophy, and telangectasia. In severe cases, necrosis and ulceration can result | Assessment via CTCAE or RTOG toxicity criteria | Moisturisers Emollients Antihistamines Distraction techniques for severe puritis |
| Enteritis | Small or large intestinal injury. Initial changes due to radiation include apoptosis, acute inflammation of the lamina propria, injury to the crypts and arterioles In the chronic phase, tissue fibrosis and arteriolar endarteritis can occur | Investigations such as OGD, MRI may be used for further evaluation | Nutritional support Medications e.g., loperamide for diarrhoea Argon plasma coagulation for treatment of radiation colitis |
| Lymphedema | Lymphedema may occur due to direct radiation‐induced damage to lymphatic vessels, or fibrosis of the lymph nodes themselves. Frequently exacerbated by surgery to lymph node basins | No specific blood test or imaging required Lymphedema may develop acutely or several months after radiotherapy | Compression garments Manual lymphatic drainage Exercises Lymphaticovenous bypass |
| Neuropathic pain | May be caused by direct radiation damage to nerves, via demyelination or injury to axons. Alternatively, indirect damage via radiation‐induced tissue fibrosis, resulting in nerve compression or tissue ischaemia, may occur | Clinical evaluation: May present as distal parasthesia, associated with weakness. Typically begins slowly, becoming more obvious over several months | Oral analgesics: eg gabapentin, pregabalin, benzodiazepines, tricyclic antidepressants. Surgical interventions: Neurolysis Physiotherapy |
| Investigations: ultrasound studies, MRI scans, nerve conduction studies, blood tests eg calcium, magnesium, vitamin D, electrolytes36 | |||
| Effects on bone health and development | Radiation can lead to significant effects on bone growth and density due to changes in vasculature and chondrocyte populations Risk factors include younger age at radiotherapy treatment and higher doses delivered. A nonhom*ogenous radiotherapy dose delivered to vertebral bodies increases the risk of kyphosis, scoliosis37 | X rays, MRI, bone density (DXA) scans Blood tests: calcium, vitamin D | Nutritional support Ensure adequate mobility Calcium supplementation Antibiotics for osteoradionecrosis Hyperbaric oxygen therapy |
3. REDUCING SIDE EFFECTS—ADVANCEMENT IN RADIOTHERAPY TECHNIQUES
In general, radiotherapy side effects, including chronic pain, are both volume and dose‐dependent. Thus, the volume of normal tissue receiving a high dose can be reduced by more focused radiotherapy techniques.
3.1. Intensity‐modulated radiation therapy
With the advent of intensity‐modulated radiation therapy (IMRT) in the 2000s, a conformal dose distribution can be delivered to the site of the tumor while sparing critical organs. This is particularly important in cases where high doses are required, such as high grade gliomas, nasopharyngeal cancers or sarcomas.38 This has improved treatment outcomes in terms of recurrence‐free survival and overall survival. However toxicities are still significant; for instance Tao et al. reported a 2year postradiation incidence of 66.7% of xerostomia in pediatric patients receiving IMRT for nasopharyngeal carcinoma.39 Furthermore, there is a recognized risk of secondary cancers resulting from the low dose distribution characteristic of IMRT.
3.2. Brachytherapy
Promising quality of life outcomes have been seen in treatments using brachytherapy, where radioactive sources are inserted at the site of the tumor/cavity with a high focal dose delivered to the PTV. In children this is typically given to soft tissue sarcomas, gynecological tumors, or retinoblastomas. Schoote et al.40 reported fewer high grade adverse effects among head and neck rhabdomyosarcoma patients treated with brachytherapy as compared to external beam radiotherapy, with no significant difference in 5year survival. However, delivery of brachytherapy requires specialized training, experience and resources.
3.3. Proton therapy
More recently, proton therapy, with its steep energy fall‐off, has potential to spare the surrounding tissue and deliver the required dose to the tumor itself. Protons have been used in tumors such as medulloblastoma, rhabdomyosarcoma, craniopharyngioma, and ependymomas. Reports, though with small sample sizes, have been promising—Ajithkumar et al. reported no grade 3 toxicities in a series of 16 children with craniopharyngioma.41 Fatigue and skin toxicity are the most commonly reported toxicities. Meanwhile, Yock et al.42 showed PFS and OS results after proton therapy that were comparable to IMRT outcomes in treatment of children with medulloblastoma.43 In patients receiving craniospinal irradiation where treatment volumes are large, protons are helpful in reducing dose to surrounding organs thereby decreasing the risk of toxicity and eventual long term adverse effects. Figures1a,b and 2a,b illustrate an example of a craniospinal irradiation plan using photons versus protons, showing comparative normal tissue sparing in the latter. However, proton therapy is currently not yet a globally available modality. The bulk of pediatric patients treated across the world are still treated using photons. Furthermore, even with advanced radiotherapy techniques, the side effects of tissue damage and chronic pain are inevitable to some extent, hence recognition and management of such effects remains important for physicians and caretakers.
(a) Craniospinal irradiation plan using protons (axial view). (b) Craniospinal irradiation plan usingphotons (axial view). Note the greater dose received by organs at risk (e.g., heart) in (b).
4. ASSESSMENT OF RADIOTHERAPY‐INDUCED PAIN
Measuring pain accurately in children can pose challenges. For children younger than 4, fortunately a small subgroup of those receiving radiotherapy, the FLACC scale is typically used. This refers to Face, Legs, Activity, Cry, Consolability,44 where a child is observed for at least 2–5min and each category is given a score of 0–2 where 0=relaxed and comfortable, while 7–10 cumulative points indicates severe discomfort.
For slightly older children between 4–7 years old, the FACES® Pain Rating Scale‐Revised helps them to rate their pain by showing a series of faces indicating how much discomfort someone is feeling. Children point to the face that represents their degree of pain.45 Meanwhile, older children are typically able to rate their pain on a 0–10 scale (0=no pain, 10=intense pain). The Adolescent Pediatric Pain Tool (APPT) is often used in teenagers as well. It covers 5 subscale scores: the number of pain sites/segments, the pain intensity score, the number of descriptors of pain quality, the number of temporal descriptors, and the percent of total pain quality and temporal descriptors against a total.46
A comprehensive pain assessment should include intensity level for each site of pain, differentiating severity with rest and activity, as well as any temporal, aggravating or relieving factors. Appropriate imaging and laboratory investigations should be considered based on the history and physical examination findings. Function; that is, mobility and limiting factors related to performing activities of daily living, should be assessed as well. Finally, knowledge—both the child's and family members' understanding of pain medications, administration, and side effects is important.47
5. MANAGEMENT OF RADIATION‐INDUCED CHRONIC PAIN
Lu et al.48 assessed 10397 cancer survivors and 3034 sibling controls from the Childhood Cancer Survivor Study, assessing pain conditions, use of prescription analgesics and pain attributable to cancer and treatment. Among these, 21% attributed pain to their cancer and treatment, and the prevalence of pain conditions and use of prescription analgesia was significantly higher than the sibling control subset. Significantly, history of Wilms' tumor, neuroblastoma, bone cancer and soft tissue sarcoma were associated with greater risk of pain, while non‐brain‐directed scatter irradiation was associated with increased migraine risk. Hence it can be seen that treatment of these cancers, requiring multiple modalities including irradiation, contributes to the incidence of chronic pain in these childhood cancer survivors.
The management of acute cancer‐related pain in children has been extensively described, with guidelines surrounding use of opioids.49 However, it is recognized that management of chronic pain is more complex and there is a reluctance by some parents and providers to give opioids long‐term due to fear of side effects.50 Assessing the etiology of the pain is important; with knowledge of the location of the primary tumor and the sites that have received radiotherapy, the practitioner would be better able to prescribe management tailored toward the child's needs. For instance, pain resulting from radiation‐induced fibrosis may respond to anti‐inflammatory medications or muscle relaxants, whereas neuropathic pain may better respond to agents such as gabapentin. Figure3 presents a flowchart for assessment of children presenting with chronic pain after radiation therapy.
The WHO pain ladder,51 beginning with nonopioids + adjuvants and subsequently adding opioids for more severe pain, has been well studied and is now recognized as bi‐directional where de‐escalation of pharmacological therapies can take place depending on the patients' condition. In some cases, specific issues such as poor sleep due to pain may respond to nonanalgesic pharmacological therapies such as melatonin. For radiotherapy‐related chronic pain in particular, pharmacotherapy may go hand in hand with mechanical means of pain management, for example massage therapy for lymphedema or physiotherapy for fibrosis. Other nonpharmacologic types of therapy tie‐in increasingly with chronic pain management, including cognitive behavior therapy, distraction and relaxation, gradually increasing the child's ability to function normally despite the presence of chronic pain.
Use of interventions is typically done as a “last resort” for refractory pain nonresponsive to noninvasive therapies.49 Such interventions include peripheral nerve blocks or plexus blocks, intrathecal infusions or intrathecal neurolysis, cordotomy, cryoablation, and kyphoplasty. Research is also being done on alternatives like low‐level laser therapy and transcutaneous electrical nerve stimulation to treat oral mucositis‐related pain.52 The majority of literature surrounding these interventions consist of case reports, and further randomized controlled trials on such interventions are awaited.
For the parent, general practitioner or social worker involved in the child's care, it is important to recognize the signs and symptoms requiring further investigation on top of the child's chronic pain.42 In general, these would include a sudden onset increase in intensity or change in the nature of pain, or presentation of symptoms such as new onset neurological symptoms, for instance visual changes or cerebellar ataxia, severe headache, persistent vomiting, bony tenderness, muscle or joint swelling, blood in stools or sputum, or persistent weight loss and poor growth. The above symptoms should prompt urgent medical attention, as well as liaison with the child's primary oncologist to evaluate for tumor recurrence.
6. CONCLUSION
In conclusion, a good understanding of the long‐term side effects of radiotherapy treatment in children is essential, not only for the treating radiation oncologist, but also for the various medical professionals that follow‐up the child in the years after the treatment has finished. For young children, the evaluation of pain is a challenge, and effects on growth, development and learning are crucial. For older children, social and psychological factors become increasingly important. This review has aimed to provide an overview of the common manifestations of radiotherapy‐induced chronic pain as well as general management options. As radiation therapy techniques continue to advance and modalities such as proton beam therapy become more widely used, the spectrum and incidence of chronic pain syndromes may change over time. Most crucially, the support of the child's family goes a long way in helping with symptom management—ensuring the child takes their regular medications, implementing physiotherapy, massage, or feeding techniques that have been taught by professionals, and ensuring that the child has a nurturing environment where he or she can grow and learn long after cancer treatment is complete.
CONFLICT OF INTEREST STATEMENT
No conflict of interest was reported by the authors.
Notes
Chua GWY, Vig PS. Overview of radiotherapy‐induced chronic pain in childhood cancer survivors: A narrative review. Paediatr Neonatal Pain. 2023;5:1‐9. doi: 10.1002/pne2.12094 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
REFERENCES
1. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation for pediatric cancers: 1973–2008. Int J Radiat Oncol Biol Phys. 2013;85(3):e151‐e155. [PMC free article] [PubMed] [Google Scholar]
2. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2012. National Cancer Institute; 2015. Accessed August 01, 2022. http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site. [Google Scholar]
3. Majeed H, Gupta V. Adverse Effects of Radiation Therapy. [Updated 2021 Nov 20]. StatPearls [Internet]. StatPearls Publishing; 2022. Accessed August 01, 2022. https://www.ncbi.nlm.nih.gov/books/NBK563259/ [PubMed] [Google Scholar]
4. Berkey FJ. Managing the adverse effects of radiation therapy. Am Fam Physician. 2010;82(4):381‐388, 394. [PubMed] [Google Scholar]
5. Koechlin H, Locher C, Prchal A. Talking to children and families about chronic pain: the importance of pain education‐an introduction for pediatricians and other health care providers. Children (Basel). 2020;7(10):179. doi: 10.3390/children7100179 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
6. Tutelman PR, Chambers CT, Stinson JN, et al. Pain in children with cancer: prevalence, characteristics, and parent management. Clin J Pain. 2018;34(3):198‐206. doi: 10.1097/AJP.0000000000000531 [PubMed] [CrossRef] [Google Scholar]
7. Ramia P, Bodgi L, Mahmoud D, et al. Radiation‐induced fibrosis in patients with head and neck cancer: a review of pathogenesis and clinical outcomes. Clin Med Insights Oncol. 2022;16:11795549211036898. doi: 10.1177/11795549211036898 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
8. Delanian S, Porcher R, Rudant J, Lefaix JL. Kinetics of response to long‐term treatment combining pentoxifylline and tocopherol in patients with superficial radiation‐induced fibrosis. J Clin Oncol. 2005;23(34):8570‐8579. doi: 10.1200/JCO.2005.02.4729 [PubMed] [CrossRef] [Google Scholar]
9. Purkayastha A, Sharma N, Sarin A, et al. Radiation fibrosis syndrome: the evergreen menace of radiation therapy. Asia Pac J Oncol Nurs. 2019;6(3):238‐245. doi: 10.4103/apjon.apjon_71_18 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Vainshtein JM, Griffith KA, Feng FY, Vineberg KA, Chepeha DB, Eisbruch A. Patient‐reported voice and speech outcomes after whole‐neck intensity modulated radiation therapy and chemotherapy for oropharyngeal cancer: prospective longitudinal study. Int J Radiat Oncol Biol Phys. 2014;89(5):973‐980. doi: 10.1016/j.ijrobp.2014.03.013 [PubMed] [CrossRef] [Google Scholar]
11. Rao AD, Ladra M, Dunn E, et al. A road map for important centers of growth in the pediatric skeleton to consider during radiation therapy and associated clinical correlates of radiation‐induced growth toxicity. Int J Radiat Oncol Biol Phys. 2019;103(3):669‐679. doi: 10.1016/j.ijrobp.2018.10.026 [PubMed] [CrossRef] [Google Scholar]
12. Bölling T, Willich N, Ernst I. Late effects of abdominal irradiation in children: a review of the literature. Anticancer Res. 2010;30(1):227‐231. [PubMed] [Google Scholar]
13. Willich N, Ernst I, Pape H, et al. Evaluation of side effects after radiotherapy in childhood and adolescence: from retrospective case reports to a prospective, multicentric and transnational approach. Strahlenther Onkol. 2009;185(Suppl 2):3‐4. doi: 10.1007/s00066-009-1003-2 [PubMed] [CrossRef] [Google Scholar]
14. Spałek M. Chronic radiation‐induced dermatitis: challenges and solutions. Clin Cosmet Investig Dermatol. 2016;9:473‐482. doi: 10.2147/CCID.S94320 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
15. Ryan JL. Ionizing radiation: the good, the bad, and the ugly. J Invest Dermatol. 2012;132(3 Pt 2):985‐993. doi: 10.1038/jid.2011.411 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the radiation therapy oncology group (RTOG) and the European Organization for Research and Treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31(5):1341‐1346. doi: 10.1016/0360-3016(95)00060-C [PubMed] [CrossRef] [Google Scholar]
17. Zhen Y, Jiang Y, Yuan L, Kirkpartrick J, Wu J, Ge Y. Analyzing the usage of standards in radiation therapy clinical studies. IEEE EMBS Int Conf Biomed Health Inform. 2017;2017:349‐352. doi: 10.1109/BHI.2017.7897277 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Bourgeois JF, Gourgou S, Kramar A, Lagarde JM, Guillot B. A randomized, prospective study using the LPG technique in treating radiation‐induced skin fibrosis: clinical and profilometric analysis. Skin Res Technol. 2008;14(1):71‐76. doi: 10.1111/j.1600-0846.2007.00263.x [PubMed] [CrossRef] [Google Scholar]
19. El Hachem M, Di Mauro G, Rotunno R, et al. Pruritus in pediatric patients with atopic dermatitis: a multidisciplinary approach—summary document from an Italian expert group. Ital J Pediatr. 2020;46(1):11. doi: 10.1186/s13052-020-0777-9 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Xie QW, Dai X, Tang X, Chan CHY, Chan CLW. Risk of mental disorders in children and adolescents with atopic dermatitis: a systematic review and meta‐analysis. Front Psychol. 2019;10:1773. doi: 10.3389/fpsyg.2019.01773 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
21. Theis VS, Sripadam R, Ramani V, Lal S. Chronic radiation enteritis. Clin Oncol (R Coll Radiol). 2010;22(1):70‐83. doi: 10.1016/j.clon.2009.10.003 [PubMed] [CrossRef] [Google Scholar]
22. Dalsania RM, Shah KP, Stotsky‐Himelfarb E, Hoffe S, Willingham FF. Management of long‐term toxicity from pelvic radiation therapy. Am Soc Clin Oncol Educ Book. 2021;41:1‐11. doi: 10.1200/EDBK_323525 [PubMed] [CrossRef] [Google Scholar]
23. Xu L, Luo Y, Yu J, Lou J, Chen X, Chen J. Pediatric radiation enteritis with intestinal failure: a case report and literature review. Medicine. 2020;99(25):e20905. doi: 10.1097/MD.0000000000020905 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
24. Donaldson SS, Jundt S, Ricour C, Sarrazin D, Lemerle J, Schweisguth O. Radiation enteritis in children. A retrospective review, clinicopathologic correlation, and dietary management. Cancer. 1975;35(4):1167‐1178. doi: 10.1002/1097-0142(197504)35:4<1167::aid-cncr2820350423>3.0.co;2-y [PubMed] [CrossRef] [Google Scholar]
25. Allam O, Park KE, Chandler L, et al. The impact of radiation on lymphedema: a review of the literature. Gland Surg. 2020;9(2):596‐602. doi: 10.21037/gs.2020.03.20 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
26. Fife CE, Farrow W, Hebert AA, et al. Skin and wound care in lymphedema patients: a taxonomy, primer, and literature review. Adv Skin Wound Care. 2017;30(7):305‐318. doi: 10.1097/01.ASW.0000520501.23702.82 [PubMed] [CrossRef] [Google Scholar]
27. Mañas A, Monroy JL, Ramos AA, et al. Prevalence of neuropathic pain in radiotherapy oncology units. Int J Radiat Oncol Biol Phys. 2011;81(2):511‐520. doi: 10.1016/j.ijrobp.2010.05.047 [PubMed] [CrossRef] [Google Scholar]
28. Delanian S, Lefaix JL, Pradat PF. Radiation‐induced neuropathy in cancer survivors. Radiother Oncol. 2012;105(3):273‐282. doi: 10.1016/j.radonc.2012.10.012 [PubMed] [CrossRef] [Google Scholar]
29. Platteaux N, Dirix P, Hermans R, Nuyts S. Brachial plexopathy after chemoradiotherapy for head and neck squamous cell carcinoma. Strahlenther Onkol. 2010;186(9):517‐520. doi: 10.1007/s00066-010-2099-0 [PubMed] [CrossRef] [Google Scholar]
30. Bjornard KL, Gilchrist LS, Inaba H, et al. Peripheral neuropathy in children and adolescents treated for cancer. Lancet Child Adolesc Health. 2018;2(10):744‐754. doi: 10.1016/S2352-4642(18)30236-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Huang IC, Brinkman TM, Kenzik K, et al. Association between the prevalence of symptoms and health‐related quality of life in adult survivors of childhood cancer: a report from the St Jude lifetime cohort study. J Clin Oncol. 2013;31(33):4242‐4251. doi: 10.1200/JCO.2012.47.8867 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Krasin MJ, Constine LS, Friedman DL, Marks LB. Radiation‐related treatment effects across the age spectrum: differences and similarities or what the old and young can learn from each other. Semin Radiat Oncol. 2010;20(1):21‐29. doi: 10.1016/j.semradonc.2009.09.001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
33. Indelicato DJ, Keole SR, Shahlaee AH, Shi W, Morris CG, Marcus RB Jr. Definitive radiotherapy for Ewing tumors of extremities and pelvis: long‐term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys. 2008;72(3):871‐877. doi: 10.1016/j.ijrobp.2008.02.023 [PubMed] [CrossRef] [Google Scholar]
34. Studer G, Studer SP, Zwahlen RA, et al. Osteoradionecrosis of the mandible: minimized risk profile following intensity‐modulated radiation therapy (IMRT). Strahlenther Onkol. 2006;182(5):283‐288. doi: 10.1007/s00066-006-1477-0 [PubMed] [CrossRef] [Google Scholar]
35. Hoeben BA, Carrie C, Timmermann B, Mandeville HC, Gandola L, Dieckmann K. Management of vertebral radiotherapy dose in paediatric patients with cancer: consensus recommendations from the SIOPE radiotherapy working group. Lancet Oncol. 2019;20(3):e155‐e166. doi: 10.1016/S1470-2045(19)30034-8 [PubMed] [CrossRef] [Google Scholar]
36. Mendoza TR, Wang XS, Williams LA, et al. Measuring therapy‐induced peripheral neuropathy: preliminary development and validation of the treatment‐induced neuropathy assessment scale. J Pain. 2015;16(10):1032‐1043. doi: 10.1016/j.jpain.2015.07.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Mostoufi‐Moab S, Ward LM. Skeletal morbidity in children and adolescents during and following cancer therapy. Horm Res Paediatr. 2019;91(2):137‐151. doi: 10.1159/000494809 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
38. Steinmeier T, Schulze Schleithoff S, Timmermann B. Evolving radiotherapy techniques in paediatric oncology. Clin Oncol (R Coll Radiol). 2019;31(3):142‐150. doi: 10.1016/j.clon.2018.12.005 [PubMed] [CrossRef] [Google Scholar]
39. Tao CJ, Liu X, Tang LL, et al. Long‐term outcome and late toxicities of simultaneous integrated boost‐intensity modulated radiotherapy in pediatric and adolescent nasopharyngeal carcinoma. Chin J Cancer. 2013;32(10):525‐532. doi: 10.5732/cjc.013.10124 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Schoot RA, Slater O, Ronckers CM, et al. Adverse events of local treatment in long‐term head and neck rhabdomyosarcoma survivors after external beam radiotherapy or AMORE treatment. Eur J Cancer. 2015;51(11):1424‐1434. doi: 10.1016/j.ejca.2015.02.010 [PubMed] [CrossRef] [Google Scholar]
41. Ajithkumar T, Mazhari AL, Stickan‐Verfürth M, et al. Proton therapy for Craniopharyngioma—an early report from a single European Centre. Clin Oncol (R Coll Radiol). 2018;30(5):307‐316. doi: 10.1016/j.clon.2018.01.012 [PubMed] [CrossRef] [Google Scholar]
42. McGrath PA. An assessment of children's pain: a review of behavioral, physiological and direct scaling techniques. Pain. 1987;31(2):147‐176. doi: 10.1016/0304-3959(87)90033-9 [PubMed] [CrossRef] [Google Scholar]
43. Yock TI, Yeap BY, Ebb DH, et al. Long‐term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single‐arm study. Lancet Oncol. 2016;17(3):287‐298. doi: 10.1016/S1470-2045(15)00167-9 [PubMed] [CrossRef] [Google Scholar]
44. Merkel SI, Voepel‐Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997;23(3):293‐297. [PubMed] [Google Scholar]
45. Bieri D, Reeve RA, Champion DG, Addicoat L, Ziegler JB. The faces pain scale for the self‐assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain. 1990;41(2):139‐150. doi: 10.1016/0304-3959(90)90018-9 [PubMed] [CrossRef] [Google Scholar]
46. Jacob E, Mack AK, Savedra M, Van Cleve L, Wilkie DJ. Adolescent pediatric pain tool for multidimensional measurement of pain in children and adolescents. Pain Manag Nurs. 2014;15(3):694‐706. doi: 10.1016/j.pmn.2013.03.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Swarm RA, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2013;11(8):992‐1022. doi: 10.6004/jnccn.2013.0119 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Lu Q, Krull KR, Leisenring W, et al. Pain in long‐term adult survivors of childhood cancers and their siblings: a report from the childhood cancer survivor study. Pain. 2011;152(11):2616‐2624. doi: 10.1016/j.pain.2011.08.006 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Le‐Short C, Katragadda K, Nagda N, Farris D, Gelter MH. Interventional pain management for the pediatric cancer patient: a literature review. Children (Basel).2022;9(3):389. doi: 10.3390/children9030389 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
50. Matziou V, Vlachioti E, Megapanou E, et al. Perceptions of children and their parents about the pain experienced during their hospitalization and its impact on parents' quality of life. Jpn J Clin Oncol. 2016;46(9):862‐870. [PubMed] [Google Scholar]
51. Anekar AA, Cascella M. WHO Analgesic Ladder. StatPearls [Internet]. StatPearls Publishing; 2022. [PubMed] [Google Scholar]
52. Lee JE, Anderson CM, Perkhounkova Y, Sleeuwenhoek BM, Louison RR. Transcutaneous electrical nerve stimulation reduces resting pain in head and neck cancer patients: a randomized and placebo‐controlled double‐blind pilot study. Cancer Nurs. 2019;42(3):218‐228. doi: 10.1097/NCC.0000000000000594 [PubMed] [CrossRef] [Google Scholar]
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