CACA guidelines for holistic integrative management of adolescent and childhood nasopharyngeal carcinoma

Abstract

Adolescent and childhood nasopharyngeal carcinoma (NPC) is a rare malignancy with unique biological and genetic characteristics, often associated with Epstein-Barr virus (EBV). This CACA guideline provides an integrative approach to the management of adolescent and childhood NPC, focusing on biology, diagnosis, staging, and treatment strategies. The incidence of NPC is higher in adolescent boys and is more frequently diagnosed at an advanced stage in adolescent and childhood population compared to adults. However, adolescent and childhood NPC generally have a better prognosis. The primary treatment is radiotherapy (RT), with intensity-modulated radiation therapy (IMRT) being the preferred technique due to its reduced damage to normal tissues. Chemotherapy, particularly induction chemotherapy, plays a significant role, especially in locally advanced disease. Personalized treatment strategies, including adjusting RT dosage based on chemotherapy outcomes, may reduce long-term adverse effects. The role of adjuvant therapy post-RT remains unclear and requires further research. The main objective of this guideline is to standardize the clinical diagnosis and treatment process of adolescent and childhood nasopharyngeal carcinoma, with a multidisciplinary approach to optimize therapeutic outcomes and quality of life for this disease.

Adolescent and childhood nasopharyngeal carcinoma (NPC), defined as individuals aged ≤ 19 years according to the World Health Organization (WHO) criteria, is a rare malignant neoplasm originating from the nasopharyngeal epithelium, accounting for 2–3% of all NPC cases. It is endemic to Southeast and East Asia. The incidence of NPC in adolescent boys is higher than that in adolescent girls (with a male-to-female ratio, 1.8:1). Most of these cases are the non-keratinizing squamous cell carcinoma, and are associated with the Epstein-Barr virus [1, 2–3]. Owing to the obscure anatomical location of NPC and the nonspecific nature of complaints in adolescent and childhood patients, most adolescent and childhood patients are diagnosed with locoregionally advanced disease (stages III–IV) compared to adults (> 90% versus approximately 70% in adults). Although a higher proportion of adolescent and childhood NPC is diagnosed at an advanced stage compared to adults, adolescent and childhood patients generally have a better prognosis than adults [4, 5]. NPC may be suspected when a child exhibits a nasopharyngeal mass with unilaterally or bilaterally painless enlarged cervical lymph nodes. Other symptoms include nasal obstruction, bleeding, earache, hearing loss, headache, neck pain, or less common neurological symptoms, such as cranial nerve palsy, which may indicate intracranial extension [6, 7].

Biology and genetic characteristics

Undifferentiated NPC, which constitutes the most common type of NPC in adolescent and childhood population, is strongly associated with Epstein-Barr virus (EBV) [2]. In regions where NPC is endemic, high levels of immunoglobulin A (IgA) antibodies against EBV antigens can predict NPC development [8]. Additionally, elevated levels of IgG and IgA antibodies against the early antigen (EA) and viral capsid antigen (VCA) are frequently observed in adolescent and childhood patients with undifferentiated NPC [9, 10]. However, higher levels of IgA against VCA and/or EA are less common in adolescent and childhood patients from Northern Africa than in adults [10].

Increased expression of EBV latent membrane protein 1 (LMP1), a key oncogene involved in cell proliferation, survival, and invasion, has been reported in adolescent and childhood NPC [11]. A previous study also reported a genetic predisposition to NPC associated with specific human leukocyte antigen (HLA) types; Asian individuals with HLA-A2, B46, and B18 have an approximately two-fold increased risk of NPC, whereas in Caucasians, the HLA-B5 allele is linked to NPC [12]. Genome-wide association studies have further confirmed a strong association between NPC and genes in the major histocompatibility complex region on chromosome 6p21, which encodes HLA genes [13]. HLA is crucial for presenting viral antigens to T cells, and alleles that are less efficient at inducing an immune response to viruses are more common in high-risk populations [14]. Other non-HLA genes such as gamma-aminobutyric acid type B receptor subtype 1 (GABBR1) and HLA complex group 9 (HCG9) are also suspected to be associated with NPC [14].

The familial clustering of NPC cases indicates that the disease may result from a complex interplay between multiple susceptibility genes and environmental factors [15]. According to the WHO classification [16], three histologic subtypes of NPC are recognized: keratinizing squamous cell carcinoma (rarely seen in the adolescent and childhood setting); non-keratinizing squamous cell carcinoma (differentiated and undifferentiated non-keratinizing squamous cell carcinoma) and basaloid squamous cell carcinoma (a rare subtype characterized by small basaloid cells, which is usually more aggressive and has a worse prognosis than the other types). In areas with a low incidence of NPC, the occurrence of NPC in younger patients is often familial and of the undifferentiated type, suggesting that genetically susceptible individuals may develop NPC through exposure to environmental factors such as EBV infection early in life [17].

Diagnosis

The diagnostic procedures include medical history collection, physical examination, fiberoptic nasopharyngoscopy, biopsy of the primary site or fine needle aspiration of the neck, magnetic resonance imaging, and computed tomography (CT) of the nasopharynx and neck with contrast [18]. [18F] Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) [19, 20], X-ray/CT of chest, sonography/CT of the abdomen, and bone scans are used to detect distant metastases. Routine blood tests, biochemical tests, and plasma EBV DNA [21] are also performed, and the diagnostic principles are consistent with those used for adult cases of NPC [22].

The distant metastasis rate in newly diagnosed NPC patients ranges from 11 to 36%. Early detection of distant metastasis is crucial for accurate staging and the formulation of treatment strategies. 18F-FDG PET/CT demonstrates higher sensitivity and specificity for detecting distant metastasis compared to conventional imaging techniques (such as chest X-ray, sonography, whole-body bone scan, etc.) [23, 24–25]. Therefore, for patients at high risk of metastasis (e.g., N0-1 with EBV DNA > 4,000 copies/mL, or N2-3, or T3-4) [24], routine PET/CT scanning is recommended before treatment. Furthermore, for patients with persistently or progressively elevated EBV DNA after treatment, in whom routine imaging fails to show positive findings, further imaging dignosis is recommended on Table 1.

Table 1. Imaging diagnosis

Region	Level I Recommendation	Level II Recommendation	Level III Recommendation
Primary Tumor Assessment	Nasopharynx plain + contrast-enhanced MRI (sequence includes T1, T2, T1 contrast enhancement, T1 fat suppression; superior: skull base, inferior: inferior border of the nasopharynx)	Nasopharynx plain + contrast-enhanced CT; PET/CT	PET-MR
Regional Lymph Node Assessment	Neck plain + contrast-enhanced MRI (sequence includes T1, T2, T1 contrast enhancement, T1 fat suppression; superior: inferior border of the nasopharynx, inferior: supraclavicular region)	Neck plain + contrast-enhanced CT; PET/CT	PET-MR; Ultrasound-guided biopsy
Distant Metastasis Assessment	Chest plain + contrast-enhanced CT; abdominal ultrasound or abdominal plain + contrast-enhanced MRI/CT; bone scan with radionuclide imaging; PET/CT	Chest X-ray; abdominal ultrasound	PET-MR; CT/ultrasound-guided biopsy

A comprehensive approach that addresses the effects of the treatment on various health parameters are recommended for adolescent and childhood NPC receiving treatment:

• Dental/prosthodontic evaluation: Dental health assessments should be performed and any oral issues that arise because of the treatment need to be addressed.

• Audiogram: Regular hearing tests should be performed to monitor and manage hearing loss, a potential side effect of therapy.

• Ophthalmological evaluation: Eye examinations need to be conducted to detect any vision-related problems that may be affected by treatment.

• Endocrine evaluation: Hormonal balance and related functions that may be disrupted by treatment should be assessed, including thyroid stimulating hormone (TSH), free T4 (FT4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (in females), testosterone (in males), growth hormone (GH), adrenocorticotropic hormone (ACTH), cortisol, prolactin, and anti-müllerian hormone (AMH) (in females).

• Screening for hepatitis B: Regular hepatitis B tests are necessary to prevent, detect, and manage the virus, especially in patients receiving therapies that may compromise the immune system.

• Multidisciplinary consultation: As needed, various specialists should be engaged in the patient care plan to ensure a holistic approach to the treatment and management of potential adverse effects or related health issues.

Staging

The Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) tumor/node/metastasis (TNM) staging system (9^th edition) guidelines are adopted for staging [26] Table 2.

Table 2. 9th AJCC staging system

T category
T1	Tumor confined to nasopharynx or extension to any of the following without parapharyngeal involvement: (1) oropharynx; (2) nasal cavity (including nasal septum)
T2	Tumor with extension to any of the following: (1) parapharyngeal space; (2) adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles)
T3	Tumor with unequivocal infiltration into any of the following bony structures: (1) skull base (including pterygoid structures); (2) paranasal sinuses; (3) cervical vertebrae
T4	Tumor with any of the following extension/involvement: (1) intracranial extension; (2) unequivocal radiological and/or clinical involvement of cranial nerves; (3) hypopharynx; (4) orbit (including inferior orbital fissure); (5) parotid gland; (6) extensive soft tissue infiltration beyond the anterolateral surface of the lateral pterygoid muscle
N category
N0	No tumor involvement of regional lymph node(s)
N1	Tumor involvement of any of the following: (1) unilateral cervical lymph node(s); (2) unilateral or bilateral retropharyngeal lymphnode(s). Tumor involvement in all of the following: (1) ≤ 6 cm in greatest dimension; (2) above the caudal border of cricoid cartilage; (3) without advanced extranodal extension
N2	Tumor involvement of bilateral cervical lymph nodes and all of the following: (1) ≤ 6 cm in greatest dimension; (2) above the caudal border of cricoid cartilage; (3) without advanced extranodal extension
N3	Tumor involvement of unilateral or bilateral cervical lymph node(s) and any of the following: (1) > 6 cm in greatest dimension; (2) extension below the caudal border of cricoid cartilage; (3) advanced radiologic extra nodal extension with involvement of adjacent muscles, skin, and/or neurovascular bundle
M category
M0	No distant metastasis
M1	M1: distant metastasis; M1a: ≤ 3 metastatic lesions in ≥ 1 organs/sites; M1b: > 3 metastatic lesions in ≥ 1 organs/sites
Stage group
I	T1, N0, M0
II	T1, N1, M0; T2, N0-N1, M0
III	T1-2, N2, M0; T3, N0-2, M0
IV	IVA: T4 or N3 M0; IVB: any T, any N, M1

Treatment

Treatments for adolescent and childhood NPC have generally been adapted from the adult regimens [4, 22]. Radiotherapy (RT) is the primary treatment for patients with non-metastatic disease, whereas patients with advanced stages of cancer must undergo comprehensive treatment along with RT and chemotherapy. Patients with metastases are primarily treated with palliative chemotherapy. For patients with recurrence, salvage surgery could be considered; otherwise, treatment mainly involves radiation therapy (RT) and chemotherapy.

Technical aspects and principles of radiotherapy

As adolescent and childhood patients are in the growth and development period, special attention should be paid to the potential damage caused by radiation to normal tissues. To avoid severe radiation-related complications, the irradiation schedule should be adjusted to reduce the field, with a daily radiation dose of 1.8 Gy/fraction and a total dose of 62–66 Gy, without an excessive increase in the radiation dose. However, in individual cases that are resistant to RT, the dose may be increased to a total dose of 70–72 Gy.

RT is the mainstay of treatment for non-metastatic adolescent and childhood NPC. Intensity-modulated radiation therapy (IMRT) has become the preferred radiation technique for adolescent and childhood NPC as it improves treatment effectiveness while reducing damage to normal tissues caused by RT [5]. Proton beam therapy (PBT), by virtue of the Bragg peak, frequently generates more favorable dosimetric profiles than IMRT. Theoretically, PBT reduces the radiation dose to at-risk organs without compromising survival outcomes. A retrospective study reported that (compared to historical studies with IMRT in adult NPC), PBT was associated with a significant reduction in the mean radiation dose to the parotid glands, cochlea, larynx, and oral cavity, with excellent initial oncological outcomes. However, no prospective clinical trials have directly compared PBT and IMRT, and the efficacy of PBT in adolescent and childhood NPC requires further investigation.

Treatment of non-metastatic adolescent and childhood NPC

RT alone is the primary treatment modality in adolescent and childhood NPC with stage IA disease [3]. In advanced-stage adolescent and childhood NPC (stages IB to III), current chemoradiotherapy with or without induction chemo- or adjuvant-chemotherapy is preferred [3, 6]. Table 3 presents the recommended treatment strategies based on clinical stage.

Table 3. Recommendations for treatment strategy based on the clinical stage

Stage	Level I recommendation	Level II recommendation	Level III recommendation
Stage IA	Radiotherapy [27] (Category 3)
stages IB to III	Induction chemotherapy + concurrent chemoradiotherapy [28, 29, 30, 31–32] (Category 2 A)	Induction chemotherapy + radiotherapy alone [33] (Category 3)
Stage IVA-B		Systemic chemotherapy + PD-1 inhibitor ± local radiotherapy [28] (Category 3)

Despite the absence of randomized-controlled clinical trials in adolescent and childhood NPC, the combination of induction chemotherapy and concurrent chemoradiotherapy is recognized as the standard treatment for locally-advanced adolescent and childhood NPC [4, 29, 32]. The benefits of induction chemotherapy in adolescent and childhood NPC are as follows:

• Reduced tumor volume: Induction chemotherapy reduces the size of the primary tumor, making it easier to manage with subsequent treatments, such as surgery or RT.

• Control of micro-metastatic disease: By targeting cancer cells that may have spread to distant sites, induction chemotherapy helps to control micro-metastatic disease, thereby potentially reducing the risk of distant metastasis, and improving long-term outcomes.

• Assessment of chemosensitivity: Response to induction chemotherapy can provide valuable information about the sensitivity of the tumor to chemotherapeutic drugs, thus guiding the selection of further treatment.

• Downstaging: In some cases, induction chemotherapy downstages the cancer, allowing for less aggressive or more conservative treatments that may not have been possible with the initial tumor size or stage.

• Preservation of organ function: By shrinking the tumor, induction chemotherapy can help preserve the function of nearby organs that may be at risk during more aggressive treatments, such as surgery or high-dose RT.

• Improvement in survival rates: In certain types of cancer, including NPC, induction chemotherapy has been reported to improve overall and progression-free survival rates when used in combination with other treatments.

• Quality of life: By managing the disease more effectively and potentially reducing the intensity of subsequent treatments, induction chemotherapy can contribute to an improved quality of life for patients.

• Personalized treatment strategy: The response to induction chemotherapy can inform a more personalized treatment strategy, tailor subsequent therapies, and help identify patients who can undergo RT de-escalation.

An Italian prospective clinical study on induction chemotherapy in adolescent and childhood NPC reported an objective response rate of 91%. When these patients received < 65 Gy of local RT combined with concurrent cisplatin chemotherapy, their 5-year overall and progression-free survival rates were 80.9% and 79.3%, respectively [30]. The current standard for induction chemotherapy in adolescent and childhood NPC involves platinum-based multi-drug combinations, such as PF (cisplatin + 5-fluorouracil [FU]), TPF (docetaxel + cisplatin + 5-FU, liposomal paclitaxel + cisplatin + 5-FU), TP (docetaxel + cisplatin), GP (gemcitabine + cisplatin), BEP (bleomycin + cisplatin + epirubicin), MPF (methotrexate + cisplatin + fluorouracil), and PMB (cisplatin + methotrexate + bleomycin) [31, 32, 34, 35]. Methotrexate and bleomycin are less commonly used because of their severe adverse effects.

Recent large-scale clinical trials have demonstrated that the addition of induction chemotherapy to concurrent chemoradiotherapy significantly improves the survival rate of patients with locally-advanced NPC [36, 37]. However, these studies did not focus on adolescent and childhood populations, and determining the most effective and least toxic induction chemotherapy regimen for adolescent and childhood NPC remains a crucial area for future research. An international phase II clinical trial compared TPF and PF regimens in adolescent and childhood NPC and found differences in survival rates between the two approaches [31]. The global research gap in this area highlights the need for more prospective clinical trials to provide robust evidence-based insights into the treatment of adolescent and childhood NPC. The recommended chemotherapy regimens and their corresponding dosages are presented in Table 4 and Table 5.

Table 4. Recommendations for chemotherapy regimen

Chemotherapy	Level I recommendation	Level II recommendation	Level III recommendation
Induction chemotherapy	Docetaxel + Cisplatin + 5-FU [31] (Category 2 A)	Gemcitabine + Cisplatin [36] (Category 3)
	Paclitaxel + Cisplatin + 5-FU [32] (Category 2 A)
	Cisplatin + 5-FU [28, 31] (Category 2 A)
	Docetaxel + Cisplatin [34] (Category 2 A)
Concurrent chemotherapy	Cisplatin [30, 31–32] (Category 2 A)
Adjuvant therapy			INF-β [9, 33] (Category 3)

Table 5. Recommendations for dosage of chemotherapy regimen

Chemotherapy	Regimen	Drug	Dosage	Medication time	Treatment cycle
Induction chemotherapy	TPF regimen	Docetaxel	75 mg/m2	D1
		Cisplatin	75 mg/m2	D1
		5-FU	750 mg/m2	D1-4
		Paclitaxel	135 mg/m2	D1
		Cisplatin	25 mg/m2	D1-3
		5-FU	750 mg/m2	D1-5
	TP regimen	Docetaxel	75 mg/m2	D1
		Cisplatin	75 mg/m2	D1
	GP regimen	Gemcitabine	1000 mg/m2	D1, 8
		Cisplatin	80 mg/m2	D1
	PF regimen	Cisplatin	80 mg/m2	D1
		5-FU	1000 mg/m2	D1-4
Concurrent Chemotherapy	Weekly cisplatin regime	Cisplatin	30–40 mg/m2	D1	QW × 7 cycles
	Triweekly cisplatin regimen	Cisplatin	100 mg/m2	D1	Q3W × 3 cycles
Adjuvant Therapy	INF-β regimen	INF-β	100,000 IU/kg	D1	Three times a week for six months

The use of IMRT has led to a marked reduction in adverse events in adolescent and childhood NPC. However, high radiation doses can still cause significant damage to normal tissues. Common late adverse events to irradiation in these adolescent and childhood NPC include dry mouth, dental damage, endocrine dysfunction, growth retardation, hearing impairment, and trismus, all of which can severely impact the post-treatment quality of life [38, 39–40]. Therefore, clinical research should focus on reducing the RT dosage while maintaining its therapeutic effectiveness to minimize the occurrence of long-term adverse effects.

Recent studies support the idea that a reduction in RT dosage is recommended in adolescent and childhood NPC who respond well to induction chemotherapy. A French retrospective study reported that lowering the RT dose to 59.4 Gy based on tumor regression after induction chemotherapy did not increase the risk of local–regional recurrence and achieved 3-year overall survival and recurrence-free survival rates of 94% and 86%, respectively [39]. The POG 9486 study showed that in patients with advanced adolescent and childhood NPC who achieved complete response (CR) after induction chemotherapy, a 5-year overall survival rate of over 75% was achieved when receiving a 61.2 Gy RT dose [28]. The American Adolescent and Childhood Cancer Group ARAR0331 study revealed high survival rates with adjusted RT dosages based on chemotherapy response. The study demonstrated that patients with stage I disease received 61.2 Gy of RT, patients with stage IIA disease received 66.6 Gy of RT, and patients with stages IIB–IV (AJCC 5th edition staging) received a combination of induction chemotherapy and concurrent chemoradiotherapy. Patients who achieved a CR or partial response (PR) after induction chemotherapy were treated with 61.2 Gy of RT, whereas those with stable disease (SD) received 70.2 Gy. After a median follow-up period of 63 months, the 5-year event-free and overall survival rates were 84.3% and 89.2%, respectively [28]. A study from the Sun Yat-sen University Cancer Center, which included 44 patients aged < 18 years, stage IVa-b (AJCC 7th edition staging), showed that patients evaluated as having CR or PR after induction chemotherapy received 60 Gy of RT, and patients with SD or disease progression (PD) received 70 Gy of RT. After a median follow-up of 38.2 months, the 3-year progression-free and overall survival rates reached 91% and 100%, respectively [32]. These studies further demonstrate that personalized RT dosages based on chemotherapy outcomes lead to high progression-free and overall survival rates. Additionally, amifostine, a broad-spectrum cytoprotective agent, has been used to mitigate severe adverse effects, such as mucositis, swallowing difficulties, and late dry mouth in adolescent and childhood patients with head and neck cancers during chemoradiotherapy.

The concurrent chemotherapy regimen in adolescent and childhood NPC includes weekly and triweekly cisplatin regimen [30, 33, 38]. However, randomized-controlled studies assessing the effectiveness of concurrent chemotherapy in adolescent and childhood NPC are currently lacking. Several single-arm prospective trials have administered concurrent cisplatin chemotherapy to patients during RT, and the results of these trials have shown improvements compared to historical data, suggesting that induction chemotherapy combined with concurrent chemoradiotherapy may be an effective strategy for the treatment of advanced adolescent and childhood NPC [28, 30, 32, 33, 38].

However, it is important to note that the use of chemotherapy during RT may increase the incidence of treatment-related adverse reactions, such as mucositis and malnutrition, which may lead to delays in RT. Some researchers maintain that patients who achieve a CR or very good partial response after induction chemotherapy may undergo RT alone. In contrast, a previous study reported that adolescent and childhood NPC who receive three cycles of chemotherapy exhibited improved 5-year disease-free survival rates compared with those who received two cycles of concurrent cisplatin chemotherapy [28].

Thus, the optimal concurrent chemotherapy strategy for adolescent and childhood NPC is still widely debated. Further research and data are required to clarify the best treatment approach to ensure that patients achieve the best therapeutic outcomes and quality of life. At the same time, it is necessary to pay attention to the potential adverse events that may occur during the treatment process and seek ways to mitigate them.

The role of post-RT adjuvant therapy in adolescent and childhood NPC remains unclear. Two studies performed by the Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) used IFN-β maintenance therapy for six months after completion of three blocks of cisplatin-based induction chemotherapy and subsequent concurrent chemoradiotherapy [9, 33]. A prospective single-arm study on 104 adolescent and childhood patients with non-metastatic cancer showed promising results, with IFN-β adjuvant therapy being considered a potential treatment option for certain patients, although the efficacy needs to be validated in future studies [33].

1. Radiation dose based on response to induction chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [41].

2. Radiation dose in patients without induction chemotherapy.

In patients who have not been treated with induction chemotherapy, the recommended dose for primary tumor is 61.2 Gy and 66.6 Gy in stages I and II, respectively, with 1.8–2 Gy daily fraction [3, 28]. Table 6 and Table 7 detail the recommended radiation doses and the associations between dose-volume metrics, age, and the risk of radiation-related toxicity.

Table 6. Recommendations for radiotherapy (RT) dose

Response to induction chemotherapy	CR (Complete response)	PR (Partial response)	SD (Stable disease)
PTVp/PTVn	60–61.2 Gy/(1.8–2.0) Gy	60–66 Gy/(1.8–2.0) Gy	68–70 Gy/2.0 Gy
PTV1	54 Gy/(1.6–1.8) Gy	54 Gy/1.8 Gy	60 Gy/1.8 Gy
PTV2	45–50 Gy/(1.6–1.80) Gy	45–50 Gy/(1.6–1.80) Gy	45–50 Gy/(1.6–1.8) Gy

Table 7. Associations between dose-volume metrics and age with risks of radiation-related toxicity [42]

Organ or tissue	Volume segmented	Endpoint	Dose and volume	Risk, %	Effect of age	Comments, including on chemotherapy
Brain	Whole brain, including brain stem	Symptomatic radiation necrosis	59 Gy to any part	5	Not analyzed	Reirradiation analyzed in more depth in a separate report
			67 Gy to any part	10
			Composite EQD2/2 of 112 Gy with brain reirradiation	5
			Composite EQD2/2 of 112 Gy with brain stem reirradiation	7
	Whole brain	For IQ < 85	36 Gy to 10% brain	5	Younger age, independently associated with decreased predicted post-RT IQ	Methotrexate administration is estimated to have an effect of ∼6-Gy whole brain uniform dose; whole (vs partial) brain is an independent adverse risk factor for post-RT IQ
			51 Gy to 10% brain	20
			29 Gy to 20% brain	5
			42 Gy to 20% brain	20
			22 Gy to 50% brain	5
			32 Gy to 50% brain	20
			18 Gy to 100% brain	5
			26 Gy to 100% brain	20
Cerebrovascular	Circle of Willis, major cerebral arteries, or surrogate (ie, suprasellar cistern [preferred] or optic chiasm)	Stroke at attained age of 35 y	D100% 30 Gy	∼1	Although attained age was analyzed, age at time of RT was not	Risks are low, but increased over general population; data were derived from prescribed dose; this dose covers the circle of Willis and surrogate structures (D100)
			D100% 45 Gy	2–3
			D100% 54 Gy	3–4
		Stroke at attained age of 45 y	D100% 30 Gy	2–4
			D100% 45 Gy	4–9
			D100% 54 Gy	7–13
		Cerebral vasculopathy at attained age of 17 y	D100% 30 Gy	∼0.2	Not analyzed
			D100% 45 Gy	∼1
			D100% 54 Gy	∼4
Optic and ocular structures	Retina	Retinopathy	42 Gy Dmax	5	Not analyzed	Higher fraction size correlates with greater risk of retinopathy and optic neuropathy
			62 Gy Dmax	50
	Optic nerve and chiasm	Optic neuropathy	57 Gy Dmax	5	Not analyzed
			64 Gy Dmax	50
	Lens	Cataract, self-reported	Mean 12 Gy	5	Childhood age does not appear to affect risks; children may have greater risks than adults (or are better screened)	Some chemotherapy agents are independently associated with cataract formation
			Mean > 40 Gy	50
	Lens	Cataract, ophthalmologist-diagnosed	No radiation	> 5
			Mean 9 Gy	50
Neuroendocrine	Hypothalamus and pituitary gland	Growth hormone deficiency	D100% 15 Gy	5	Unable to quantify or model potential effects of age on risks, although cohorts with younger age had greater crude risks	-
		Central hypothyroidism	D100% 22 Gy	20
		Adrenocorticotropic hormone deficiency	D100% 34 Gy	20
Spinal cord	Spinal cord	Myelopathy	Without chemotherapy: D0.03 cc < 54 Gy D1 cc < 50.4 Gy	Rare	Data insufficient to analyze	NTCP modeling was not feasible; chemotherapy use (particularly intrathecal chemotherapy) appears to lower threshold for toxicity
			With chemotherapy: D0.03 cc < 50.4 Gy; D1 cc < 45 Gy
Cochlea and middle ear	Cochlea	Hearing loss: if a threshold exceeds 20 dB at any frequency	With no chemotherapy	Greatest risk in children < 5 y, although independent effects of dose and age were not elucidated	Higher-frequency hearing loss is more common; platinum-based chemotherapy adds to risks; 300 mg/m2 shifts the dose–response curve by ∼7 Gy
			Mean < 35 Gy	< 5
			Mean 50 Gy	30
Salivary glands	Both parotid glands	Acute grade > 2 xerostomia	Mean 35–40 Gy	32	Not analyzed	Mean < 26 Gy recommended
		Chronic grade > 2 xerostomia	Mean 35–40 Gy	13–32%
Dentition	Primary and permanent teeth	Dental developmental abnormalities	Data not pooled or modeled; based on 1 study, recommend avoiding > 20 Gy, particularly for ages < 4 y		Younger age and earlier stage of dental development associated with increased risk	Alkylating agents increase risk
Thyroid gland	Thyroid gland	Compensated (subclinical) hypothyroidism (all patients)	Mean 10 Gy	12	Aged 14–30 y: 1.3-fold greater risk than younger patients; Table 6 in thyroid report breaks down risks of any hypothyroidism (clinical and subclinical) by age and sex	Females: 1.7-fold greater risks vs males
			Mean 20 Gy	25
			Mean 30 Gy	44
		Uncompensated (clinical) hypothyroidism (all patients)	Mean 10 Gy	4
			Mean 20 Gy	7
			Mean 30 Gy	13

Abbreviations: CNS central nervous system, D100 minimum dose to 100% of organ, or minimum organ dose, Dmax maximum dose to organ at risk, Dx% minimum dose received by the hottest x% of the organ, EQD2/X equivalent dose at 2 Gy per fraction calculated via the linear-quadratic model assuming an alpha/beta ratio of X Gy, IQ intelligence quotient, NTCP normal tissue complication probability, RT radiation therapy

Treatment of recurrent/metastatic adolescent and childhood NPC

Research on the treatment of recurrent or metastatic adolescent and childhood NPC is limited. Current treatment options for such cases follow principles similar to those for adults, but with special consideration of the patient’s age, potential long-term adverse effects, and ability to tolerate an intensive treatment. Immunotherapeutic approaches, such as EBV-specific cytotoxic T lymphocytes (CTLs), and programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors have been reported in adult studies. However, their efficacy in adolescent and childhood recurrent/metastatic NPC remains uncertain and requires further investigation [43, 44]. However, gemcitabine, cisplatin, and PD-1 inhibitors remain the preferred treatment regimes [45, 46–47]. For patients with de novo metastasis, RT of the primary tumor is recommended to control metastatic lesions. Local treatment of the metastatic sites is emphasized in patients with oligometastases. Surgical treatment may be an option for patients with a limited recurrent disease [40].

Adolescent and childhood NPC is a rare malignancy, and its clinical diagnosis and staging follow the same principles as those in adults. RT, particularly IMRT or computed tomography-guided IMRT (tomotherapy), is the cornerstone of its treatment. Patients with early-stage disease may receive radical RT alone, whereas patients with locoregionally advanced disease are primarily treated with combined chemoradiotherapy, with induction chemotherapy playing a vital role. Given the potential for long-term survival, there is a need to focus on minimizing the long-term adverse effects of RT. Adjusting the RT intensity in adolescent and childhood NPC who respond well to induction chemotherapy may further reduce the long-term adverse effects; however, more research is needed in this area. Novel RT technologies such as proton therapy offer dosimetric advantages over traditional photon therapy, and may provide better protection to the normal tissues. Therefore, they constitute promising areas for further exploration for the treatment of adolescent and childhood NPC.

Authors’ contributions

Conception and design of the guidelines: Hai-Qiang Mai. Manuscript writing: Li-Ting Liu, Hai-Qiang Mai, Qiu-Yan Chen, Jun-Lin Yi, Ying Wang, Hong-Mei Ying, Min Kang, Xiao-Zhong Chen, Lin-Quan Tang,Ji-Shi Li, Jing-Jing Miao. Final approval of the final manuscript: members of the Integrated Rehabilitation Committee for Nasopharyngeal Cancer of the Chinese Anticancer Association.

Funding

This study was funded by grants from the National Key Research and Development Program of China (2022YFC2705005) and the Sanming Project of Medicine in Shenzhen (SZSM202211017).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Consent for publication has been obtained from all authors of this manuscript.

Competing interests

The authors have no conflicts of interest to declare.

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