Update in pediatric nasopharyngeal undifferentiated carcinoma

Abstract

Many of the principles established in adults with undifferentiated nasopharyngeal carcinoma (NPC) apply to children, adolescents and young adults. However, NPC in young patients should be distinguished from the adult form by several points. This review focuses mainly on differences between adult and pediatric NPC. The role of biology and genetics in pediatric NPC is discussed. Systemic treatment modalities including type of chemotherapy induction, timing of treatment, role of immunotherapy as adjuvant treatment, or in relapsing/ metastatic diseases are reported. Radiation modalities (doses, techniques…) in children are also reviewed. Long-term effects including secondary cancers are finally be discussed in this young NPC population.

Epidemiology

Nasopharyngeal carcinomas (NPC) represent less than 1% of all childhood cancers. The first peak of incidence is 10–20 years, with a median age of 13 years at diagnosis. In one of the largest pediatric Chinese report on 176 patients, 24% of the patients were under 14 year old¹ European and American studies have reported an incidence rate nil before 10 years, 0.73 per million between 10 and 14 years, and one per million between 15 and 17 years of age.^2–4 In contrast, the NPC incidence reaches 1/100,000 to more than 20/100,000 in endemic regions such as southern parts of China, Southeast Asia, Alaska, and in the Mediterranean Basin.^1,5–8 Age distribution is different in these endemic regions. Children under 16 year old account for 1–2% of all NPC in China versus 10–18% in Mediterranean basin and in Africa. Sex ratio ranges from 1.7 to 4.8 in pediatric series.^3,9–12 More than 95% of the patients have nodal involvement in the largest pediatric series although distant metastases remain quite rare (3–10%).^3,4,10–14

Role of biology and genetic

EBV is especially associated with undifferentiated type which is the most frequent in children.^15–17 High levels of immunoglobulin A (IgA) antibodies against EBV antigens are predictive of NPC in endemic areas.¹⁸ Elevated antibody titers of IgG and IgA against early antigen (EA) or viral capsid antigen (VCA) are also commonly seen in child with undifferentiated NPC.^14,19 Elevated IgA against VCA and/or EA are less common in young patients from northern Africa than in adults.¹⁹ Higher expression of EBV-latent membrane protein 1 1, a major EBV oncogene involved in proliferation, survival and invasion has been observed in tumors from younger patients with NPC.²⁰

Asian individuals who have HLA-A2, B46 and B18 types were found to have an approximately twofold increased risk of NPC while in Caucasians, the HLA-B5 allele was shown to be associated with NPC.²¹ More recently, genome-wide association studies have confirmed that genes within the major histocompatibility complex region on chromosome 6p21 that codes for the HLA genes are strongly associated with NPC.²² HLA plays an important role in presenting the viral antigens to the T cells. Alleles less efficient to induce immune response to viruses were shown to be more frequent in high-risk population.²³ Other non-HLA genes are suspected in association such as the GABBR1 and HCG9 genes.²³ Finally, familial clustering of NPC has been well described and suggests that the development of NPC may result from a complex interaction between multiple susceptibility genes and environmental factors.²⁴ In low-incidence areas, younger cases of NPC tend usually to be familial cases and of undifferentiated type, suggesting that NPC may develop through exposure to environmental factors such as EBV infection in early life in genetically susceptible individuals.²⁵

Specific clinical characteristics

The revealing symptom is often a neck mass reported in 60–90% of all the patients in major pediatric series.^9,13,26–28 Nasal, auditory and neurological symptoms are correlated with the primary nasopharyngeal involvement. Nasal symptoms (obstruction, bleeding and discharge), auditory symptoms (otalgia, serous otitis and hearing loss) are respectively described for 30–70% and 20–45% of children^9,13,26,28 and often non-symptomatic for a long time.²⁹ Neurological symptoms (base skull involvement) include headaches (11–32%), cranial nerve deficit (5–22%).^1,9,27 Other symptoms (trismus, taste disorders, dysphagia, difficult swallowing) are more rarely described in pediatric series.

Treatment modalities in non-metastatic NPC

The type of treatment depends on the tumor stage, according to the eighth Edition of the American Joint Committee on Cancer Staging System updated in 2017 (Table 1).³⁰ Surgery is not part of the treatment of NPC except for initial biopsy. For Stage I and II (N0), the rare patients usually receive exclusive RT, leading to a 98% 10 year overall survival (OS) rate.³¹

Table 1. .

The eighth edition of American Joint Committee on Cancer staging system

American Joint Committee on Cancer staging system30
Primary tumor
T1	Tumor confined to the nasopharynx or tumor extends to oropharynx and/or nasal cavity without parapharyngeal extension
T2	Tumor with extension to parapharyngeal space and/or infiltration of the medial pterygoid, lateral pterygoid, and/or prevertebral muscles
T3	Tumor invades bony structures of skull base cervical vertebra, pterygoid structures, and/or paranasal sinuses
T4	Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, parotid gland and/or infiltration beyond the lateral surface of the lateral pterygoid muscle
Nodes
N1	Unilateral metastasis, in cervical lymph node(s) above the caudal border of cricoid cartilage, and/or unilateral or bilateral metastasis in retropharyngeal lymph nodes, 6 cm or less,
N2	Bilateral metastasis in cervical lymph node(s), 6 cm or less above the caudal border of cricoid cartilage
N3	Metastasis in cervical lymph node(s) greater than 6 cm in dimension and/or extension below the caudal border of cricoid cartilage
Distant metastases
MX	Distant metastases cannot be assessed
M0	No distant metastases
M1	Distant metastases
Stage
I	T1 N0 M0
II	T1-T2 N1 M0, T2 N0 M0
III	T3 N0-1 M0, or T1-3 N2 M0
IVA IVB	T1-T4 N3 M0, T4 N0-2 M0 Any T, N, M1

In contrast, advanced-stages pediatric NPC treated historically by RT alone have demonstrated poor prognosis, with 4 year disease-free-survival (DFS) about 40% due to metastatic relapses.^27,32 The positive impact of chemotherapy (CT) in addition of radiotherapy (RT) has been clearly demonstrated in adults.³³ Several retrospective studies have reported a better survival after combined treatment in pediatric series: Cheuck et al reported 81% 15-year OS with the use of cisplatin as compared with 54% after RT alone.¹² Combined treatment has become a standard in children considering the survival improvement reported in more recent prospective studies for Stages II (N1), III and IVa.^3,4,11,14 CT modalities (induction CT and/or concomitant CT) are more debatable and discussed below. Metastatic patients (IVb) are treated with multimodal strategy with initial CT regimens, locoregional RT, whenever possible focal treatment of metastases and maintenance therapy.^3,34

Induction chemotherapy regimen

Some recent large Phase III trials and meta-analysis comparing induction CT versus no neoadjuvant CT in adults did report an improvement in OS in favor of induction chemotherapy,³⁵ while some others did not.^35–39 Cisplatin-based regimen is a standard, but a recent meta-analysis could not determine the optimal neoadjuvant CT combination.⁴⁰

In children, no prospective comparative studies have been performed to assess the role of neoadjuvant CT. A recent large retrospective study compared induction cisplatin-based CT followed by concurrent chemoradiotherapy (CT–RT) in 130 patients, versus only concurrent CT–RT in 64 patients with no difference in term of survival.⁴¹ A matched analysis identified 43 well-balanced patients in both two groups. With a median follow-up of 51.5 months, a trend in favor of induction CT was found in 5 year OS (83.7% vs 74.6%, p = 0.153), and PFS (79.2% vs 73.4%, p = 0.355) but induction CT was associated with increased rates of severe neutropenia.

However, non-randomized prospective pediatric studies leading to the most favorable outcomes include neo adjuvant CT in children NPC.^3,4,11,14,42 A better outcome for patients in good response after neoadjuvant CT, as compared with patients in partial or minor response has been reported.¹³ The optimal type of induction CT is not consensual but all the prospective studies have reported optimal response using cisplatin-based CT in combination with 5-fluorouracil (FU).^3,4,11,14 Methotrexate was included in the two oldest prospective reports^4,14 but omitted in more recent protocols with the intention of reducing the rate of severe mucositis, without compromising neither response to induction CT nor survival.^3,11

In children, the only prospective Phase II randomized study on 77 patients with NPC, median age 16 years, showed that the addition of docetaxel to cisplatin-5-FU induction therapy did not provide any benefit in terms of local control rate and outcomes in children and adolescents.⁴³

Concomitant chemotherapy

In adults, a meta-analysis including eight randomized trials (1753 patients) compared cisplatin-based CT-RT versus RT alone in locally advanced NPC. A significant benefit was found for OS (6% at 5 years) and EFS (10% at 5 years) with the addition of CT.³³ An update on 19 trials and 4806 patients, confirmed this benefit.⁴⁴

In children, no randomized studies are available. Some retrospective studies have not demonstrated any impact of concomitant RT–CT in term of outcomes as compared with induction CT alone and RT.^42,45 However, concomitant RT–CT have been used in recent prospective trials of NPC in children leading to very good outcomes, with DFS reaching more than 90% in the best series.^3,11 As a consequence, most of the current protocol or guidelines consider concomitant RT–CT as a standard for the treatment of locally advanced pediatric NPC, in all the patients or only in selected patients after a poor response (stable disease or response <50%) to induction CT.^34,46

RT–CT may, however, be responsible for additional acute toxic effects, especially in terms of mucositis (up to 42% Grade 3 and 4 in some series) and skin toxicity. Patients must have a close follow-up of nutritional status before and during the whole treatment.^9,11,45,47

The role of interferon beta as maintenance therapy

In the large majority of studies, except in German series, patients did not receive systematic adjuvant therapy.¹¹ Interferon β (IFN-ß) was shown to have antiproliferative effects, cytotoxic effects and enhancement of cell surface antigen expression. In a first single arm prospective GPOH trial, 59 young patients were treated with 6 months of IFN-ß. After RT–CT, 72% of the patients were in complete remission. At the end of IFN-ß therapy, 98% of the patients achieved complete remission.⁴⁸ In another GPOH study, 45 young patients received IFN-ß for 6 months after completion of RT-CT. Two-third of the patients were in complete response or very good partial response after RT–CT, and 78% at the end of IFN-ß therapy respectively, with a good tolerance.¹¹ A retrospective French review has finally reported, 17 patients out of 95 treated with maintenance IFN-ß. No relapse was interestingly observed in these patients.⁴² The preliminary results plead in favor of the prospective evaluation of this drug after the completion of initial treatment by CT and RT.^11,42

radiation therapy

RT is crucial in the treatment of NPC, which are usually radiosensitive tumors. Every step in the RT delivery is highly important: immobilization device, target volume and critical organs definitions, choice of RT technique and RT dose

Immobilization, and planning-CT scan

Optimal immobilization is recommended in a supine position with a thermoplastic mask covering the head to the shoulders. The primary lesion and lymph nodes involvements are defined at diagnosis by conventional scan with contrast, axial contrast-enhanced MRI with thin slices (<3 mm), endoscopy examination and 18-fludeoxyglucose (FDG) positron emission tomography (PET)/scan when available. Its advantages are increasingly recognized in term of staging, especially to detect metastasis and clarify ambiguous MRI findings.^11,49 In addition, ¹⁸F-FDG-PET/scan has been reported to change treatment volume delineation of the gross tumor volumes (GTV) in adult series.^50,51 Dose escalation by using 18-FDG-PET/CT guided dose-painting IMRT has shown improved survival with no increased toxicities compared with CT-based IMRT in a retrospective large study in adults.⁵⁰ No data are available in pediatric NPC concerning the interest of 18-FDG-PET/Scan in delineation optimization but should clearly be investigated in the future considering the potential interest. In pediatric NPC, at least axial contrast-enhance MRI with thin slices (<3 mm) and endoscopy examination should be performed again after two or three cycles of induction CT to evaluate tumor response that may allow RT dose adaptation. Target volumes and most of critical organs are delineated using both planning scan (with contrast) and fusion MRI, which is highly recommended. Fusion MRI should include at least three-dimensional (3D)-contrast-enhanced axial T1 with thin slices.

Target volume definition and critical organs

Target volumes are similar to those well-defined in adults.⁵² Briefly, the gross tumor volume 1 (GTV1) includes the primary nasopharyngeal carcinoma, retropharyngeal nodes, and gross nodal disease defined at diagnosis on scan, MRI and endoscopy examination. In childhood, a gross target volume 2 (GTV2) is often delineated as the residue (primary tumor or/and nodes) after induction CT and is considered as the higher-risk volume.

The clinical target volume 1 (CTV1) includes the GTV1 with a 3–5 mm margins, and must include the potential areas of microscopic spread of disease. CTV1 should include the entire nasopharynx, half (posterior) of nasal cavity, entire sphenoid sinus, posterior third of ethmoid sinuses, clivus, pterygoid fossae, parapharyngeal spaces, skull base. Sham et al have shown that the protection of pituitary gland did not lead to increase local failure if the skull base was not involved, which can be interesting in childhood.⁵³ The CTV1 should also include lymph nodal groups involved at diagnosis. The CTV2 includes GTV2 (tumor and residual nodes after induction CT) and a 3 to 5 mm margin. Prophylactic RT is recommended in Level II, III, IV, V, VII, (and sometimes IB cervical lymph nodes) if they were not involved at diagnosis (and thus not included in CTV1 or CTV2). Finally, the planning target volumes PTV (PTV1 and 2) is defined as the CTV (CTV1 or CTV2) with a margin of 3–5 mm, to take into account setup margins and patient motion.

Critical organs to be delineated and doses to be respected as far as possible include : parotid glands (mean dose <25–30 Gy), sub maxillary glands (mean dose <35 Gy), brain stem (max. dose <54 Gy), upper spinal cord (max dose <45 Gy), hypophysis (max dose <45–50 Gy), chiasma (max dose <50–54 Gy), optic nerves (max dose <50–54 Gy), brain/temporal lobes (max dose <60 Gy), thyroid, eyes (mean dose <35 Gy), anterior chamber of the eyes, lens (mean dose <5–10 Gy), retina (max dose 45 Gy), internal ears and/or cochlea (mean dose <45 Gy), and larynx (mean dose <20 Gy), mouth cavity (max dose <55 Gy), temporomandibular joints (max dose <60 Gy).^46,54

Total radiation doses in children an AYA patients

Historically, childhood NPC were treated with RT doses quite comparable with adult doses, up to 66 to 70 Gy to the high risk areas, around 60 Gy on standard-risk areas, and 50 to 54 Gy on prophylactic lymph node regions.^55–58 Considering both the good prognosis and the high risk of severe late effects, several studies have more recently reported a RT dose reduction strategy in patients with good tumor response after induction chemotherapy in order to limit long-term RT toxicities in children or AYA NPC.^4,11,13,48 In the POG 9486 study, patients received a limited dose of RT (50.4 gray Gy to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy), in case of complete or partial response to neo adjuvant CT. 5-years OS and EFS were over 75%% despite the “limited” RT dose.⁴ In a French study, 34 children were treated for AJJC-TNM Stage IV NPC. After CT, cervical nodal RT was reduced (<50 Gy) in the 15 cases of a good response to chemotherapy (≥90% of initial tumor volume). The overall prognosis was not influenced by the dose of local RT delivered or response to the initial CT, but EFS was better in patients with a good response to CT. The cervical local failure rate was low despite RT dose reduction in the case of a good response to neo adjuvant chemotherapy.¹³

In the GPOH study, patients with Stage III/IV disease received 3 courses of induction CT. The cumulative RT dose was reduced to 54 Gy in five patients, who achieved complete remission after neoadjuvant CT, and 59.4 Gy in the remaining 40 patients, in combination with cisplatin, and followed by interferon. After a median follow-up of 30 months, the OS was excellent, over 97%.¹¹

These results are in favor of RT dose reduction in children and young adults providing a good response to induction CT, in order to decrease the risk of severe late RT effects. Several national guidelines recommend such a strategy of decreasing RT dose after induction CT, providing a complete or good partial response to induction CT.^3,34,42,46 Figure 1 represents the philosophy of current RT doses, recommended in pediatric NPC, depending both on the tumor/nodes involvement and on response to CT. Patients in minor response, stable disease or refractory disease (rare situations) are still treated with high RT doses, up to 66 Gy on tumor bed or involved nodes sites.

Figure 1. .

Representation of the RT doses levels according to the tumor and nodal involvements after induction chemotherapy. RT doses are adapted according to the risk of relapse, leading to several levels of doses (prophylactic = PTV0, standard risk = PTV1, high risk = PTV2). RT doses are also adapted to the chemotherapy response in several current guidelines. Chemo, chemotherapy; RT, radiotherapy; PTV, planning target volume

Fractionation

Historically, radiation oncologists prefer delivering RT using dose per fraction of 1.8 to 2 Gy in children and AYA, considering the risk of late effects is higher over this threshold. Randomized studies in adults have shown no significant difference between sequential boost and simultaneous integrated boosts (SIB) in terms of adverse events or tumor control.⁵⁹ Only one retrospective small study on 34 patients is available in children with no evidence of more toxicity.⁶⁰ Lots of clinicians consider SIB as an option even in pediatric practice but usually recommend a maximum dose per fraction of 2 Gy for high-risk volumes (Figure 2).

Figure 2. .

Principle of SIB as compared with sequential treatments (Gy: Grays). SIB, simultaneous integrated boost.

RT techniques

Randomized studies in adults have reported both increased local control and survival, as well as an improved quality of life of patients with NPC using intensity modulated radiotherapy (IMRT), as compared with conformal radiation therapy (3D-CRT).^61–63 Several reports in childhood are also in favor of IMRT use in NPC, considering the decrease of acute severe toxicity (skin, mucous membrane, and pharynx mainly), late effects and a better prognosis in survival.^1,56,64

The clinical benefit of protons in NPC is poorly known even in adults: the availability remains limited and the technique is complex to implement while volumes are large and highly complex. Most of the studies reporting dosimetric data, show similar adequate target coverage as compared with IMRT, while a better sparing of critical organs, especially parotid glands, cochlea, maxillary, and larynx.^65,66 Clinical results after protons are still rare and awaited especially to evaluate the benefit of protons on late effects.⁶⁷

Systemic treatment in distant metastatic patients

In metastatic situation and after relapse in adults, CT regimen based on gemcitabine/cisplatin has been defined as standard in a Phase III trial.⁶⁸ No specific pediatric study has been conducted in children with Stage IVb NPC. The 5-year OS is poor, <20%.^3,38 Since metastatic NPC is usually chemo sensitive at the beginning of the treatment, clinicians use a multimodal strategy with initial prolonged multidrugs cisplatin-based CT regimens, followed by locoregional head and neck RT, focal treatment of metastases lesions if feasible. Maintenance therapy with interferon-ß is finally suggested by some groups.^34,42

An oxaliplatin-containing regimen in combination with gemcitabine was recently reported on 14 children with relapsed NPC, and shows that this combination is a reasonable choice for first-line salvage therapy.⁶⁹ Immune-based therapy could be a promising treatment in case of relapses or refractory NPC and need to be evaluated in pediatric situations. In particular, some adult studies have reported both feasibility and safety of EBV-stimulated cytotoxic T-lymphocyte (EBV-CTLs) immunotherapy in EBV-related cancer including NPC, with or without previous lymphodepleting regimen.^70–72

Results and survival in young patients

Despite more advanced disease in AYA patients as compared with adults,^73,74 prognosis seems better: 5 year OS is over 75–80% (Table 2). Local and locoregional failures are rare (<8% in the vast majorities of the series), and distant relapse is the predominant mode of tumor failure. Relapses occur mainly within the first 2 years of follow-up, (Table 3). OS and DFS are very close : NPC relapses have a poor prognosis and the salvage gap after tumor events is low.⁷⁶

Table 2. .

Results in recent studies in childhood and AYA NPC patients

	N	Type of study	Stage	Age (years)	Treatment	OS	DFS
Jouin, 201942	95	Retrospective	All M0	Med. 15 y.	CT (90%) +RT/CT (59%) +IFN (18%)	five y : 94%	five y : 91%
Qiu, 20171	176	Retrospective	All M0	7–20 y. 24% < 14 y.	CT +RT : 28% CT +RT/CT : 44% RT/CT : 23%	five y : 76–90%	five y : 71–86%
Sahai, 20179	41	Retrospective	1/41 M1 (3%)	6–20 y. Med. 14 y. 34% < 12 y.	CT +RT/CT (68%)a	three y : 84%	three y : 56%
Guo, 201645	95	Retrospective	All M0	<25 y. 30% < 18 y.	CT (100%) +RT/CT (52%) +adj. CT (30%)	four y : 91%	4y : 79%
Chen, 201528	32	Retrospective	All M0	11 to 18 y. Mean 15 y.	CT+ RT/CT (40%) or CT +RT + CT (31%)*	five y : 86% III - 65% IV	NR
Liu, 201427	158	Retrospective	All M0	8 to 20 y. Median 16 y.	RT/CT 46% RT alone 54%	five y : 83%	NR
Daoud, 201374	69	Retrospective	All M0	10 to 20 y.	RT + CT 85% RT/CT 7%	five y : 66%	five y : 66%
Hu, 2013 (78)	95	Retrospective	All M0	9 to 20 y. 16 y.	CT + RT (38%)or RT alone (62%)	five y : 54%	four y : 49%
Casanova, 20123	46	Prospective	5/46 M1 (10%)	9 to 17 y. Med 13 y.	CT +RT/CT	five y : 81%	five y 87% (M0) and 20% (M1)
Buerhlen, 201211	45	Prospective	All M0	8 to 20 y. Med.15 y.	CT + RT+IFN	30 m : 97%	30 m 92%
Cheuk, 201112	59	Retrospective	2/59 M1 (3%)	Med. 14 y.	CT +RT/CT (88%) RT alone (12%)	15 y : 67% With cisplatin : 81% Without cisplatin : 54%	15 y : 63%
Afqir, 200910	46	Retrospective	4/46 M1 (9%)	Med.16 y.	CT +RT	five y : 73%	five y : 41%
Orbach, 200813	34	Retrospective	1/34 M1 (3%)	Med.12 y.	RT +CT (91%) or RT 9%	five y : 75%	five y : 73%
Rodriguez Galindo, 20054	17	Prospective	All N2/N3 and/or M0/1	Med. 13 y.	CT +RT	four y : 77%	four y : 75%
Mertens, 200514	59	Prospective	All M0	Med. 13 y.	CT +RT + IFN	nine y : 95%	nine y : 91%

AYA, adolescents and young adults; CT, chemotherapy; DFS, disease-free survival; IFN, interferon; MO, no mets; N, number of patient; NPC, nasopharyngeal carcinoma; NR, not reported; OS, overall survival; RT, radiotherapy; adj CT, adjuvant chemotherapy.

^aother patients treated with various RT/CT sequences

Table 3. .

Sites and timing of relapses in young NPC patients

Study	N	Local failure	Metastatic failure or combined	Time of relapse
Sahai, 20179	41	2.4%	41%	Med. 9 months
Guo, 201645	95	5%	16%	Med. 29 months
Greenwalt,201675	10	5%	40%	NR
Liu, 201427	165	5%	24%	All <15 months
Hu, 2013 (78)	95	14%	37%	NR
Daoud, 201374	69	1.4%	NR	All <24 months
Cheuk, 201112	59	5%	25%	NR
Afqir, 200910	46	0%	29%	NR

N, number of patients; NPC, nasopharyngeal carcinoma;NR, not reported.

Late effects

The most frequent late radiation effects are shown in Table 4. IMRT was shown to decrease the hearing loss rates and xerostomia as compared with 3D-CRT. Protons should also limit some toxicities but in contrast with IMRT, this is not yet clinically proven.^65–67 Protons may induce less xerostomia and as a consequence less cavities, as well as a potential gain on ear and endocrine toxicities. Other rare severe late complications include temporal necrosis (3–12%),^38,74 neuropathy (3–8%),²⁷ myelitis (<1%), osteonecrosis (1–5%)^12,27 and hemorrhage.

Table 4. .

Most frequent late radiation effects of radiotherapy in childhood NPC, and impact of the IMRT use

	All grades (2D–3D CRT)	All grades (IMRT)	Grade 3–4 (2D–3D CRT)	Grade 3–4 (IMRT)	Positive impact of IMRT vs 2D–3D CRT on late effect incidence
Hearing loss	40–54%1,12,27	22–50%1,27,45	5–10%12,27	027	Yes1 No27
Xerostomia	52–97%1,74	34–48%1,45	0%27	0%27	Yes1,27
Neck fibrosis	34–94%1,27	22–85%1,27,35	7–19%27,74)	9%27	Yes1 No27
Hypothyroidism	3–52%27,64,74	0–50%27,45	0% (27,80)	0%27	No1,27
Growth retardation	4–17%1,12	2–20%62,71	NR	NR	No (1,45,80)
Trismus	15–56%1,27,74	<10%62,71	8%27	5%27	Yes27 No1
Caries	22%4	2%7	NR	NR	NR

CRT, conformational radiation therapy; IMRT, intensity modulated radiation therapy; NPC, nasopharyngeal carcinoma; NR, not reported; positive impact, significative or trend (p < 0.

Secondary cancers are described in Table 5. In the future, the use of protontherapy which reduce integral dose, and may limit this risk.

Table 5. .

Risk of secondary cancer after NPC

	RT Technique (number of patients)	Second cancer (time of diagnosis since treatment when known)
Guo,45	IMRT (95)	0 %
Jouin, 201942	3D CRT38 IMRT57	3% (6–8 years)
Liu, 201427	3D CRT (103) IMRT55	3.8% (3–11 years)
Daoud, 201374	2D/3D CRT69	2.5 %
Casanova, 20123	2D/3D CRT30 IMRT18	3 %
Cheuk, 201112	2D/3D CRT52 IMRT6	8.5% (8–27 years)
Greenwalt, 201675	IMRT10	10% (meningioma)

CRT, conformational radiotherapy; IMRT, intensity modulated radiation therapy; NPC, nasopharyngeal carcinoma.

Conclusions

NPC in young patients are often advanced diseases but have a better prognosis than adults. 5 year OS is over 80% for non-metastatic disease, using combined strategies of induction CT, followed by concomitant CT and RT. Adapted-RT dose according to response to induction CT seems feasible but is still under larger evaluation. Adjuvant treatment such as IFN-ß may be of interest but need comparative studies. Protons should be more investigated to evaluate the long-term benefit in term regard of late effects, while they remain highly frequent and severe, especially after treatment in childhood and adolescence. International collaborations are clearly needed to pool the data and the knowledge.⁷⁵