Nasopharyngeal Carcinoma

RadOnc Dr Revanth M Khandke

ANATOMY

Description: The nasopharynx is a cuboidal chamber, slightly broader in the transverse dimension than the anterior-posterior dimension.

Boundaries and Communications

Anterior: Continuous with the nasal cavity via the posterior choanae
Posterior: Communicates with the oropharynx

Structural Components

Roof ▼

Formed by the basilar portion of the occipital bone
Superior surface of the soft palate and nasopharyngeal isthmus

Lateral Walls ▼

Eustachian Tube: The pharyngotympanic tube opens on the lateral wall
Torus Tubarius: Prominence formed by the cartilage of the pharyngotympanic tube
Fossa of Rosenmüller: Pharyngeal recess or fossa of Rosenmüller - the most common origin of nasopharyngeal malignancies

Muscular and Fascial Components ▼

Superior Pharyngeal Constrictor Muscle: Extends superiorly to skull base
Pharyngobasilar Fascia: Serves to attach the constrictor muscle to base of skull, continuous with pterygoid muscle

Innervation and Vascular Supply ▼

Nerve supplyThe afferent innervation of the nasopharynx anterior to the pharyngotympanic tube orifice is provided by the maxillary division of the trigeminal nerve (V2)and, posterior to the tubal orifice, the glossopharyngeal nerve. Motor supply via pharyngel branchs of glossopharyngeal nerve, vagus nerve, superior cervical ganglion
Arterial Supply: ascending pharyngeal artery, splenopaletine artery, artery of pterygoid canal
Venous Drainage: Internal jugular system and pterygoid plexus

EPIDEMIOLOGY

Age-Adjusted Incidence Rates by Region

Region/Population	Incidence Rate (per 100,000)
United States & Japan	0.6
Algeria	5.8
Philippines	11.0
Singapore	11.0
Eskimos, Indians, Aleuts (Alaska)	17.2
Hong Kong	26.9
Southern China	26.9

Demographics

Gender Ratio: Male to female ratio of 2:1 to 3:1
Age Distribution (Low-Risk Populations): First peak at 15-25 years, second peak at 50-59 years (bimodal distribution)
Age Distribution (High-Risk Populations): Fourth and fifth decade of life
The remarkably high incidence rates in Southern China and among Chinese populations worldwide can be attributed to a combination of environmental and genetic factors.

Risk Factors

Dietary Factors ▼

Preserved Foods: High intake of salted fish, preserved meats, and vegetables
Nitrosamines: Carcinogenic compounds formed during preservation process

Environmental Factors ▼

Salted Fish Consumption: High consumption of salted fish in Southern China
Dimethylnitrosamine: A carcinogen found in salted fish
Occupational Exposure: Exposure to dust, fumes, formaldehyde, cigarette smoke

Genetic Susceptibility ▼

Susceptibility Loci: Three susceptibility loci identified at HLA locus
HLA Haplotypes: A2, B46, B17, B58 associated with increased risk

Viral Etiology ▼

EBV Association: Strong association with Epstein-Barr Virus (EBV)
Histologic Type: Especially associated with nonkeratinizing undifferentiated type

NATURAL HISTORY

Local Extension Patterns

Anterior Extension ▼

Nasal fossa invasion is common
Lateral wall of nasal fossa leads to maxillary sinus involvement
Pterygoid plates
Posterior ethmoid and maxillary sinuses (less common)
Orbital apex invasion through inferior orbital fissure

Superior/Posterior Extension ▼

Base of skull invasion
Sphenoid sinus
Clivus
Foramen lacerum
Rosenmüller fossa - vulnerable spot to cavernous sinus and middle cranial fossa
Cranial nerves II to VI invasion

Inferior Extension ▼

Oropharynx extension not unlikely
Tonsillar pillars, tonsillar fossa
Lateral and posterior oropharyngeal walls
C1 vertebra invasion in advanced disease

Lateral Extension ▼

Lateral parapharyngeal space involvement
Levator and tensor veli palatini muscles
Pterygoid muscles invasion
Lateral retropharyngeal lymph nodes
Jugular foramen invasion affects cranial nerves IX-XI
Hypoglossal canal affects cranial nerve XII
Internal carotid artery compression
Middle ear through Eustachian tube

Structures Locally Infiltrated

Structure	Frequency (%)
Soft Tissue
Adjacent soft tissue	87
Nasal cavity	87
Pterygopharyngeal space, carotid space	68
Pterygoid muscle (medial, lateral)	48
Oropharyngeal wall, soft palate	21
Prevertebral muscles	19
Bony Erosion/Paranasal Sinus
Clivus	41
Sphenoid bone, foramina lacerum, ovale, rotundum	38
Pterygoid plate(s), pterygomaxillary fissure, pterygopalatine fossa	27
Petrous bone, petro-occipital fissure	19
Ethmoid sinus	6
Maxillary antrum	4
Jugular foramen, hypoglossal canal	4
Pituitary fossa/gland	3
Extensive/Intracranial Extension
Cavernous sinus	16
Infratemporal fossa	9
Orbit, orbital fissure(s)	4
Cerebrum, meninges, cisterns	4
Hypopharynx	2

LYMPHATICS

Lymphatic Network

Network Description: Vast avalvular lymph capillary network in mucous membrane
Presentation with Nodes: 85% to 90% of patients present with lymph node involvement
Bilateral Spread: Approximately 70% demonstrate bilateral lymph node spread

Anatomic Study - Lymphatic Drainage Pattern ▼

One Lymph Collector: Runs along lateral side of pharyngeal wall
Empties Into: Lateral pharyngeal node and retrofacial node of jugulodigastric chain
Retropharyngeal Group: 5th nodes posterior
Additional Involvement: Supraclavicular nodes can develop; submental and occipital nodes can be involved

Retropharyngeal Nodes ▼

Nodes of Rouvière
Lateral retropharyngeal nodes
Retropharyngeal group

Nodal Level Distribution

Nodal Level	Involvement (%)
RP (Retropharyngeal)	80
II	17
III	85
VA	46
VB	17
IV	19

Hematogenous Dissemination ▼

At Presentation: 6% of patients have distant metastases at initial presentation
During Disease Course: 18% to 50% develop distant metastases during the course of disease
Most Common Site: Bone is the most common distant metastatic site
Second Most Common: Lungs are the second most common site
Prognostic Note: Lung metastasis associated with better prognosis
Rare Sites: Brain and skin metastases rarely occur

CLINICAL PRESENTATION

Three Main Presenting Categories

Neck Masses: Usually appearing in upper neck/retropharyngeal area
Presence of Tumor Mass in Nasopharynx: Epistaxis, nasal obstruction, discharge
Skull Base Erosion and Cranial Nerve Palsy: Headaches, diplopia, facial pain, numbness

Symptoms and Physical Signs at Presentation

Symptom/Sign	Chao and Perez (n=164) %	Lee et al. (n=4,768) %
Neck mass	66	76
Enlarged nodes	—	75
Nasal symptoms	37	73
Aural symptoms	41	62
Headache	40	35
Cranial nerve palsy	23	20
Ophthalmic symptoms	—	11
Facial numbness	—	8
Slurring of speech	—	2
Sore throat	16	—
Weight loss	—	7
Trismus	—	3
Distant metastases	—	3
Dermatomyositis	—	1

Cervical Lymphadenopathy ▼

Prevalence: Present in up to 87% of patients
Location: Mass observable in upper posterior neck and palpable beneath superior portion of sternocleidomastoid muscle
Cause: Metastasis to parapharyngeal nodes or superior-posterior cervical nodes of spinal accessory chain

DIAGNOSIS

Workup Overview:

Medical History ▼

Epistaxis
Nasal discharge
Neck mass
Headache
Diplopia, facial pain, hearing loss, tinnitus, ear pain
Duration of each symptom
Presence of enlarged cervical lymph nodes

Physical Examination ▼

Testing of Cranial Nerves: Especially cranial nerves II-XII
Nasopharyngoscopy and Biopsy: Essential for diagnosis
Neck Examination: Palpation of neck nodes for size, number, laterality, mobility
Baseline Audiologic Testing: Particularly if cisplatin is being considered
Laboratory Studies: CBC, chemistry, LFTs
Dental Evaluation: Pre-treatment assessment
Smoking Cessation Counseling: If relevant

Imaging Modalities:

CT Scan ▼

Extent MRI for head and neck with contrast for tumor extent evaluation
Detect bone invasion
Evaluate skull base involvement

MRI (Preferred Imaging Technique) ▼

Preferred Status: MRI is the preferred imaging technique in staging evaluation
Parapharyngeal Space: Accurately defines tumor extension into parapharyngeal space
Skull Base: Superior to CT for skull base involvement
Sensitivity/Specificity: Better sensitivity and specificity for detecting NPC (100% sensitivity, 91% specificity)
T1 Images: Assess lymph node size and abnormal ultrasound findings
T2 Images: Detect skull base tumor extent
T2-weighted Fat-Saturated Images: Improve detection of submucosal infiltration

PET-CT Scanning ▼

18F-FDG-PET: Superior for detecting metastasis
Cervical Lymphadenopathy: Superior to CT alone and ultrasound for cervical lymphadenopathy detection
Treatment Response: Can assess treatment response
Recurrence Detection: Useful for recurrent disease detection
Performance: Sensitivity and specificity at 100% and 93% respectively

Table 44.4: Incidence of Cranial Nerve Involvement

Cranial Nerve	Chao and Perez (%)
II	2.4
III	3.4
IV	0.6
V1	2.8
V2, V3	13.8
V (all)	15.8
VI	3.4

Recommended Pre-Treatment Diagnostic Evaluations

Evaluation
Complete H&P with endoscopy
Nasopharyngoscopy and biopsy (mandated)
MRI of primary site and neck with contrast preferred
Chest imaging (CT or PET/CT)
PET/CT preferred for staging
Dental evaluation
Speech and swallowing evaluation
Audiology examination
Nutritional counseling
Plasma EBV DNA testing

Distant Metastasis Workup ▼

Model:lymph nodes that are borderline (distant evaluation of nodal enlargement by palpation and imaging)
Considerations: Size and location of nodes, bilateral/contralateral involvement, supraclavicular location
Boundaries: At level of supraclavicular fossa with superior boundary apex of lung, inferior limit clavicular heads

PROGNOSIS

Prognostic Factors Overview

Extent of local invasion
Regional lymphatic spread
Distant metastasis
T category
N category

T Category Correlation with Outcomes ▼

Advanced T category associated with worse local control and overall survival
Patterns of failure and survival rate vary for different T and N categories

M1 Presentation Impact ▼

M1 upon presentation usually indicates poor prognosis
Typically treated with conventional, palliative treatment approaches

Bone Erosion and Cranial Nerve Palsy ▼

Bone erosion associated with poorer prognosis
Cranial nerve palsy indicates worse outcomes
Lower nodal levels associated with poorer prognosis

Parapharyngeal Extension - Topic of Controversy ▼

Study of 803 Patients:

Tumor limited to prestyloid space showed 5-year local control of 72% vs 86%
Distant failure-free survival: 68% vs 87%

Other Investigators:

Similar significant findings reported
Key factor in distant metastasis

Contradictory Findings:

Cheng et al. did not find parapharyngeal space involvement to be significant
Ao et al. also did not find it to be significant

Definition Variation:

Varying definitions of parapharyngeal space extension in different studies
This may contribute to conflicting results

2010 AJCC Staging System Changes ▼

Major Change:

Downgraded involvement of oropharynx/nasal cavity without parapharyngeal extension from T2a to T1

Rationale:

No significant difference in disease failure hazard ratios

Analysis Details:

Soft-tissue disease of T2 stage group in AJCC 2002 and T1 in AJCC 2010
Study included 1,605 patients all staged by MRI

GTV-P: Tumor Volume as Prognostic Factor ▼

Definition:

GTV-P: Gross Tumor Volume of Primary tumor

Correlation:

Highly correlated to T-stage, but with considerable overlap

Significance:

Increasingly suggests tumor volume as independent significant factor
Studies show it better predicts local control than T category alone per AJCC/UICC

Multivariate Analysis:

Confirmed GTV-P as strong significant factor independent of T category

Threshold Study:

GTV-P >15 cm³ had significantly higher L-FFR than those with ≤15 cm³
97% vs 85%, P < .01

Gender and Age Effects ▼

Gender:

Females found to have significantly better prognosis
Males have worse cancer-specific death rates (HR=1.28, P=.02)

Age Distribution Studies:

Younger patients: Higher 5-year survival rate (70% in <40 years vs 40%, P=.002)
Males comparison: 45% vs 28% in patients younger than 40 versus older than 60
Age did not significantly affect the 10-year survival rate
Patients older than 50 years: Worse cancer-specific death rates (HR=1.79, P<.001)

Histology Differences ▼

General Finding:

Many found nonkeratinizing and undifferentiated carcinomas (former WHO lymphoepithelioma) to have better prognosis than keratinizing squamous cell carcinoma

Ethnic Difference:

Some authors found prognostic difference between ethnic Asian and non-Asian patients with nonkeratinizing carcinoma

BIOMARKER

EBV Association with NPC ▼

Association:

Strong association with Epstein-Barr Virus (EBV)
Especially nonkeratinizing type

Viral Proteins:

Latent Membrane Proteins: LMP1, LMP2A, LMP2B
Nuclear Antigens: EBNA1, EBNA2

Molecular Mechanisms:

C-terminal activating regions of protein activate variety of signaling pathways
Pathways include: MAP kinases, PI3K, NF-κB, EGFR

LMP1 Role:

Required for cell transformation
Present in 80-90% of NPC tumors
Likely etiologic role for EBV in NPC

Plasma EBV DNA ▼

Median Copies by T Stage

T Stage	GTV-P	Median EBV DNA
T1	2 ml	0
T2	7 ml	13,260
T3	18 ml	28 fold increase
T4	32 ml	65 fold increase

Detection Accuracy:

Sensitivity: 96%
Specificity: 93%

Key Studies:

Lo et al.: Showed plasma EBV DNA had high sensitivity (96%) and specificity (93%) for detecting NPC
Ma et al.: Levels correlated with tumor load
Lu et al.: High pretreatment levels associated with advanced stages and poor prognosis
Lin et al.: Independent prognostic factor for OS (HR=2.34, 95% CI 1.29-4.24, P=.005)

Prognostic Significance ▼

Patients with detectable EBV DNA had 2-year OS of 84% vs 98% for non-detectable
3-year DFS: 71% vs 85%

Treatment Monitoring Applications ▼

Combined EBV DNA measurements with persistently detectable EBV DNA could predict prognosis

Adjuvant Chemotherapy Considerations ▼

Early evaluation of plasma EBV DNA can identify patients at high risk for recurrence
Useful for guiding adjuvant therapy decisions

HPV Status Discussion ▼

Recognition:

HPV-associated oropharyngeal carcinomas recognized as separate entity from HPV-negative

Prevalence:

10-20% of NPC cases are HPV positive
24% of HPV positive are EBV-negative
Prevalence varies by geographic region and ethnicity

Geographic Studies:

Robinson (Southern China): 0% HPV positive
Stamford (California): 10% HPV positive in Chinese cohort, 25% in non-Chinese
Rassekh: 27% HPV-positive

Prognosis:

Similar OS in EBV-positive vs. HPV/EBV-negative patients

Other Biomarkers ▼

VEGF: Associated with prognosis
p53 and Ki67: Cell turnover rate markers
EGFR: Epidermal growth factor receptor
HER2: Human epidermal growth factor receptor 2
p53 Monoprotein: Tumor suppressor protein marker
PD-1: Found to be only independent prognostic factor in some studies
Hepatitis B: HBsAg antibody positivity 57%, pathologic analysis T4 (CA, DA)

T	Criteria
TX	Primary tumor cannot be assessed
T0	No tumor identified, but EBV-positive cervical node(s) involvement
T1	Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement
T2	Tumor with extension to parapharyngeal space and/or adjacent soft tissue involvement (e.g. medial/lateral pterygoid, prevertebral muscles)
T3	Tumor with infiltration of bony structures at skull base (clivus), cervical vertebra, pterygoid structures, and/or paranasal sinuses
T4	Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, or extensive soft tissue infiltration beyond lateral pterygoid muscle

N	Criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Unilateral metastasis in cervical lymph node(s) and/or retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above caudal border of cricoid cartilage
N2	Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above caudal border of cricoid cartilage
N3	Unilateral or bilateral metastasis in cervical lymph node(s) >6 cm in greatest dimension and/or extension below caudal border of cricoid cartilage

M	Criteria
M0	No distant metastasis
M1	Distant metastasis present

When T is…	And N is…	And M is…	Then the stage group is…
Tis	N0	M0	Stage 0
T1	N0	M0	Stage I
T1, T0	N1	M0	Stage II
T2	N0	M0	Stage II
T2	N1	M0	Stage III
T3	N0	M0	Stage III
T3	N1	M0	Stage III
T4	N0	M0	Stage IVA
T4	N1	M0	Stage IVA
T4	N2	M0	Stage IVA
Any T	N3	M0	Stage IVA
Any T	Any N	M1	Stage IVB

TRIALS & KEY STUDIES

Below is a transcription / summary of the screenshot 'Notable Studies' — organized as tables and key points for quick reference.

Benefit of ChemoRT over RT Alone

Name / Inclusion	Arms	Outcomes	Notes
Intergroup-0099 Al-Sarraf et al., JCO 1998 Phase III RCT, Stage III–IV NPC N = 147	Definitive RT vs Concurrent cisplatin/RT + adjuvant cisplatin	Concurrent cisplatin/RT + adjuvant cisplatin improved 3-y PFS: 24% vs 69% (P < .001) and OS: 46% vs 78% (P = .005)	Established 70 Gy in 1.8–2 Gy/fx (66 Gy for involved nodes, 50 Gy for elective nodes) with concurrent chemo
Singapore phase II Wee et al., JCO 2005 Phase II RCT, endemic population	Definitive RT vs Concurrent cisplatin/RT + adjuvant cisplatin	Concurrent cisplatin/RT + adjuvant cisplatin improved 2-y OS (78% vs 85%; HR = 0.51, P = .0061)	Confirmed Intergroup-0099 results in Asian population
MAC-NPC meta-analysis Blanchard et al., Lancet Oncol 2015 19 trials, N = 4806	Concomitant CRT vs RT alone	Benefit with CRT: 10-y OS benefit ~9.9%; 10-y PFS benefit ~9.5%	No OS benefit for induction or adjuvant in pooled analysis

Benefit of IMRT for Nasopharynx Cancer

Study	Arms	Outcomes	Notes
Kam et al., JCO 2007 RCT T1–T2b N0–N1, N = 60	IMRT vs 2D CRT	1 year post-RT: IMRT arm had lower xerostomia rates (39.3% vs 82.1%, P = .001)	66 Gy in 33 fractions to gross tumor and 60–54 Gy to node-negative regions
Pow et al., IJROBP 2006 RCT T2N0–1M0, N = 51	IMRT vs Conventional RT	IMRT significantly improves QoL (P < .001) — greatest improvement in xerostomia-related symptoms at 12 months	Supports IMRT for salivary sparing and QoL

Induction Chemotherapy

Study	Arms	Outcomes	Notes
GORTEC NPC 2006 Huang et al., Eur J Cancer 2015? (shown as 2006 in screenshot) — Advanced NP, N = 408	Induction followed by CCRT vs Induction followed by RT	No OS benefit (50.4% vs 48.8%, P = .71); no LRF benefit (79% vs 82.5%, P = .41)	No distant failure-free survival benefit (67.7% vs 66.1%, P = .90). No significant 10-y survival differences between IC+CCRT and IC+RT arms shown in screenshot.
Sun et al., Lancet Oncol 2016 Phase III multicenter RCT, locally advanced	Induction TPF (cisplatin, fluorouracil, docetaxel) + chemoRT (cisplatin) vs chemoRT alone	3-y failure-free survival improved in induction group (80% vs 72%, P = .034)	Induction TPF + chemoRT may improve outcomes compared with chemoRT alone in locally advanced NPC
Cao et al., Eur J Cancer 2017 Phase III multicenter RCT, locoregionally advanced NPC N = 476–480	Induction (cisplatin + fluorouracil) + chemoRT (cisplatin) vs ChemoRT alone	Induction improved 3-y DFS (82% vs 74%, P = .028); DMFS improved (88.2% vs 82%, P = .056). No OS difference at shown follow-up	Significant increase (P < .001) in grade 3–4 toxicity in induction arm
Zhang et al., NEJM 2019 Phase III multicenter RCT, N = 480	Induction gemcitabine + cisplatin + CRT vs Concurrent CRT	Improvement in 3-y RFS (85.3% vs 76.5%, P = .001) and OS (94.6% vs 90.3%) with HR 0.43 (P < .05)	Higher grade 3–4 toxicity in induction arm; median follow-up ~42.7 mo in screenshot

Adjuvant Chemotherapy

Study	Arms	Outcomes	Notes
Chen et al., Eur J Cancer 2017 Phase III multicenter RCT, locoregionally advanced NPC, N = 251	CCRT vs CCRT + adjuvant chemo	No significant difference in 5-y failure-free survival (adjuvant 75% vs no adjuvant 71%, P = .45)	Long-term outcomes: adjuvant cisplatin associated with increased late grade 3–4 toxicity (adjuvant 27% vs no adjuvant 21%, P = .14 in screenshot)

Key takeaways

Concurrent cisplatin + RT (with/without adjuvant cisplatin) — proven OS and PFS benefit vs RT alone (Intergroup-0099, Singapore data, meta-analysis).
IMRT — improves xerostomia and QoL (Kam et al., Pow et al.).
Induction chemotherapy — several trials (Sun 2016, Zhang 2019, Cao 2017) show improvements in DFS/DMFS/RFS in selected regimens (TPF, gemcitabine+cisplatin), but with increased toxicity; pooled meta-analysis shows benefit primarily with concomitant CRT.
Adjuvant chemotherapy — inconsistent survival benefit in modern trials; increased toxicity is a concern.

MANAGEMENT

Treatment Algorithm

Stage	Recommended Management (summary)
Stage I	Definitive RT alone
Stage II–IVA	Concurrent chemoRT ± adjuvant chemotherapy OR induction chemotherapy followed by concurrent chemoRT
Stage IVb	Chemotherapy alone or concurrent chemoRT (palliative/individualised)

Radiotherapy ▼

Dose / Targets (Definitive)

Gross disease (CTV_HD):
- Dose: 70 Gy in 33–35 fractions, daily
- Target: GTV (tumour + involved nodes) + 5–8 mm margin (tighter margins if near critical neural structures)
Intermediate risk (CTV_ID):
- Dose: 59.4–63 Gy in 33–35 fractions
- Target: entire nasopharynx, retropharyngeal nodes, clivus (anterior 1/2 if uninvolved), pterygoid fossa, parapharyngeal space, sphenoid sinus (inferior 1/2 if uninvolved, entire if involved), posterior 1/3 maxillary sinus and nasal cavity, cavernous sinus if locally advanced, and skull base foramina as indicated.
- Target neck (excluding CTV_HD): cover remaining neck levels not covered by CTV_HD, approximately +2 cm cranio-caudal margins as needed clinically.
Low risk (CTV_ED):
- Dose: 54–56 Gy in 33–35 fractions
- Target: levels II–IV in N0 neck; in involved necks include IB–V and bilateral RP nodes as indicated.
PTV expansion: typically 3–5 mm depending on immobilization and IGRT.

Chemotherapy ▼

Concurrent

Cisplatin: 30–40 mg/m² weekly OR 100 mg/m² on days 1, 22 and 43 (goal cumulative cisplatin ≈ 200 mg/m²).
Carboplatin may be used if cisplatin contraindicated or not tolerated.

Adjuvant

Example regimen from screenshot: Cisplatin 80 mg/m² weekly + 5-FU 1000 mg/m² q4wk × 3 cycles (as listed in screenshot summary).

Induction

No single universally accepted induction standard; screenshot lists commonly used regimens:

Regimen	Notes
Cisplatin + Gemcitabine	Top choice in several modern trials (eg. NEJM 2019 gemcitabine+cisplatin benefit).
TPF (Docetaxel + Cisplatin + 5-FU)	Used in trials showing DFS/FFS benefit (Sun et al., etc.).
Cisplatin + 5-FU	Traditional doublet induction regimen.
Cisplatin + Epirubicin + Paclitaxel	Alternative combinations reported in some series.

Practical points

Concurrent cisplatin + RT is the evidence-based backbone (Intergroup-0099, Singapore, meta-analyses).
Induction regimens may increase DFS/DMFS in selected trials but increase grade 3–4 toxicity; choose regimens and patients carefully.
Adjuvant chemotherapy results are mixed and can increase late toxicity; assess benefit/risk per individual patient and trials.
Always use modern IMRT with image guidance to optimize tumor coverage and reduce toxicity (xerostomia, etc.).