Head & Neck Flashcards
Discuss EGFR in the context of H&N SCC
EGFR = Transmembrane/cell surface glycoprotein, part of receptor tyrosine kinase family; role in signal transduction
Structure - consists of 3 domains:
- Extracellular Ligand-Binding Domain: binds epidermal growth factor and other ligands. Binding of the ligand to domain causes a conformational change that activates the receptor
- Transmembrane Domain: single alpha-helix segment spans across the cell membrane - role in the receptor’s dimersiation with ligand binding
- Intracellular Tyrosine Kinase Domain: within the cell, this domain has tyrosine kinase activity. Upon activation, it autophosphorylates specific tyrosine residues, triggering downstream signalling pathways.
EGFR in H&N SCC
- Overexpression:
□ EGFR often overexpressed in head and neck SCC → associated with poor prognosis and aggressive tumour behaviour.
□ Overexpression leads to enhanced signalling that promotes cell proliferation, survival, and migration
- Target for Therapy:
□ eg. EGFR inhibitors which aim to block signalling (or its down stream signalling molecules); thereby inhibiting tumour growth and progression
□ Eg. cetuximab (a monoclonal antibody)
□ Eg. Erlotinib (tyrosine kinase inhibitor)
- Predictive Biomarker:
□ EGFR expression levels and mutations can serve as biomarkers to predict the response to targeted therapies.
□ High EGFR expression may indicate a better response to EGFR inhibitors.
- Resistance Mechanisms:
□ Despite efficacy of EGFR-targetted therapioes, resistance can develop.
□ includes mutations in the EGFR gene, activation of alternative signalling pathways, and phenotypic changes in cells.
Describe the epidemiology and biological behaviour of HPV associated H&N cancers and compare to HPV negative cancers
- Aetiology
* Mainly mediated by HPV 16
* E6 inactivates p53, E7 inactivates RB- Microscopic appearance
- Usually non-keratinising SCC (basaloid type), predominantly oropharynx (BoT, tonsil)
- IHC - p16 positive (surrogate marker)
- HPV detection through ISH or PCR
- Biologic behaviour
- Earlier T stage, but more advanced N stage than non-HPV cancer
- Favourable prognosis
- 5yr OS St 3-4 (AJCC 7th edition) 80% vs. 40% cf. non-HPV associated oropharyngeal cancer
- Responds better to treatment
- Epidemiology
- Increased incidence of BoT and tonsil cancer, despite decreased incidence of smoking and H&N cancer at other site
- Incidence: Increasing, 70% of oropharyngeal SCC in Australia
- Age: Middle-aged (younger than non-HPV)
- Sex: M>F
- Often higher socioeconomic status, non-smokers
- Microscopic appearance
Describe HPV mediated carcinogenesis
HPV has high-risk and low-risk subtypes
* HPV 16, 18, 31, 33 are high-risk
* Remainder are low risk (e.g. 6, 11)
HPV replicates by entering a cell and incorporating its own DNA into the cellular DNA. In this way, the cellular machinery is manipulated to create many copies of the virus, which is then released for further spread and infection. The E6 and E7 oncoproteins of the high-risk HPV subtypes manipulate cellular machinery in such a way to cause carcinogenesis * E6 associates with the p53 protein and leads to the ubiquitination, thereby inhibiting its function. E6 also causes other more minor protease-mediated cellular damage * E7 associates with the Rb (retinoblastoma) protein and causes its proteasome-mediated degradation. E5 is also oncogenic, but less potent * E5 can activate EGFR signalling and thus promote cellular growth This in turn, causes carcinogenesis in the following ways * Cellular immortality (disabled apoptotic pathways) * E6 disables p53 * Genomic instability (impaired cellular DNA repair pathways) * Disabled apoptosis allows accumulation of genetic damage without an endpoint * Unregulated cellular proliferation (removal of cell-cycle arrest mechanisms) * E6 disables p53 * E7 disables Rb * Sustained proliferative signalling * E5 can activate EGFR pathway * Impaired immunity (ongoing infection and inflammation) * E6/7 inhibit interferon signalling (impair innate immunity) * E5 down-regulates MHC-I expression * This leads to persistence of infection (which is required for carcinogenesis --> accumulate genetic damage) * Other * E7 induces angiogenesis * E7 induces Warburg effect (altered metabolism)
Describe the pathological features of leukoplakia and erythroplakia
- Leukoplakia
* Definition / clinical features: Clinical descriptive term. White patch or plaque on mucosa (solitary or multiple) that cannot be scraped off and cannot be characterised clinically or pathologically as any other disease
* I.e. if a white lesion can be given a specific diagnosis, it is not leukoplakia
* Location: Commonly buccal mucosa, floor of mouth, ventral surface of tongue, hard palate
* Microscopic appearance:
* Spectrum of epithelial changes ranging from:
* Hyperkeratosis overlying a thickened, acanthotic but orderly mucosal epithelium; to
* Markedly dysplastic changes, sometimes merging into carcinoma in situ
* With increasing dysplasia there is an increasing frequency of subepithelial inflammatory infiltrate of lymphocytes and macrophages
* Biologic behaviour:
* 5-10% progress to invasive disease
* Considered pre-malignant
* Management:
* Options: observe or resect
* Decision based on compliance with follow up, location (ease of resection) and presence of erythroplakia (higher malignant transformation potential)
* All patients should encouraged to cease smoking and alcohol- Erythroplakia
- Clinial appearance: Red velvety, possibly eroded lesion
- Epidemiology: Less common but more ominous
- Microscopic: ]
- Only rarely consist of orderly epidermal maturation
- Virtually all (~90%) contain superficial erosions, with dysplasia, carcinoma in situ or already developed carcinoma in the surrounding margins
- Often an intense subepithelial inflammatory reaction with vascular dilatation is seen that likely contributes to the reddish appearance
- Biologic behaviour: 30-50% progress to invasive carcinoma
- Management: Should be resected due to high risk of malignant transformation
- Erythroplakia
Describe the incidence and RF for oral cavity cancers
Incidence (Australian statistics)
- ALL = 4500 cases annually
- ORAL = 2000 cases annually
- Approx 8 per 100000 people
Rising incidence of young people < 40yo (especially females)
- Likely HPV related
Median age is 60 years
Male predominance (up to 4:1)
Aetiology
1) Smoking (RR is up to 10x) a. ALSO - cigar use, chewing tobacco, betel nut 2) Alcohol use (RR is up to 5x) a. Synergistic with smoking 3) Leukoplakia a. Up to 10-25% of these lesions will progress to cancer 4) Occupational exposure a. Asbestos b. Mustard Gas c. Nickel d. Tar 5) Viral a. HPV is implicated (less strongly than for oropharynx) 6) Immunosuppression 7) Nutritional deficits a. Fruits and vegetables are protective 8) Poor oral hygiene & periodontal disease 9) Previous radiation 10) Genetic factors a. Fanconi anaemia b. Ataxia telangiectasias c. Xeroderma pigmentosum
Metachronous lesions
- Second H+N primary = 20% risk
- Lung = 5-10%
- Oesophagus = <5%
Describe the pathological features of hyperplasia and dysplasia
- Squamous hyperplasia
* Response to carcinogen exposure, mechanical irritation or other noxious stimuli. Tobacco is the most common cause
* Favoured locations
* Buccal mucosa
* Floor of mouth
* Ventral surface of tongue- Squamous dysplasia
- Explanatory notes:
- In normal squamous mucosa, mitotic activity is confined to the basal layer of cells (small cuboidal cells with dark nuclei and scant cytoplsam) and immediately adjacent cells (para-basal)
- As cells mature -> move up, acquiring more cytoplasm -> become progressively keratinised
- Near surface, cells flatten out and nucleus disappears
- In squamous dysplasia, normal architectural pattern of maturation is disturbed, indicative of neoplastic transformation
- Progressive disorganisation and loss of maturation (polarity) of the squamous epithelium as cells move upward from the basal layer to the nonkeratinised surface
- Dyskeratosis (out of sequence individual cell keratinisation) often accompanies loss of polarity
- In normal squamous mucosa, mitotic activity is confined to the basal layer of cells (small cuboidal cells with dark nuclei and scant cytoplsam) and immediately adjacent cells (para-basal)
- Morphology
- Loss of polarity, often accompanied by dyskeratosis extending from the basal layer of the epithelium
- Mitotic figures
- Nuclear pleomorphism may be present in all grades but is not a conspicious feature
- Degree of dysplasia is graded based on extent of thickness of eptihelial layer involved with dysplastic basal type cells
- Mild dysplasia: Abnormal architectural and cytological features largely confined to hte lower thrid of the epithelium
- Moderate dysplasia: Dysplastic process extends to middle thirdof epithelium
- Severe dysplasia: Extension of preoces sinto the upper third of the epithelium
- Carcinoma in situ: Full thickness invovlement is present in the absence of invasion (for practical purposes severe dysplasia and carcinoma in situ are synonymous
- Biologic behaviour
- May regress spontaneously
- May progress to invasive malignancy
- Relationship less well defined than for cervix SCC
- Moderate dysplasia: 4-11% risk
- Severe dysplasia: 20-35% risk
- Invasive malignancy may develop in the absence of surface dysplasia
- Explanatory notes:
- Clinical appearance
- Both squamous hyperplasia and dysplasia may present as leukoplakia
- Erythroplakia usually represents squamous dysplasia, carcinoma in situ or invasive carcinoma
- Squamous dysplasia
Describe the mechanisms for developing synchronous tumours in the Head and neck.
Field cancerisation
- Due to equal carcinogenic distribution, all areas are likely to have mutational damage
- Ie. Entire mucosal surface of upper aerodigestive tract exposed to carcinogens (smoking, ETOH, HPV, chronic inflammation), leading to widespread genetic alterations and a higher risk of developing multiple primary tumours
Monoclonal seeding:
- multiple primary tumours may arise from the clonal expansion of a single mutated cell that has spread across different sites aerodigestive tract
- through intraepithelial migration or dissemination (and re-implantation) of malignant cells within the mucosal field
- Seemingly new tumour deposit proliferates
Genetic predisposition
- Mutations in tumor suppressor genes (e.g., TP53) or DNA repair genes increase the risk of multiple primary cancers.
What are the histological subtypes for oral cavity cancers?
- Squamous Cell Carcinoma (95%)
○ Verrucous carcinoma (5%)
○ Spindle cell
○ Basaloid- Salivary gland
- Neuroendocrine
Describe the pathological features of oral cavity SCC.
- By far, the most common histological subtype of oral cavity cancer
- Macroscopic
○ Pink/grey area of mucosal thickening
§ Ulcerated mass when late/advanced
○ May be superimposed on leukoplakia - Microscopic
○ Nests of keratinising squamous cells which invade the basement membrane
§ Keratin pearls and intercellular bridges
○ Variable cellular anaplasia - Variants
○ Verrucous –> white, warty, cauliflower like lesion
§ Low metastatic potential
○ Sarcomatoid/spindle cell –> biphasic mixed carcinoma with spindle component
§ Aggressive disease course
○ Basaloid –> small basaloid cells with peripheral palisading and high-grade features (high N;C ratio, pleomorphism, hyperchromatic nuclei, mitoses)
§ Aggressive disease course
§ o Positive stains: 34beta E12, EMA, AE1/3, CAM 5.2, neuron specific enolase, CEA, S100
○ o Negative: chromogranin, syanptophysin, muscle specific actin, GFAP
○ adenosquamous - Immunohistochemistry
○ POS = AE1/AE3, HMWCK
- Macroscopic
What are the subsites of the oral cavity and what is their respective lymphatic drainage routes?
What are the prognostic factors for oral cavity cancers?
Patient Factors
- Age and performance status
- Nutritional status
- Immunosuppression
- Smoking (local control and toxicity)
- Anaemia
○ Non-reversible –> transfusion does not improve outcomes
Tumour Factors
- TNM stage
- Tumour site
○ Tongue is worse
- Depth of Invasion
- Pattern of invasion (discohesive cells at tumour front)
○ Worst is pattern 5 = satellites >1mm from main tumour, or PNI, LVI outside tumour
- Grade (of limited value)
- LVI
- PNI
- ECE
Treatment Factors
- High-volume experienced centre
- Surgical margins
- Addition of adjuvant radiotherapy
○ Overall treatment time
What features on history and examination for oral cavity cancers are important?
- History
○ HPI
§ Observation
□ Non-healing ulcer (painful or painless)
□ Ill-fitting dentures
□ Exophytic mass or leukoplakia
□ Red area
§ Odynophagia
§ Speech deficits
§ Bleeding
§ Otalgia (referred)
§ Trismus
Neck lumps (30% LN mets at diagnosis. ○ ant tongue common 50-60%
○ Hard palate/aveolar ridge uncommon
○ lip <10%, but more common in T3/4 or with commisure involvement. Rare to have distant mets
).
○ PMHx:
§ Previous H+N cancer
§ Previous radiotherapy
§ Immunosuppression
○ Meds:
§ Immunosuppression
○ Social:
§ Smoking
§ Alcohol
§ Other (e.g. betel nut)- Examination
○ Thorough oral cavity examination
§ Ulcerated lesions
§ Fixation to underlying structures
○ Should inspect remaining mucosa for synchronous lesions
○ Mental nerve function
○ Cervical lymphadenopathy
○ Flexible Nasendoscopy to exclude synchronous lesions
- Examination
What investigations would you order for oral cavity cancers?
- Biopsy
○ EUA
○ Biopsy any equivocal neck nodes (unless already proceeding with neck dissection)
§ USS guided FNA
§ If unresectable or metastatic disease then core bx for immune-genomic testing- MR Head and Neck
○ Surgical evaluation - FDG-PET
○ Nodal and distant staging - Diagnostic CT Head and Neck
○ Evaluate bony invasion - Pre-chemotherapy bloods
○ FBC
○ EUC, CMP
○ LFT and coags
○ HepB sAg, sAb, cAb
○ Hep C serology
○ HIV serology - Dental assessment
- OPG
- MR Head and Neck
What is the TNM staging for oral cavity cancers?
- Stage I
○ T1N0- Stage II
○ T2N0 - Stage III
○ T3 OR N1 - Stage IV
T4+ OR N2+
- Stage II
What are the general principles when managing oral cavity cancers?
- Always aim to use as few modalities as is feasible (reduce morbidity)
- Always establish relevant supportive care early
○ Smoking cessation
○ Dietician and speech pathology input
§ Consideration of prophylactic gastrostomy
○ Dental input
§ Pre-RT OPG
○ Social & psychological supports as appropriate - In general, options may include
○ Early Stage (stages I-II)
§ Surgical resection alone (+/- adjuvant RT)
§ Radiotherapy alone (uncommon)
○ Advanced Stage (stages III-IV)
§ Surgical resection + adjuvant RT
§ Chemoradiotherapy (less common)
- Always establish relevant supportive care early
In general compare surgery vs RT, for oral cavity cancers.
Surgery preferred
· Less morbidity à ± adjuvant RT or CRT
· Allows pathological stagin
· Control rates poorer in early stage dis
· Easily accessible to sx, often good fu’nal and cosmetic results
· RT can have signif tox
· Elective neck for T1-2 (D’Cruz, 2015, demonstrated OS benefit)
RT
· Can’t tolerate sx or sx resection would result in severe fu’nal impair
· Uncommon in stage I/II oral tongue & FOM
· May be applicable to early tumors of lip or retromolar trigone
· Absolute contraind: bone involve, airway compromise
Relative contraind: cartilage involve, poor organ fu’n, connective tissue (CT) dis
In general what is the management for Stage I-II oral cavity cancers?
- Surgery to the primary forms the basis of management
○ Aim for macroscopic margin of 10mm (for path margin of 5mm)
§ In the case of positive margins, re-resection should be attempted
○ Always consider the functional deficit with surgery
○ Associated with less morbidity (even with adjuvant RT)
○ Allows for pathological staging (including depth of invasion)- Definitive radiotherapy should be considered if medically or technically inoperable
○ Indications for Definitive RT over surgery
§ Lip: oral commissure involved, >2cm, >50% of lip, upper lip
§ Buccal mucosa - T1-2N (Tx ipsilateral Ib-II)
§ RMT with tonsillar pillar involvement - Most patients should have elective neck management (except for early tongue DOI <1mm or T1 lower lip, otherwise all need elective neck management)
○ Laterality is dependent on primary site
○ In most cases, should include levels I-III
§ Consider level IV in oral tongue (skip lesions)
○ Exceptions to elective nodal management
§ T1 SCC of the lower lip
§ Small T1 SCC of limited DOI (<1mm)
- Definitive radiotherapy should be considered if medically or technically inoperable
Describe management options for oral tongue and floor of mouth cancers.
Describe management options for Retromolar trigone and buccal mucosa cancers.
What are the indications for adjuvant RT in oral cavity cancers?
- Consider adjuvant post-operative radiotherapy alone if (INTERMEDIATE RISK):
○ Close/positive margins
○ ENE on histopathology
○ T3/T4 disease
○ 2+ nodes involved (i.e. N2+ disease)
○ DOI >4mm (specific for oral cavity)
○ LVI
○ PNI- Add concurrent cisplatin (CRT): positive margins and ENE
○ Improved LRC and DFS. No difference in OS
- Add concurrent cisplatin (CRT): positive margins and ENE
Describe management options for oral lip and hard palate cancers.
What is the management for stage III/IV oral cavity cancers?
- Surgery to the primary forms the basis of management
○ Aim for macroscopic margin of 10mm (for path margin of 5mm)
§ In the case of positive margins, re-resection should be attempted
○ Always consider the functional deficit with surgery- Definitive radiotherapy should be considered if medically or technically inoperable
- Adjuvant radiotherapy is typically required for all patients
○ Criteria remain as above - Elective nodal management is typically required for all patients
○ Bilateral nodal management is required if
§ Approaching midline (<10mm)
§ Multiple ipsilateral nodes
§ Ventral tongue or floor of mouth (always bilateral)
○ The cN0 contralateral neck can be managed with RT
§ Minimises toxicity compared with bilateral neck dissections
Describe the types of mandibular resections
What is the evidence for use of radiotherapy in oral cavity cancers?
Retrospective NCDB study (Ellis, 2018)
○ 20779 patients with stage I-II oral cavity SCC were retrospectively reviewed
§ Note that 95% had surgical management
○ Outcomes
§ Primary radiotherapy was associated with increased risk of mortality (HR 1.97)
§ Probability of receiving RT was associated with
□ Age >70; black; Medicare only (no insurance); clinical stage II; low-volume treatment centre
□ HIGHLY BIASED DATA
Retrospective single-institution review (Hinerman, 2004) ○ 226 patients treated with post-operative RT for oral cavity SCC § More than half were T3-T4 § More than half were cN positive ○ Outcomes § Variable impacting locoregional control include □ T-stage and N-stage □ ENE □ Surgical margins □ PNI and LVI
What is your definitive radiotherapy technique for oral cavity tumours?
Patients
1) Stage I-II (no chemotherapy)
1. Consider brachytherapy boost
2) Stage III-IV (concurrent chemotherapy)
Pre-simulation
MDT Discussion (review path)
Dietician + speech path involvement
- Consider prophylactic PEG
OPG + Dental review
Audiometry
Smoking cessation
Simulation
Supine with thermoplastic mask
- Handgrips
- Vacbag and ankle/knee-blocks
Wire any surgical scars
CT (2mm with IV contrast)
- Vertex to mid chest
Fusion
PET-CT and MR fusion
Dose prescription
SIB technique
- 70Gy/35F to the involved region
- 63Gy/35F to the high-risk region
- 56Gy/35F to the elective nodal regions
Concurrent chemotherapy (if stage III-IV)
- Cisplatin 100mg/m2 q3wk
- Cisplatin 40mg/m2 q1wk
VMAT technique
10 days per fortnight
- Accelerate to 6F per week if no chemotherapy
Volumes
GTVp = macroscopic primary disease
GTVn = macroscopic nodal disease
CTV70
- (GTVp + GTVn) + 5mm
CTV63
- GTVp + 10mm
- If BOT or soft palate, include entire organ
CTV56
- Elective nodal regions
PTV
- CTV + 5mm
Nodal regions
- Highest risk = levels I-III - If oral tongue = include level IV - If bulky level II = include VII - If multiple nodes = include contralateral neck - Bilateral inclusion dependent on location ○ FOM and ventral tongue ○ <1cm from midline
Target Verification
Daily CBCT
OARs
Brainstem + Optic Nerves/Chiasm
- Dmax < 54Gy
Cochlear
- Mean < 45Gy
Lacrimal Gland
- Dmax < 30Gy
Eye
- Mean < 35Gy
- Dmax < 50Gy
Lens
- Dmax < 7Gy
Parotid (spare 1 gland)
- Mean < 26Gy (optimal)
Oral cavity
- Mean < 30Gy
Mandible
- Dmax < 70Gy
Larynx
- Mean < 45Gy
Oesophagus
- Mean < 35Gy
Pharyngeal constrictors
- Mean < 50Gy
What is your adjuvant radiotherapy technique for oral cavity tumours?
Adjuvant Therapy
Patients 1) Intermediate risk (RT alone)
* Close margins
* T3/T4 disease
* 2 or more LN involved (i.e. N2+ disease)
* PNI/LVI
* DOI >4mm
2) High Risk (concurrent chemotherapy)
* Positive margins
* ECE
Pre-simulation MDT Discussion (review path)
Dietician + speech path involvement
- Consider prophylactic PEG
OPG + Dental review
Audiometry
Smoking cessation
Simulation Supine with thermoplastic mask
- Handgrips
- Vacbag and ankle/knee-blocks
Consider intra-oral appliances
- Bite-block (immobilise or displace tongue)
- Wax buccal spacer (for buccal primary)
Wire any surgical scars
CT (2mm with IV contrast)
- Vertex to mid chest
Fusion Pre-op PET-CT and MR fusion
Dose prescription
SIB technique
* 60Gy/30F to tumour bed and surgical bed
○ If gross macro residual --> Treat as Definitive [alternatively boost to 66Gy]
○ If pos margin or close margin --> 63Gy
* 54Gy to elective nodal regions
VMAT technique
10 days per fortnight
Concurrent chemotherapy (if positive margin or ECE)
- Cisplatin 100mg/m2 q3wk
- Cisplatin 40mg/m2 q1wk
Volumes Pre-op GTVp = based on original MR
GTVp = residual macroscopic disease
CTV63 = pre-op GTVp + 5mm
- If gross residual --> CTV66 = GTVp + 5mm
CTV60= Tumour bed (GTVp+10mm )
Entire surgical bed
GTVn+10mm
CTV54 = elective nodal regions
- Generally I, II, III
- Consider level IV
- Consider 5a/5b for N2, 7b if bulky II
PTV = CTV + 5mm Target Verification Daily CBCT
OARs Brainstem + Optic Nerves/Chiasm
- Dmax < 54Gy
Cochlear
- Mean < 45Gy
Lacrimal Gland
- Dmax < 30Gy
Eye
- Mean < 35Gy
- Dmax < 50Gy
Lens
- Dmax < 7Gy
Parotid (spare 1 gland)
- Mean < 26Gy (optimal)
Oral cavity
- Mean < 30Gy
Mandible
- Dmax < 70Gy
Larynx
- Mean < 45Gy
Oesophagus
- Mean < 35Gy
Pharyngeal constrictors
- Mean < 50Gy
What is your follow up for oral cavity cancers. What is the expected 5yr OS (by stage) and 2 year LC (by T stage) for oral cavity cancers
- Clinical review every two months for the first two years (shared care)
○ Clinical examination
○ Consider CT NCAP once at 12mo- Clinical review every three months for years 3-5
○ Clinical examination - Annual surveillance thereafter for late effects
- Single FDG-PET at 12 weeks post RT
- Consider TFTs if neck irradiated
- Regular dental review (every six months)
- Supportive care
○ Smoking cessation
○ Dietician and speech path review PRN
○ Lymphoedema review PRN
- Clinical review every three months for years 3-5
What is the evidence for 6# a week in head and neck RT?
Summary:
- Altered fractionation improves oncological outcomes
○ Most benefit found with larynx SCC
- Increase in early toxicity, but this appears tolerable
Concurrent chemotherapy is superior to altered fractionation
DAHANCA 6 & 7 (Overgaard, 2003)
○ 1476 patients with H+N SCC were randomised to 5F vs 6F per week
§ DAHANCA 6 = glottic SCC
§ DAHANCA 7 = all other SCC
○ Up to 68Gy in 2Gy/F was administered (without chemotherapy)
§ Nimorazole was randomized in DAHANCA 7 only
○ Outcomes
§ Acceleration improved LRC (HR 0.66) and CSS (HR 0.71)
□ Larynx SCC benefited most
§ No improvement in OS (HR 0.98)
○ Significant increase in early toxicity in the accelerated arm
§ Confluent mucositis = 55% vs 33%
○ No difference in late toxicity between arms
IAEA-ACC study (Overgaard, 2010) ○ 908 patients with H&N SCC were randomised to 5F vs 6F per week § 66-70Gy/33-35F without systemic therapy ○ Outcomes § 6F per week was associated with improved LRC (42% vs 30%) □ Biggest benefit gained for larynx SCC § Only a borderline OS benefit was seen (HR 0.70; p=0.07) § Significant increase in early skin and mucositis toxicity □ No difference in late toxicity
What is the evidence for chemotherapy with H&N RT
MACH-HN (Lacas, 2017)
○ 107 trials including 19805 patients were included in the analysis
§ Trials investigated the integration of chemotherapy into H+N SCC management
○ Outcomes
§ Concurrent chemotherapy
□ Associated with improved OS (HR 0.83), CSS (HR 0.79) and LRC (HR 0.71)
□ Absolute OS benefit is 6.5% at 5 years
§ Induction chemotherapy
□ Benefit seen for distant failure (HR 0.76)
□ No benefit seen with respect to LRC, CSS or OS
§ Adjuvant chemotherapy
□ No benefit seen with respect to OS
§ Concurrent chemotherapy is superior to induction chemotherapy (OS = HR 0.84)
○ Age is an important factor
§ Decreased impact of concurrent chemotherapy with increasing age
Marked increase in non-cancer death when age > 70 years
MARCH meta-analysis (Lacas, 2017) ○ 34 trials including 11969 patients were included § SCC of the oral cavity, oropharynx, hypopharynx and larynx § Trials investigated altered fractionations (acceleration or hyperfractionation) ○ Outcomes § Altered fractionation was associated with improved OS compared with RT alone (HR 0.94; 3.1% at 5 years) □ OS benefit isolated to the hyperfractionated group □ Acceleration associated with improvement in CSS and LRC Altered fractionation resulted in worse OS compared with chemoradiotherapy (HR 1.22)
What is the evidence for Cetuximab vs cisplatin in H&N ChemoRT?
Summary
- Cetuximab initially proposed as a form of treatment de-escalation in the setting of reducing cisplatin toxicity
- Cetuximab is inferior to cisplatin as a concurrent agent (In terms of Tumour control, OS, PFS)
However, there is efficacy and it can be considered in patients where cisplatin is contraindicated
- Randomised Bonner trial (Bonner, 2006) ○ 424 patients with stage III-IV H+N SCC were randomised to § 70Gy with cetuximab vs placebo ○ Outcomes § Improved OS with cetuximab (HR 0.03) § Improved LRC with cetuximab (HR 0.68) ○ Increase in acneiform rash and infusional reactions seen § All other toxicity unchanged - ARTSCAN III trial (Gebre-Medhin, 2021) ○ 298 patients with stage III-IV H+N SCC were randomised to § 68-73Gy of RT with either weekly cisplatin vs cetuximab ○ Outcomes § Trial ceased early due to safety concerns § Cisplatin resulted in improved OS at 3 years (88% vs 78%) § Cisplatin resulted in improved LRF rates at 3 years (23% vs 9%) ○ Cetuximab is inferior to cisplatin - RTOG 1016 (2020) and DeESCALTE (2018) trials ○ RTOG cetuximab inferior for OS and PFS compared with cisplatin + RT for HPV positive OPSCC DeEcalate cetuximab no benefit in terms of reduced toxicity, but detriment in terms of tumour control
What is the evidence for adjuvant RT in H&N treatment?
Summary:
- Adjuvant radiotherapy at doses of 60Gy effectively control intermediate risk factors
○ No dose response relationship is seen
- Positive margins and ECE are independently associated with worse prognosis
○ Proven long-term benefit with concurrent chemotherapy
○
* Peters (IJROBP 1993)
○ RCT from MDACC
○ 302 pts randomised to dose of PORT
○ Found that pts with high risk for LR recurrence had either ECE or 2 of: oral cavity, close/+ve margin, 2+ LNs, LN >3cm (N2+), PNI (or treatment delay >6 weeks)
* Ang (IJROBP 2001)
○ Prospective trial validating risk factors and need for PORT
* Low risk patients (no RFs)- 5yr LRC 90% without RT
* Intermediate risk patients (1 RF, not ECE) -5yr LRC 94% with PORT, 57.6Gy.
▪ As pts with intermediate risk did as well as patients with low risk if got PORT- validates the use of PORT
* High risk pts (ECE or 2+ of others) -> 5yr LRC 68% with 63Gy PORT
○ Indications for primary and nodal PORT should be considered separately on their merits
* Interpretation:
○ Peters detected certain factors predicting for worse LRC. These factors were validated by Ang, who found that patients with intermediate risk had same level of LRC as low risk patients if had PORT, hence this trial validates the risk factors and shows PORT decreases LR risk
MDACC Adjuvant Radiotherapy Trial (Rosenthal, 2017)
○ 301 patients with H+N SCC of any primary site and any stage underwent surgical management
§ Randomised on the basis of risk factors
□ Primary = T-stage, margins, PNI
□ Nodes = number of nodes, size and ECE
§ Randomised to one of three dose levels for adjuvant RT
□ 57.6Gy/32F
□ 63Gy/35F
□ 68.4Gy/38F
○ Outcomes
§ No dose response seen between cohorts (i.e. above 57.6Gy)
§ Positive margins and ECE were the only major high-risk factors associated with prognosis
□ Intermediate risk factors were not associated with increase in LRC (i.e. adjuvant RT was effective for these)
§ Overall treatment time was associated with prognosis
What is the evidence for adjuvant ChemoRT in H&N Treatment.
2x RCT Improved LRC and DFS. No difference in OS
RTOG 9501 trial (Cooper, 2012) ○ 410 patients with locally advanced H+N SCC underwent surgical resection and had high-risk features § High-risk = positive margins, ECE or number of LN (>2) § Randomised to adjuvant RT 60Gy +/- cisplatin chemotherapy ○ Outcomes § At long-term follow-up for the overall cohort, no persistent LRC benefit seen with cisplatin (HR 0.73) § For the "ECE or positive margin" group, there is persistent benefit □ LRC (HR 0.56; p=0.02) □ OS (HR 0.76; p=0.07) § There is no benefit by number of LN involved EORTC 22931 (Bernier, NEJM 2004) High risk: N2-3, positive margin, PNI, vascular tumour embolism, involved nodes at level IV/V from oral cavity/oropharynx primary RT +- 3 weekly cisplatin Improved LRC and DFS. No difference in OS Worse acute gr 3-4 toxicity
What is the evidence for definitive ChemoRT vs RT alone?
Intergroup trial RCT –stopped early. CRT superior to RT alone for LRC and OS
* Intergroup trial (Aldelstein JCO 2003) ○ Stopped due to slow accrual, 295/463 pts, Stage III-IV OC, OPx, Larynx, HypoPx ○ RT alone 70Gy/35F vs CRT 70Gy/35F weekly Cis vs Split course CRT (30Gy, break, 30-40Gy) with 3 weekly Cis+5FU. ○ CRT is superior to RT alone, but benefit is mitigated with split course. ○ 3yr DSS - CRT 51%, RT alone 33%, Split CRT 41% ○ 3yr OS - CRT 37%, RT alone 23%, Split CRT 27% * GORTEC trial (Calais JNCI 1999) ○ RT 70Gy/35F +/- Chemo (3 weekly carbo/5FU) CRT better than RT alone in 5yr LRC ( 25-> 48%), DSS (17-> 27%) and OS (16 -> 22%)
What is the epidemiology for Oropharyngeal Ca?
Incidence (Australian statistics)
- ALL = 4500 cases annually
- OROPHARYNX = 1500 cases annually
- Approx 4 per 100000 people
HPV considered distinct clinical disease w regard to risk factor profiles, treatment response and prognosis
- Incidence of HPV positive OPSCC rising
○ Frequently male, young (<50) and good performance status
○ More likely to present in the tonsils, PD, early T stage and advanced N stage
○ Better cure rates then alcohol or tobaccco OPSCC
- Incidence of HPV negative OPSCC decreasing
Rising incidence of young people < 50yo (both males and females)
- Likely HPV related
Median age is 60 years
- Younger for HPV positive
Male predominance (up to 4:1)
- Approaches parity in HPV positive
Aetiology
1) Smoking (RR is up to 10x), both HPV and nonHPV a. ALSO - cigar use, chewing tobacco, betel nut 2) Alcohol use (RR is up to 5x) a. Synergistic with smoking 3) Viral (HPV) a. HPV is implicated in up to 60-80% of cases b. Behavioural risk factors --> number of sexual partners, oral sex, age at first intercourse 4) Occupational exposure a. Asbestos b. Mustard Gas c. Nickel d. Tar 5) Immunosuppression 6) Nutritional deficits a. Fruits and vegetables are protective 7) Poor oral hygiene & periodontal disease 8) Previous radiation 9) Genetic factors a. Fanconi anaemia
Metachronous lesions
- Second H+N primary = 20% risk
- Lung = 5-10%
- Oesophagus = <5%
HPV-related cancers have a lower risk of metachronous lesions
- Lack of field effect change
- Other RF:
○ Number of sex partners
○ Not alcohol
○ No precancerous lesions
○ More nonkeratinising
Describe SCC HPV mediated carcinogenesis.
HPV-mediated carcinogenesis
HPV has high-risk and low-risk subtypes
* HPV 16, 18, 31, 33 are high-risk
* Remainder are low risk (e.g. 6, 11)
HPV replicates by entering a cell and incorporating its own DNA into the cellular DNA. In this way, the cellular machinery is manipulated to create many copies of the virus, which is then released for further spread and infection.
The E6 and E7 oncoproteins of the high-risk HPV subtypes manipulate cellular machinery in such a way to cause carcinogenesis
* E6 associates with the p53 protein and leads to the ubiquitination, thereby inhibiting its function. E6 also causes other more minor protease-mediated cellular damage
* E7 associates with the Rb (retinoblastoma) protein and causes its proteasome-mediated degradation.
E5 is also oncogenic, but less potent
* E5 can activate EGFR signalling and thus promote cellular growth
This in turn, causes carcinogenesis in the following ways
* Cellular immortality (disabled apoptotic pathways)
○ E6 disables p53
* Genomic instability (impaired cellular DNA repair pathways)
○ Disabled apoptosis allows accumulation of genetic damage without an endpoint
* Unregulated cellular proliferation (removal of cell-cycle arrest mechanisms)
○ E6 disables p53
○ E7 disables Rb
* Sustained proliferative signalling
○ E5 can activate EGFR pathway
* Impaired immunity (ongoing infection and inflammation)
○ E6/7 inhibit interferon signalling (impair innate immunity)
○ E5 down-regulates MHC-I expression
○ This leads to persistence of infection (which is required for carcinogenesis –> accumulate genetic damage)
* Other
○ E7 induces angiogenesis
○ E7 induces Warburg effect (altered metabolism)
○ P16 induced but doesn’t slow cell cycle due to E7/RB
Can test for via P16 IHC –80% specific in oropharynx, DNA or RNA ISH
On cytology p16 maybe patchy (done on unknown primary)
Better prognosis, more treatment sensitive, lower mutation rates/genetic mutations.
Describe non-HPV related H&N SCC carcinogenesis.
Dysplastic spectrum within the epithelium –occurs on surface epithelium (rather than palatine/lingual tonsil crypts)
- Mild atypia
- High-grade dysplasia
- Carcinoma in-situ
- Invasive carcinoma
Driven by chronic inflammation or chronic carcinogen exposure
Note that withdrawal of smoking can result in regression of dysplasia
What are the subtypes for H&N SCC. Describe the Macroscopic and Microscopic features.
Squamous Cell Carcinoma
- By far, the most common histological subtype of oral cavity cancer
- Macroscopic ○ Pink/grey area of mucosal thickening § Ulcerated mass when late/advanced ○ Verrucous and spindle cell variants may be more exophytic or polypoid in appearance - Microscopic ○ Nests of keratinising squamous cells which invade the basement membrane § Keratin pearls and intercellular bridges § Grade/differentiation is dependent on keratinising features ○ Large polygonal cells with variable cellular anaplasia ○ For nonkeratinising (HPV): § Nodules/sheets of cells –often arising from crypts § Focal areas of sqaumous/keratin <10% § Comednecrosis frequent § Permeated lymphocyes § No grading for HPV, no insitu disease - Variants ○ Verrucous § White, warty, cauliflower like lesion § Low metastatic potential ○ Sarcomatoid/spindle cell § Biphasic mixed carcinoma with spindle component § Aggressive disease course ○ Basaloid (HPV associated) § Small basaloid cells with peripheral palisading and high-grade features (high N:C ratio, pleomorphism, hyperchromatic nuclei, mitoses) § Aggressive disease course (but not when HPV associated) ○ Papillary ○ Lymphoepithelial like –syncytial appearance –indistinct cell borders, plasma and lymphocytes+ - Immunohistochemistry ○ POS = AE1/AE3, HMWCK, p40, p63 - Molecular ○ P16 overexpression is used as a surrogate for HPV status § Can be IHC or ISH § There is still a reasonable false negative (20%) rate ○ HPV PCR is the most accurate § Also gives information on the particular subtype present --> prognostic
What are the subsites of oropharynx cancers?
- Tonsils
- BOT
- Soft palate
- Upper lateral and posterior pharyngeal walls
What are the prognostic factors for oropharyngeal cancers?
Patient Factors
- Age and performance status
- Nutritional status
- Immunosuppression
- Smoking (local control and toxicity)
- Anaemia
○ Non-reversible –> transfusion does not improve outcomes
Tumour Factors
- TNM stage
- HPV status (see risk groups below)
nonHPV
- Depth of Invasion (oral cavity)
○ Measured from basement to depth of tumour
- Grade (of limited value)
- LVI
- PNI
- ECE >2mm –often seen in LN >3cm
Treatment Factors
- High-volume experienced centre
- Overall treatment time (if chemoRT)
- Surgical margins
○ Addition of adjuvant radiotherapy
How would you work up a patient with an oropharyngeal lesion?
Consultation
- History ○ HPI § Dysphagia, aspiration or odynophagia § Otalgia/ear effusion (Eustachian obstruction or referred pain from CN 9 + 10) § Sensation of pharyngeal mass § Palpable cervical node ○ PMHx: § Immunosuppression § HPV infection § Other metachronous H+N/lung malignancy ○ Meds: § Immunosuppressants § Radiosensitisers ○ Social § Smoking § EtOH § Social supports ○ Family History - Examination ○ General examination § Fitness and performance status § Nutrition § Dental condition ○ H+N examination § Palpable lymphadenopathy § Oral cavity examination (including trismus) § Nasoendoscopy □ Examine primary site □ Examine remaining mucosa □ Examine cords
Work-Up
- Biopsy ○ MUST include p16 staining ○ Biopsy any equivocal neck nodes (unless already proceeding with neck dissection) - MR Head and Neck ○ Surgical evaluation - FDG-PET ○ Nodal and distant staging - Diagnostic CT Head and Neck ○ Evaluate bony invasion - Pre-chemotherapy bloods ○ FBC ○ EUC, CMP ○ LFT and coags ○ HepB sAg, sAb, cAb ○ Hep C serology ○ HIV serology
What is the staging for Oropharynx cancers?
FYI P16+ve staging
N-Staging
N1 Any ipsilateral nodes (<6cm)
N2 Any contralateral nodes (<6cm)
N3 Any node >6cm in size
M-Staging
M1 Distant metastasis
Stages
* Stage I
○ T1-2 and N0-1
* Stage II
○ T1-3 and N2
* Stage III ○ Tany and N3 ○ T4 and Nany * Stage IV ○ M1
In general how would you manage Oropharynx cancers?
General Principles
- Always aim to use as few modalities as is feasible (reduce morbidity) - In general, options may include ○ Early Stage (stages I-II) § Surgical resection alone § Radiotherapy alone ○ Advanced Stage (stages III-IV) § Chemoradiotherapy - Always establish relevant supportive care early ○ Smoking cessation ○ Dietician and speech pathology input § Consideration of prophylactic gastrostomy ○ Dental input § Pre-RT OPG ○ Social & psychological supports as appropriate
What would be your management for Stage I-II Oropharynx cancers?
- Definitive options include
1) Definitive radiotherapy
§ 70Gy/35F alone (no concurrent chemotherapy)
§ Aim to accelerate where feasible (6 fractions per week)
§ Ipsilateral RT if tonsil (less than 1cm extention to soft palate/BOT and N0-1 (single <3cm)
2) Surgical resection
§ TORS + neck dissection
□ Aim for small functional deficit (T1-2 tonsillar fossa, lateral BOT, L pharyngeal wall)
□ Contraindication: soft palate, posterior arch (affects speech), central BOT (remove less than half of tongue), trismus, fixed tumour, carotid invasion
□ If TORS is not feasible, opt for radiation instead (i.e. do not jaw split)
□ Still risk of needing adjuvant RT
□ PH2 TORS (3mm margin) + 50Gy vs 60Gy similar
§ Ipsilateral neck dissection is reasonable if well lateralised primary (e.g. tonsil)
□ Bilateral neck dissection if BOT, soft palate or posterior wall primary- In the absence of high-level evidence, decision making is based on functional outcome and treatment morbidity
- Consider adjuvant post-operative radiotherapy alone if (INTERMEDIATE RISK):
○ Close/positive margins
○ ENE on histopathology -hard to predict on MRI/CT due to inflammatory reaction
○ T3/T4 disease
○ 2+ nodes involved (N2+ disease)
○ LVI
○ PNI - Only positive margins and ENE justify adjuvant concurrent chemoradiotherapy (HIGH RISK)
- There is no role for adjuvant chemotherapy
○ MACH meta-analysis
What would be your management for Stage III-IV Oropharynx cancers?
- General approach
○ Aim for single modality therapy to minimise toxicity
○ In this way, TORS has a limited role
§ If adjuvant radiotherapy is likely, prefer to proceed with definitive chemoradiotherapy
○ Extensive surgery (including mandibulectomy) should be performed if gross bony invasion is present
§ Adjuvant RT will always follow- Standard therapy is concurrent chemoradiotherapy (OS and LRC better than RT alone)
○ 70Gy/35F (5F per week)
○ High dose Cisplatin 100mg/m2 every 3 weeks
§ Alternative is weekly cisplatin at 40mg/m2
§ Carbo/5FU
- Standard therapy is concurrent chemoradiotherapy (OS and LRC better than RT alone)
How would management change for HPV related oropharyngeal cancers?
- In general, the approach is very similar to the HPV-negative cohort
- Key differences
○ T1-2 and N1 (single node < 3cm) can be considered for single agent RT
§ Only if low-risk patients (i.e. non-smokers) - Unknown primary node positive
○ PET will detect 25-50%, most common tongue base or tonsil
○ Unilateral tonsillectomy (lateral oropharyngectomy) and lingual tonsil (no tongue muscle) - Treatment de-intensification should not be considered routine at this time
○ Data are inconclusive and immature
○ Trials:
§ Surgical resection
§ Reduce radiation dose or omit chemotherapy
□ Reduced RT dose 50 vs 60Gy –similar outcomes
□ Omit chemotheray = higher locoregional failure
□ Alternative chemo: cetuximab worse survival
Induction chemo then deescalate responders
- Key differences
What is the evidence for oropharynx cancer management with RT vs Surgery?
ORATOR (Nichols, 2022)
○ 68 patients with T1-2 N0-2 SCC of the oropharynx were randomised to
§ Definitive radiotherapy (concurrent chemotherapy if N1-2)
§ TORS with neck dissection (adjuvant RT as indicated)
○ Outcomes
§ RT had improved dysphagia scores (MD Anderson Dysphagia Inventory)
□ Improvement at 1 year (uncertain clinical significance of small change)
□ Declining absolute difference at years 2 and 3
§ TORS had worse pain and dental concerns in the first year
□ Resolved by year 2-3
§ Increased xerostomia in the RT arm
MA—similar DSS and OR w/ TORS vs. RT for early-stage tumour. ○ PORT indicated in ~70% and post-op chemoRT in ~30%. ○ RT tox: oseophageal stenosis, ORN, gastrostomy tube. ○ TORS tox: haemorr, fistula, 12% needs trachy but mostly decannulated prior to DC. MA 2002 Parsons—51studies OPX tx w/ surg vs RT. Similar 5yr LC, LRC, OS and CSS. However, Poor functional outcomes/complications w/ surg, Thus, Def CRT was adopted as SOC.
What is your radiotherapy technique for definitive and adjuvant oropharynx cancers?
Adjuvant Therapy
1) Stage I-II (no chemotherapy)
2) Stage III-IV (concurrent chemotherapy)
Definitive Therapy
1) Intermediate risk (RT alone)
* Close margins
* T3/T4 disease
* 2 or more LN involved (i.e. N2+ disease)
* PNI/LVI
2) High Risk (concurrent chemotherapy)
* Positive margins
* ECE
MDT Discussion (review path)
Dietician + speech path involvement
- Consider prophylactic PEG
OPG + Dental review
Audiometry
Smoking cessation
Supine with thermoplastic mask
- Handgrips
- Vacbag and ankle/knee-blocks
Wire any surgical scars
CT (2mm with IV contrast)
- Vertex to mid chest
Supine with thermoplastic mask
- Handgrips
- Vacbag and ankle/knee-blocks
Wire any surgical scars
CT (2mm with IV contrast)
- Vertex to mid chest
PET-CT and MR fusion
Pre-op PET-CT and MR fusion
Target Verification
- Daily CBCT
OARs
Brainstem + Optic Nerves/Chiasm
- Dmax < 54Gy
Cochlear
- Mean < 45Gy
Lacrimal Gland
- Dmax < 30Gy
Eye
- Mean < 35Gy
- Dmax < 50Gy
Lens
- Dmax < 7Gy
Parotid (spare 1 gland)
- Mean < 26Gy (optimal)
Oral cavity
- Mean < 30Gy
Mandible
- Dmax < 70Gy
Larynx
- Mean < 45Gy
Oesophagus
- Mean < 35Gy
Pharyngeal constrictors
- Mean < 50Gy
What is the elective nodal volumes for p16-ve oropharynx cancers?
What is the prognosis and follow up for oropharynx cancers?
Follow-Up
- Clinical review every two months for the first two years (shared care) ○ Clinical examination ○ Consider CT NCAP once at 12mo - Clinical review every three months for years 3-5 ○ Clinical examination - Annual surveillance thereafter for late effects - Single FDG-PET at 12 weeks post RT ○ SUV decrease by 50% = 50% predictor for complete response, especially SUV<2.5 § Negative predictive value 92-97% ○ HPV nodes take longer to go. § Mild uptake -repeat PET § Enlarged but no activity -clinical followup ○ Also surgery relatively easy -less fibrosis than later - Consider TFTs if neck irradiated - Regular dental review (every six months) - Supportive care ○ Smoking cessation ○ Dietician and speech path review PRN ○ Lymphoedema review PRN
Ongoing research in to PET at 2-3 weeks during RT -less tumour uptake is reponse. Before toxicity/inflammation
What is the epidemiology and risk factors for Larynx and hypopharynx cancers?
Incidence (Australian statistics)
- LARYNX = 650 cases annually
- Approx 2 per 100000 people
Median age is 65 years
Male predominance (up to 4:1)
Aetiology
1) Smoking (RR is up to 10x) 2) Alcohol use (RR is up to 5x) a. Synergistic with smoking 3) Occupational exposure a. Asbestos b. Mustard Gas c. Nickel d. Tar 4) GORD a. Presume chronic inflammation 5) Viral a. HPV is implicated (less strongly than for oropharynx) 6) Immunosuppression 7) Nutritional deficits a. Fruits and vegetables are protective 8) Previous radiation 9) Genetic factors a. Fanconi anaemia
Metachronous lesions
- Second H+N primary = 20% risk
- Lung = 5-10%
- Oesophagus = <5%
List the subsites of the larynx and hypopharynx and their respective LN Drainage
Supra-glottis: AVISA
What are the prognostic factors for Larynx and Hypopharynx cancers?
Patient Factors
- Age and performance status
- Functional larynx
- Nutritional status
- Immunosuppression
- Smoking (local control and toxicity)
- Anaemia
○ Non-reversible –> transfusion does not improve outcomes
Tumour Factors
- TNM stage
- Tumour site
○ Hypopharynx is worse than larynx
- Grade (of limited value)
- LVI
- PNI
- ECE
Treatment Factors
- High-volume experienced centre
- Surgical margins
Overall treatment time (if chemoradiotherapy)
How would you work up a patient with a larynx or hypopharynx cancer?
- History
○ HPI
§ Dysphonia or impaired cough
§ Dysphagia, aspiration or odynophagia
§ Otalgia/ear effusion (Eustachian obstruction or referred pain from CN 9 + 10)
§ Sensation of pharyngeal mass
§ Palpable cervical node
○ PMHx:
§ Immunosuppression
§ Other metachronous H+N/lung malignancy
○ Meds:
§ Immunosuppressants
§ Radiosensitisers
○ Social
§ Smoking
§ EtOH
§ Social supports
○ Family History- Examination
○ General examination
§ Fitness and performance status
§ Nutrition
§ Dental condition
○ H+N examination
§ Palpable lymphadenopathy
§ Oral cavity examination (including trismus)
§ Nasoendoscopy
□ Examine primary site
□ Examine remaining mucosa
□ Examine cords
- Examination
Work-Up
- Biopsy ○ EUA + microlaryngoscopy ○ Biopsy any equivocal neck nodes (unless already proceeding with neck dissection) - MR Head and Neck ○ Surgical evaluation - FDG-PET ○ Nodal and distant staging - Diagnostic CT Head and Neck ○ Evaluate bony invasion - Pre-chemotherapy bloods ○ FBC ○ EUC, CMP ○ LFT and coags ○ HepB sAg, sAb, cAb ○ Hep C serology ○ HIV serology - Dental Ax + OPG; dietician and SP review; prophylactic enteral feeding.
What is the staging for Larynx cancers?
Stages
* Stage I
○ T1N0
* Stage II
○ T2N0
* Stage III ○ T3 OR N1 * Stage IV T4+ OR N2+
What is the staging for Hypopharynx cancers?
Subsites:
Postcricoid, hypopharyngeal wall, pyriform sinus
Stages
* Stage I
○ T1N0
* Stage II
○ T2N0
* Stage III ○ T3 OR N1 * Stage IV ○ T4+ OR N2+
How would you manage a stage I-II supraglottic cancer?
§ Either RT or laser surgery
All patients need elective bilateral nodal therapy (either surgical or RT)
- prospective data only no RCT for Sx Vs. RTx
Supraglottis
- Rich lymphatics: T1-2 (30-40% N+) and T3-4 (55-65% N+)
1. Definitive RTx alone to 70/56Gy primary + bilateral neck nodes (preferred dt voice preservation, less morbid, surgical salvage option of recurrence).
○ LC T1 90%, T2 80-90%
2. Surgery - Laser excision or Supraglottic laryngectomy + bilateral ELND (retention of vocal and swallowing function, but high aspiration risk)- not suitable if poor lung function
○ LC T1 100%, T2 81%
○ Alternative - Total laryngectomy + bilateral ELND
How would you manage a stage I-II Glottic cancer?
§ Either RT or laser surgery
No elective nodal therapy required
Glottis
- Definitive small field RT (Hypofn 2.25Gy/#) –> 63Gy/28F (T1) or 65.25Gy/29 (T2) ↑ LC (15%) vs. 2 Gy/F. NO neck ENI needed
○ LC: T1 90%, T2 75-80%.
○ Organ preservation - 80-90%. Surgery salvageable in 90-95%
○ LVH uses 60Gy/25F for T1
○ Stage carefully as T3 chemorads may do better
- Uk guideline rt 63gy/28, 50gy/16, 55/20
- Surgery- Laser excision - T1 or T2 non-bulky.
○ LC: same as RT
○ Contraindication for laser: deep pre-epiglottic space extension, infiltration of the cricoarytenoid joint leading to vocal cord fixation, paraglottic space encroachment, anterior commissure infiltration and inadequate exposure of the larynx.
○ Don’t disrupt vocal ligament (deeper layer of vocal cord) -will affect voice quality
○ Alternative- Partial/hemilaryngectomy or total laryngectomy (based on anatomic considerations, poor voice quality).
- Note:
○ Data suggest similar oncological and vocal preservation outcomes between options
○ Decision making is as per institutional experience and patient preference
Salvage laryngectomy is the ultimate treatment for failure after either approach
What are the advantages and disadvantages of managing a T1-2 Glottic cancer with EBRT vs Laser resection vs Surgery?
How would you manage a stage I-II Subglottic cancer?
Subglottis
○ Rare, no consensus
○ Definitive 70/56/35# RTx alone (preferred) to primary and bilateral neck nodes (lower neck and upper mediastinal nodes)
§ LC: 75%
§ 5yrs DFS Stage I. 70%, Stage II 40%
§ 5yrs OS Stage I 85%, Stage II 50%
Surgery - Total laryngectomy + bilateral ELND (usually Stage III-IV and usually presents with airway obstruction)
How would you manage a stage I-II Hypopharynx cancer?
- Rare for T1, as usually late presentation
- Definitive options include
1) Definitive radiotherapy
§ Due to limited organ-preserving surgical approaches, definitive radiotherapy is the standard of care. In the absence of high-level evidence, decision making is based on functional outcome and treatment morbidity
§ Definitive RTx alone to 70/56Gy primary + bilateral neck nodes- better functional outcomes.
○ LC: T1 89%, T2 77%, pyriform sinus worse
§ Aim to accelerate where feasible (6 fractions per week)
2) Surgical resection (very limited role)
§ TORS + neck dissection
○ Partial or total pharyngolaryngectomy+ bilateral ELND
○ If TORS/minimally invasive surgery is not feasible, opt for radiation instead
§ All require bilateral neck dissection - Due to limited organ-preserving surgical approaches, definitive radiotherapy is the standard of care
○ In the absence of high-level evidence, decision making is based on functional outcome and treatment morbidity
- Definitive options include
When would you consider adjuvant radiotherapy and adjuvant chemoradiotherapy in head and neck cancers?
- Consider adjuvant post-operative radiotherapy alone if (INTERMEDIATE RISK):
○ Close/positive margins
○ ENE on histopathology
○ T3/T4 disease
○ 2+ nodes involved (N2+ disease)
○ LVI
○ PNI- Only positive margins and ENE justify adjuvant concurrent chemoradiotherapy (HIGH RISK)
- There is no role for adjuvant chemotherapy
○ MACH meta-analysis
How would you manage Stage III-IV Hypopharynx and Larynx cancers?
- General approach
○ Aim for single modality therapy to minimise toxicity
§ In this way, TORS has a limited role
§ If adjuvant radiotherapy is likely, prefer to proceed with definitive chemoradiotherapy
○ Aim for organ-preserving therapy where feasible
○ Laryngectomy if poor voice, immobile cords, poor swallow/aspiration.- Concurrent chemoRTx 70Gy/35F (5F/week) w/ 3 weekly (100mg/m2, RCT) or weekly (40mg/m2) cisplatin (expert consensus EVIQ)- SOC with organ preservation
○ LC 50-60%, larynx preservation 60%
○ NOT IF T4b or extending into BOT (not eligible for RTOG 91-11)
○ <T4 pts 28% salvage laryngectomy Vs T4 pts 58% (SS –> VA larynx trial)
○ T4 disease:
§ 60% pf patients may require salvage laryngectomy due to poor post chemoRTx larynx function
§ 20-25% of patients will need long term PEG/tracheostomy due to treatment toxicity.
○ OS same at 10 yrs (as per RTOG trial, but better LC with concurrent treatment)
○ Concurrent ChemoRT RTOG 91-11 (concurrent just as good as induction chemo/sx + RTx or RTx alone)
§ If not well enough for CRTx, consider RTx only with altered fractionation
○ Only worthwhile if larynx is salvageable and likely to have adequate function after Rx
§ Mainly in regards to aspiration/swallowing/airway rather than voice quality - Standard therapy is concurrent chemoradiotherapy =50-60% local control, larynx preserved 60%, permanent PEG 25%
- Laryngectomy + bilat LND should be considered if:
○ T4 disease
○ Non-functional larynx (trache dependent/PEG dependent/Recurrent aspiration)
○ Elderly unable to tolerate chemoradiotherapy - Adjuvant radiotherapy almost always follows laryngectomy
- Consider stomal boost if:
○ Pre-operative tracheostomy (especially if emergent)
○ Locally advanced disease (involvement of anterior neck
○ Subglottic disease location
○ Positive surgical margins
- Concurrent chemoRTx 70Gy/35F (5F/week) w/ 3 weekly (100mg/m2, RCT) or weekly (40mg/m2) cisplatin (expert consensus EVIQ)- SOC with organ preservation
What is the evidence for chemotherapy for head and neck cancer in elderly patients?
- Elderly
○ MACH-HN meta-analysis provides some guidance for management
§ Concurrent chemoRT has limited benefit if > 70years
§ Likely to be harmful if >80 years (increase in non-cancer mortality)
○ Alternatives to cisplatin-based concurrent chemoradiotherapy
§ Sequential induction chemotherapy –> RT alone
§ Definitive RT alone
§ Concurrent carboplatin (single-agent) or cetuximab
What is the evidence for radiotherapy in early stage larynx cancers?
Summary:
- Data are inconclusive and somewhat conflicting
○ Radiotherapy is likely an appropriate alternative to surgical management
§ Similar oncological outcomes
§ Similar or better vocal outcomes
○ Small chance of slightly inferior laryngeal preservation with RT
Seminal Russian RCT (Ogol'tsova, 1990) ○ 269 patients with stage I-II laryngeal cancer were randomised to § Surgery alone (partial laryngectomy) § Radiotherapy alone § Chemoradiotherapy ○ Outcomes § With respect to 5 year OS □ Surgery --> T1 = 100% & T2 = 97% □ RT alone --> T1 = 92% & T2 = 89% § No benefit to chemoradiotherapy Meta-analyses (multiple) ○ T1 glottic SCC (Mo, 2017) § Laser surgery improves laryngeal preservation and OS § No difference in LRC ○ T1 glottic SCC (Yoo, 2014) § No difference in LRC or OS § Suggestion of superior vocal outcomes with RT ○ Tis/T1a glottic SCC (Guimaraes, 2018) § Laser surgery improves laryngeal preservation and OS § No difference in LRC § RT delivers possible benefit with respect to vocal quality ○ T2 glottic SCC (Warner, 2017) § No difference in 5yr OS between groups § Increase in local failure with T2b (irrespective of cohort)
What is the evidence for hypofractionation in early glottic SCC
Osaka Yamazaki 2006 (IJROBP)
○ 180pt, T1 RCT. 60-66Gy/30-33F vs 56.25Gy/25F (<2/3 of VC) or 63Gy/28F (>2/3 of VC)
○ 5yr LC better in hypofractioanted arm 92% vs 77%
○ 5yr CSS 97 vs 100% (NS)
KROG 0201 ○ 156pts, 60-66Gy/30-33F vs 63Gy/28F for T1 and 70Gy/35F vs 67.5/30F for T2 ○ 5yr LPFS was better for the hypofractionated arm ( 77.8% for CR arm vs 88.5% in HP arm), No significant difference in toxicity profile. - Mendenhall- U Florida Lit Review- hypoFx provide Comparable LC, voice preservation, LC and OS compared to pe with transoral last excision, open partial layrngectomy, and RT. ○ pt with anterior comminsure involvement may have a higher risk of LC recurrence after partial laryngectomy but doesnt no influence LC after RT - 2017 NCD analysis showed that HypoFn (2.25Gy/F to 63-65.25Gy) in T1-T2 N0 glottic ca, improve OS when compared to conventional Fx
What low risk elective nodes would you include in your larynx treatment for different nodal stages?
What low risk elective nodes would you include in your hypopharynx treatment for different nodal stages?
What is the local control and OS for larynx and hypopharynx cancers by T-stage?
What are the different methods of voice production post laryngectomy?
1) Tracheo-oesophageal Speech àpulmonary driven –
à By inhaling air and then occluding the stoma (with thumb or hands free speaking valve), the air is diverted through the voice prosthesis and into the oesophagus. This allows for voice to occur via a new source of vibration – the neoglottis.
à The voice prosthesis incorporates a one way valve, and retaining flanges at each end. It is sized by a Speech Pathologist according to the length (mm) & diameter (Fr.) required. 2 types – pt changeable non-indwelling or semi-permanent (3-6m) indwelling fitted by speech path.
2) Electronic Devices à held against the neck (or intra-orally with small tube) and the mechanically generated sound is transmitted through the tissue and sets the static air within the vocal tract into vibration. This sound is then shaped into speech by the lips, teeth and tongue. The Servox Digital and NuVois are two commonly used hand held devices
3) Oesophageal Speech à produced by inhaling or injecting air into the oesophagus. When the air pressure in the oesophagus is great enough to overcome the pharyngo-esophageal segment (neoglottis) resistance, the PE tissue is set into vibration. Air passing through the vibrating PE segment is then shaped into intelligible speech by the lips, teeth and tongue
Describe the pathology for nasopharynx cancer.
Histological types
- WHO subtypes of SCC (95%)
○ Non-keratinising SCC –> endemic
§ WHO 2 Differentiated type (30%)
§ WHO 3 Undifferentiated type (>50%)
○ WHO 1 Keratinising SCC (20%) –> sporadic
○ Basaloid SCC –more aggressive
- Lymphoma (5%)
Macroscopic
- Mass within the nasopharyngeal space
○ May have associated ulceration or bleeding
- Distortion of normal anatomy (e.g. Fossa of Rosenmuller, Torus tubarus)
Microscopic
- Non-keratinising undifferentiated (50%) (Type 3)
○ Two key patterns
§ Syncytial arrangement of cells with indistinct margins
§ Diffuse infiltrate of non-cohesive cells
○ Moderate cytoplasm, round nuclei
○ No keratinising features
○ Apoptosis and mitosis common
○ No necrosis
○ Dense lymphocytic stroma infiltrate
○ Strong EBV
- Non-keratinising differentiated (Type 2)
○ Interconnecting cords of tumour with little keratinisation
○ Cells with well-defined cell borders
○ Variable stroma lymphoplasmacytic infiltrate
○ No desmoplastic stroma
○ EBV 50/50
- Keratinising (Type 1)
○ As per keratinising SCC of the remaining pharynx
§ Keratin pearls, intercellular bridges
§EBV negative
- Basaloid (Non-WHO - Rare)
○ As per basaloid SCC of the remaining pharynx
§ Sheets of cells with peripheral palisading
§ High-grade features (high N:C ratio, scant cytoplasm, nuclear pleomorphism)
○ Poor prognosis
Immunohistochemistry
- POS = EBV LMP, PanCK, HMWCK, p40, p63
- NEG = CK7, CK20
Molecular
- EBER ISH
- EBV PCR
What is the staging for Nasopharynx cancer?
Stages:
- Stage I
○ T1N0
- Stage II
○ T1-2 N0-1
- Stage 3 ○ T3+ OR N2+ - Stage IV ○ T4 OR N3
How would you manage a locoregional recurrence of nasopharynx cancer?
○ Local recurrence rate up to 10% especially for larger tumours. Difficult surgery as prev IR tissue, deep in skull
○ A carefully selected subset of patients with locoregionally recurrent NPC may achieve long-term survival when managed with salvage surgery and/or re-irradiation
○ Workup
§ Hx + PE
§ MRI H&N
§ PET/CT to exclude distant metastasis
○ Management options
§ Salvage chemo -cisplatin/gemcitabine
□ Alternative: other single agent chemo
□ Immunotherapy trials second line (not PBS)
§ Salvage surgery only for select cases, T1-2N0M0
□ RE-RT is indicated if close or pos margin
HOWEVER, Re-irradiation NOT suitable IF: disease interval < 12mo, toxicity >G1 in critical organs and > G3 in non-critical organs
□ potential long term OS in select cases
□ Options
® IMRT (60-66Gy/33#)
® Intracavitary and interstitial brachytherapy
® SBRT
® Proton beam RT
□ Choice depends on local expertise and technical considerations including location and extent of recurrent disease
® Local recur: prefer endoscopic > Re-RT
® Re-RT (No Chemo) 65Gy/54F bid (Guangzhou), 3yOS 70 vs 50% favour bid (d/t late TRM, not DRM), G3 Tox and death rate were significantly lower with BiD regimen
◊ Volume: GTV, CTV 5mm, PTV 3mm
◊ Constraints:
Spinal Cord: max 60Gy
B’stem optic: max 70Gy
Temporal lobe: 90Gy
Carotid artery: 125Gy
What would be your elective neck lymph node targets in nasopharynx cancer?
What would be the expected 5year overall survival for nasopharynx cancer patients?
What is the staging for salivary gland cancer?
What is the evidence for adjuvant radiotherapy in salivary gland tumours?
- Data available is scant
○ Poor quality
○ Predominantly retrospective
○ Small numbers per series
○ Improved LRC and OS- There is no randomised data available to guide practice
- Mahmood 2011 SEER database multivariate analysis- Adj RT improved OS HR 0.76
- Terhaard 2004 Retrospective analysis
○ 538 pt, major salivary gland tumour, Surg+ PORT vs Surg alone. LRC was better for Surg+PORT.
○ Relative risk for Surg alone for Local Recurrence 9.7 and regional recurrence 2.3 - Mendehall 2005
○ 224 pt, Surg+PORT vs Surg alone.
○ 10 LC for Surg+PORT vs Surg alone- 96% vs 75% for T1-3; 70% vs 21% for T4
○ 10yr OS for T4 27% in Surg+PORT vs 21% in Surg alone - Safdieh 2017- retro data of NCDB= significant OS associated with PORT
○ 5yr and median OS- 56% and 73mo in PORT vs 50.6% and 61mo in Surg alone. HR 0.79 (SS)
What is the staging for sinonasal tumours?
Describe the management of Esthesineuroblastoma/ olfactory neuroblastoma.
- These tumours are quite chemo and radiosensitive
○ Benefit is especially seen for higher-grade lesion- Despite this, without surgery these tumours have high recurrence rates
- General treatment paradigm is dependent on local extent of disease
○ Early-Stage (Kadish A)
§ Endoscopic surgical resection (preferred)
§ Definitive RT alone (70Gy)
○ Intermediate-Stage (Kadish B)
§ Endoscopic surgical resection
□ Adjuvant RT may be required (60Gy)
§ Definitive RT alone is an alternative
○ Advanced-Stage (Kadish C+D)
§ Neoadjuvant chemoradiotherapy
□ 45-50Gy with concurrent Cisplatin + Etoposide
§ Surgical resection + Adj RT (for Kadish C)
What elective lymph node regions would you cover for sinonasal cancers?
What is the expected 5 year OS by stage and by histology
What are the periorbital complications from radiotherapy?
A fit 60-year-old male is diagnosed with a locally advanced squamous cell carcinoma of the glottic larynx with bilateral cervical lymph nodes. There is no evidence of distant metastatic disease. (Stage T3N2cM0)
Discuss the advantages and disadvantages of the different treatment strategies available for locoregionally advanced laryngeal carcinoma (Stages IlI and IV). (5 marks)
