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GRAFTS AND FLAPS IN HEAD AND NECK RECONSTRUCTION
Sternal
Clavipectoral fascia
riomioclavicular
to axilla
tion
Anatomy: Main supply from pectoral branch (to sternocostal head) and deltoid branch (to
clavicular head) of the thoraco-acromial artery. Pectoral branch emerges near junction of
middle and outer thirds of clavicle. Also supply from internal mammary perforators and
lateral thoracic artery.
Use: Pedicled proximally for salvage neck cases (e.g. resur facing), pharynx patches, oral reconstruction (e.g. mandible +/− bone), and cutaneous defects up to the level of the zygomatic arch.
Advantages: Large area of muscle with good donor closure, reliable blood supply with
straightforward harvest, potentially two-team.
Disadvantages: Muscle is bulky. Large skin paddles require split skin gra (SSG) violating
breast in females. Osteomyocutaneous ap using h rib has unreliable bone.
Technique for myocutaneous ap
Patient position: Supine with arm abducted on arm table
•
Plan:
•
Pre-operatively check for pectoralis major (absence of sternocostal head indicates
•
Poland’s syndrome).
Pedicle: Extend a line from acromium to xiphoid and a line from the sternal
•
notch, meeting rst perpendicularly; the point where the lines meet is where the
vascular pedicle runs towards the xiphisternum. Next, mark two thirds along the
clavicle from the sternal notch to the coracoid; the pedicle runs curved from here
to the bisection point.
Skin: Plan length in reverse from pivot point. Template defect as paddle on distal
•
pedicle. Skin paddle is vertical (lateral sternal edge, medially nipple, sixth rib) or
oblique or horizontal in fold in women. Skin paddle distal to pectoralis is random
pattern and needs rectus sheath (not reliable).
Muscle: Access incision from proximal paddle to axilla or along fold (latter gives
•
less access).
‘Defensive approach’: Mark deltopectoral ap. e boundaries are clavicle, delto-
•
pectoral groove, fourth rib, sternum, and intercostal spaces for perforators. Area
not harvested is ‘lifeboat’.
notch
Figure 71.1 Myocutaneous pectoralis major ap markings.
368 Head and Neck
with pedicle origin
Ac
joint
Pedicle direc
Incision in
Skin paddle
Xiphisternum
GRAFTS AND FLAPS IN HEAD AND NECK RECONSTRUCTION
Table 71.3 Free ap aims and options for various defects
Defect Aims Options
Cutaneous Cover with correct thickness and
colour
Oral cavity Volume, mobility, palatal closure Small/Moderate: RFF
Pharynx
(tubed)
Mandible Length, height (osseointegration),
Other Functional transfer (e.g. for
•
Mucosalised conduit, motility
for swallowing, speech with
tracheoesophageal puncture
(TEP)
composite tissue
facial palsy)
Procedure: Incise skin paddle to muscle, raise adjacent anterior fasciocutaneous aps
Small/Moderate: Radial forearm ap (RFF)
Moderate/Large: ALT, latissimus dorsi, scapula, DIEP
Moderate/Large: ALT, scapula, DIEP
F/C: ALT (adequate speech but risk of stricture)
Enteric: Jejunum (good swallow but poor speech)
Workhorse: Fibula, DCIA
Uncommon: Scapula/radius
Gracilis, ALT
to expose anterior muscle, release inferior border of muscle, raise posterior ap in subpectoral plane, leaving pectoralis minor behind, ligate lateral thoracic artery branch
laterally and internal mammary perforators medially, visualise pedicle under clavicular head, create window, and pass ap into neck.
Free Flaps
General Considerations
a. Flap choice (for options, see Table 71.3)
Recipient factors include defect size, location, tissue composition, bed (e.g. radiation),
and available vessels. Donor factors include best size and composition match, pedicle
length and diameter, donor morbidity, and ability to two-team. Patient factors include
age and comorbidity.
b. Recipient vessels
Radical neck dissections sacrice the jugular vein, but selective dissection gives more
venous options. External carotid branches are used (e.g. superior thyroid for pharyngeal reconstruction, facial for variety in skin and oral reconstruction, and supercial
temporal vessels for scalp defects). Transverse cervical vessels are a secondary option
if they were preserved in dissection.
c. Postoperative care
First 72 hours to 1 week are critical. Monitor for ap (artery and vein), theatre (anesthetic, neuropraxia) and systemic (clot, chest, cardiac) complications. Suboptimal
systemic factors (e.g. blood pressure) or local factors (e.g. compression, haematoma)
aect perfusion. Flap monitoring is done clinically (e.g. colour, capillary rell, turgor,
temperature), by hand-held or implantable Doppler.
Radial Forearm Flap (RFF)
Background: Fasciocutaneous workhorse ap (rarely osseocutaneous).
Anatomy: Based on radial artery (RA), with venous drainage by venae comitantes (VCs) or
cephalic vein. Skin perforators extend vertically from RA through septum to skin. Lateral
antebrachial cutaneous nerve provides sensation. Palmaris longus (PL) tendon (and bone)
can be ~10 cm.
Use: Cutaneous defects. Mucosal defects (e.g. oor of mouth/tongue, buccal mucosa, palate,
and oropharynx/tongue base). Composite defects (e.g. lip with PL sling).
Advantages: Consistent anatomy and easy raise. Long pedicle up to 15 cm. Large vessels
3–5 mm. Moderate skin island. in and pliable. Option for a sensate ap (e.g. for oral cavity).
Good colour match in darker skin. Allows two-team approach.
Head and Neck 369
GRAFTS AND FLAPS IN HEAD AND NECK RECONSTRUCTION
Disadvantages: Sacrice of major vessel (RA). Minimal volume if large dead space. May be
hairy. Donor requires unsightly gra (ipsilateral forearm gra or hatchett ap improves this).
Tech niqu e
Patient position: Supine, tourniquet, hand table.
•
Plan: Allen’s test, outline supercial veins (e.g. cephalic), plan ap centering on RA.
•
Procedure: Start ulnar, go subfascial and over PL and exor carpi radialis (FCR) to
•
artery. Radial incision is next, protecting supercial radial nerve and move over brachioradialis to artery, keeping cephalic vein within ap if needed and keep paratenon
on tendons. Distal incision controlling the distal end of the artery/vein. Raise pedicle,
keeping it with septum and skin to antecubital fossa.
Anterolateral Thigh Flap (ALT)
Background: Fasciocutaneous workhorse ap.
Anatomy: Profunda femoris gives lateral circumex femoral artery, which has two branches.
Descending branch gives ALT perforators, ascending branch to tensa fascia lata (TFL) is used
as ap ‘lifeboat’. Descending branch in mid-lateral thigh gives skin perforators, which are
either septocutaneous (20%) or musculocutaneous (in vastus lateralis; 80%). Nerve supply is
lateral femoral cutaneous nerve.
Use: Cutaneous defects anywhere, oral cavity, skull base, and tubed for total pharynx
reconstruction.
Advantages: Large skin island (38 cm × 15 cm) with the donor closed primarily. in and
pliable but can incorporate the vastus lateralis for bulk. Long pedicle (15 cm) with good
diameter (1–3 mm). Allows two-team approach.
Disadvantages: Perforator anatomy is variable, so dissection is challenging. Perforator susceptible to compression. In thicker thigh, ap is bulky and donor needs SSG. Colour match
poor. Hair-bearing skin transferred.
Tech niqu e
Patient position: Supine with sandbag under ipsilateral hip.
•
Plan: Draw line between iliac spine and superolateral patella. At midpoint, draw circle
•
of radius 3 cm. Doppler perforators (one is sucient, but two are ideal for big aps).
Procedure: Longitudinal incision 2 cm medial to line. Take 1 cm cu of fascia medi-
•
ally. Move subfascially laterally until perforators are identied. Release perforators
down to pedicle. Follow descending branch proximal. Template defect over perforator.
Cut posterior skin incision subfascially and isolate perforator.
Gracilis Flap
Background: Muscle ap usually for facial reanimation.
Anatomy: Profunda femoris gives the medial circumex femoral artery, which enters deep aspect
of gracilis 8–10 cm below the pubic tubercle. Flap can be innervated by the obturator nerve.
Use: Good for functional transfer (i.e. facial reanimation).
Advantage: Constant anatomy.
Disadvantages: Skin paddle not reliable, muscle is a little bulky, and pedicle is moderate
length (6 cm) and diameter (1–2 mm).
Tech niqu e
Patient position: Supine with hip abducted and externally rotated.
•
Plan: Line from insertion of adductor longus on pubic ramus to media l femora l condyle.
•
Procedure: Longitudinal incision 3 cm behind line. Incise to fascia. Raise fascia poste-
•
riorly and nd pedicle on deep aspect of gracilis. Divide other distal perforators. Raise
anterior fascia, protecting the pedicle. Chase pedicle between adductor longus and
brevis. Cut nerve. Divide tendinous insertions.
370 Head and Neck
RADIOTHERAPY AND CHEMOTHERAPY
Conclusions
Gras and local aps are benecial for small defects. Locoregional or distant aps are important
in salvage cases (e.g. free ap failed or vessel depleted neck) but disadvantages include lack of size
or reach and being bulky. Free tissue transfer improves functional outcomes and can transfer
large volumes of composite tissue in a single stage procedure. e disadvantages include complex and lengthy operations with chance of failure and systemic post-operative complications.
KEY POINTS
• Reconstructive principles include the ‘toolbox’, ‘subunits’, and RSTLs.
• There are key differences between and within grafts and aps.
• Specic areas and defects require specic aps.
Further Reading
1. Gabrysz-Forget F, Tabet P, Rahal A, Bissada E, Christopoulos A, Ayad T. Free versus
pedicled aps for reconstruction of head and neck cancer defects: a systematic review.
J Otolaryngol Head Neck Surg 2019; 48(1): 13.
2. Huang TC, Cheng HT. ALT vs. jejunum: have we found the ideal ap for circumferential pharyngoesophageal reconstruction? A meta-analysis of comparative studies. J
Plast Reconstr Aesthet Surg 2019; 72(2): 335–354.
3. Largo RD, Garvey PB. Updates in head and neck reconstruction. Plast Reconstr Surg
2018; 141(2): 271e–285e.
72. RADIOTHERAPY AND CHEMOTHERAPY
RADIOTHERAPY
Introduction
Radiotherapy, either as a single modality or combined with synchronous chemotherapy, is
capable of high rates of tumour control. Head and neck radiotherapy uses photons produced
in a linear accelerator. e photon beam produced can be shaped using collimators that are
able to move, enabling delivery of intensity-modulated radiotherapy (IMRT), and the gantry of the linear accelerator can move around the patient’s head to deliver dierent beam
angles (dynamic IMRT). Photons cause tissue ionization and free-radical formation, which
causes cell death through single- or double-strand breaks in DNA. e dierential response
ogists to maximise the therapeutic ratio.
Radiotherapy Process
Preparation
Multidisciplinary meeting (MDT)
•
Patient information, education, discussion
•
Consent
•
Consideration of prophylactic versus reactive feeding tube placement
•
Dental assessment
•
Head and Neck 371
RADIOTHERAPY AND CHEMOTHERAPY
Immobilisation
Use a patient-specic mask to immobilise the head and shoulders. is is subject to regular
departmental audit, and the data are used to inform the planning target volume (PTV) margins.
Imaging
Computed tomography (CT) with IV contrast: 2-mm slice, in mask. Fused with prior diagnostic images.
Target Volume
e oncologist will dene the gross tumour volume (GTV) based on MRI and CT. A small
margin is added (5–10 mm) to allow for microscopic spread/limitations of fusion/imaging
employed; this forms the high-dose clinical target volume (CTV) that will receive treatment.
Adjacent areas and nodal regions felt to be at high risk of harbouring microscopic disease
may be included in a prophylactic CTV to receive a smaller dose. PTV margins (normally
3–5 mm) are added to both CTVs.
Organs at Risk
Organs at risk are anatomical structures with critical functional properties located in the
vicinity of the target volume (i.e. spinal cord, brainstem, contralateral parotid, brain, and
mandible). Other regions which need contouring in an attempt to reduce toxicity include
oral mucosal volume, laryngeal framework, and swallowing muscles.
Peer Review of Contours
e CTV dened by the oncologist should be peer reviewed, particularly in complex cases.
Treatment Planning
e departmental dosimetrists produce an IMRT plan, which is reviewed by the oncologist
and subjected to quality assurance.
Delivery
e treatment planned is delivered over the dened number of weeks. At each treatment
session, a cone-beam CT or megavoltage image is taken to check positioning and to assess
any changes in contour due to weight loss or tumour shrinkage, which may aect dosimetry.
Supportive Care
Supportive care is reviewed weekly during treatment by various members of the MDT.
Altered Fractionation
Although 70 Gy in 35 fractions (overall treatment time, 46 days/7 weeks) is one of the most
common radiotherapy dosing schedules, prior to chemoradiation’s being accepted as standard treatment, several dierent fractionation schemes had been studied. Acceleration is
a reduction in the overall treatment time below the standard 46 days. Hyperfractionation
is use of <2 Gy per fraction, and hypofractionation is use of >2 Gy per fraction. Altered
fractionation may be required if radiotherapy appointments are missed, for example. Dose
escalation is an increase in the total physical dose above 70 Gy.
A meta-analysis of altered fractionation grouped trials found an overall survival benet only
in the hyperfractionated dose-escalated group. is survival benet is approximately the
same as that seen with the addition of synchronous chemotherapy to standard radiotherapy.
Dose-Escalated Radiotherapy or Synchronous Chemoradiotherapy
e addition of synchronous chemotherapy to standard radiotherapy has been associated
with an 8% survival advantage, which is the same benet that can be achieved with doseescalated radiotherapy. Studies show, however, that synchronous chemotherapy, rather than
dose-escalated hyperfractionated radiotherapy, is more benecial when local control and the
risk of grade 3 mucositis are considered.
372 Head and Neck
RADIOTHERAPY AND CHEMOTHERAPY
KEY POINTS
• Parotid-sparing radiotherapy reduces late xerostomia.
• Dose-escalated hyperfractionated radiotherapy increases overall survival by 8% at
5 years compared with conventionally fractionated radiotherapy alone.
• The addition of synchronous chemotherapy to radiotherapy increases survival by 8% at
5 years compared with conventionally fractionated radiotherapy alone.
• Two randomised trials have failed to show evidence for a survival benet of
synchronous chemotherapy and accelerated radiotherapy over synchronous
chemotherapy and conventionally fractionated radiotherapy.
CHEMOTHERAPY
Introduction
Chemotherapy alone cannot cure head and neck cancer. It is used in conjunction with surgery and radiotherapy to improve outcomes, such as better local control, organ preservation
with continued organ function, and decreased incidence of subclinical micro-metastatic
spread. Chemotherapy is given for its direct tumouricidal eect at both the local primary
and distant metastatic sites. If given with radiotherapy, it can have a radiosensitising eect,
making cancer cells more susceptible to radiotherapy and increasing the cancer cell kill.
Induction (Neoadjuvant) Chemotherapy
Chemotherapy can be used as induction or neoadjuvant treatment before the primary treatment
(more oen surgery than radiotherapy) in order to shrink an advanced primary tumour or to
reduce and render xed cervical nodes mobile, potentially enabling technically easier surgery. If
induction chemotherapy can improve local control, then there is a greater chance of functional
organ preservation, and the initial response to chemotherapy can give prognostic information.
However, because most patients who have induction chemotherapy go on to have concurrent
chemotherapy as well, there is a risk that the subsequent denitive radiotherapy will not be
completed or will require breaks in delivery because of the morbidity caused by induction
chemotherapy, and this could result in poorer outcomes.
Overall, evidence has failed to show a survival benet with induction chemotherapy compared to primary surgery or radiotherapy alone, and there is debate about the benet of
induction chemotherapy followed by concurrent chemoradiotherapy over concurrent
chemoradiotherapy alone.
Concurrent or Concomitant Chemotherapy
Concomitant chemotherapy is chemotherapy given at the same time as radiotherapy. It can
be administered aer neoadjuvant treatment, as a stand-alone treatment, or as an adjuvant
aer primary treatment. It is given for its direct cell-killing eect and for sensitising cancer
cells to the eects of radiotherapy. e most commonly use concurrent chemotherapy regimens use cisplatin (100 mg/m2 at days 1, 22, and 43 of radiotherapy), either alone or with
5-FU (1 g per day on days 1 to 4).
Increas ed toxicity produced by add ing platinum chemot herapy to radiother apy can be considerable, with more marked mucositis, dysphagia, nephrotoxicity, ototoxicity, myelodysplasia,
and neutropenia. Chemotherapy toxicity can also interfere detrimentally with radiotherapy
delivery, causing breaks in treatment, which are associated with poorer outcomes.
Evidence shows there is a survival benet of chemotherapy when it is added to radiotherapy
alone, giving a 6.5% decrease in mortality at 5 years. In absolute terms, however, this benet
was not seen in patients over 70 years old, but patients over age 70 formed a very small number of the total patients reviewed.
Head and Neck 373
RADIOTHERAPY AND CHEMOTHERAPY
If cisplatin is contraindicated because of renal function status/neuropathy/tinnitus/deafness,
carboplatin can be considered, because it causes less nephrotoxicity, ototoxicity, and peripheral neuropathy, but it is more myelosuppressive. Also, carboplatin is not thought to be as
tumouricidal as cisplatin; for this reason, the epidermal growth factor receptor (EGFR)
inhibitor cetuximab can be used instead when cisplatin is contraindicated.
Adjuvant Chemotherapy
Adjuvant chemotherapy is given aer the principal treatment. When primary surgery has
been the denitive treatment, and when adjuvant chemotherapy is given with adjuvant radiation, it has been shown to improve local control and to increase survival. is benet is seen
in patients who have a higher risk of recurrence, as indicated by positive surgical margins,
nodal involvement (especially in multiple nodes), or extracapsular spread.
Targeted Biological Agents
Targeted therapies in head and neck cancer, such as the monoclonal antibody cetuximab,
were developed with the recognition that EGFR overexpression occurs in most head and
neck cancers (in up to 90% in some studies) and is associated with a poorer prognosis.
Initial hopes were that cetuximab would have less toxicity than standard chemotherapy
and therefore could be given to older patients and those with poorer performance status.
Although cetuximab has been shown to cause less nephrotoxicity, ototoxicity, and peripheral
neuropathy, it causes more intense grade 3 and grade 4 radiation dermatitis.
In patients with HPV-positive oropharyngeal tumours, the De-ESCALaTE HPV trial compared the standard regimen of concurrent radiotherapy with cisplatin to the regimen of
cetuximab and radiotherapy. e cetuximab group showed no benet in terms of reduced
toxicity, but instead showed signicant detriment in terms of tumour control (higher 2-year
recurrence and lower 2-year overall survival); therefore, cisplatin is recommended as the
standard of care.
Chemotherapy for Recurrent or Metastatic Head and Neck Cancer
Chemotherapy or targeted biological agents may be indicated for patients with recurrent
and/or metastatic disease, although patients with metastatic disease have a median survival
of approximately 6–12 months. Oen, the most important considerations are the tness and
performance status of the patient and whether they could tolerate the proposed chemotherapy, as well as how much it would reduce their pre-treatment quality of life, for whatever
limited survival time they have.
Locoregional Failure
Locoregional failure has been reported in up to 50% of patients with head and neck cancer.
In these patients, if salvage surgery or retreatment with radiotherapy/chemoradiotherapy is
being considered, it is important to assess for the presence of distant metastatic disease and
to exclude second primary tumours. Metastatic disease is not an absolute contraindication
to salvage treatments, as locoregional failure and metastatic disease can receive two separate management plans. If locoregional control can be achieved relatively easily by a salvage
procedure, the presence of metastatic disease (especially small-volume metastatic disease)
should not necessarily stop treatment to the locoregional site.
Distant Metastases
Chemotherapy is oen indicated as part of a best supportive care package for distant metastases,
but it has not been shown to signicantly extend survival. e presence or absence of symptoms
will inuence when patients receive chemotherapy, and chemotherapy may be appropriate when
the patient still has a suitable performance status to receive and benet from it, with t he trade-o
being an improved symptom prole for the inevitable morbidity caused by the chemotherapy. A
shared decision-making approach is required to allow a fully informed decision.
374 Head and Neck
IMMUNOTHERAPY IN HEAD AND NECK CANCERS
e most common reg imens use cisplati n or carboplatin w ith 5-FU, and they give an expec ted
response rate of approximately 40%. Carboplatin is used more oen, because although it
is deemed slightly less eective than cisplatin, it is less toxic and is considered to be more
appropriate in the palliative setting. Elderly patients appear to respond to platinum-based
chemotherapy in the metastatic setting, but they experience more toxicity. Cetuximab with
cisplatin and 5-FU can increase both response rate and improve short-term survival slightly.
Cetuximab as a single agent has a low response rate of approximately 10–15%.
KEY POINTS
• Concurrent chemoradiotherapy is the standard of care for treatment of locally
advanced head and neck cancer, with a conrmed absolute survival benet of 6.5% at
5 years.
• Targeted biological agents, such as cetuximab, have roles to play in both advanced
head and neck cancer and recurrent or metastatic disease, but those roles are still
being established.
• Elderly patients benet least in terms of survival with the use of concurrent
chemotherapy.
Further Reading
1. Nutting CM, Morden JP, Harrington KJ, et al. PARSPORT trial management group.
Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck
cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol
2011; 12(2): 127–136.
2. Pignon JP, le Maître A, Maillard E. MACH-NC Collaborative Group. Meta-analysis
of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised
trials and 17,346 patients. Radiother Oncol 2009; 92(1): 4–14.
3. Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al.
Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive
oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled
phase 3 trial. Lancet Oncol 2019; 393(10611): 51–60.
73. IMMUNOTHERAPY IN HEAD AND NECK CANCERS
Introduction
Cancer is a genetic disease that develops when DNA is damaged or wrongly decoded. is
alters gene expression and impairs normal protein function.
Genetic changes leading to cancer have two general eects:
Overactivity of genes that stimulate cell growth, survival, and spread
•
Underactivity of genes that repress these processes
•
us, the fundamentals of cancer are derangements of the interplay between growth and
repression.
Oncogenes and Tumour Suppressor Genes (TSG)
Two classes of genes, oncogenes and TSG, are fundamental to understanding cancer
biology.
Head and Neck 375
IMMUNOTHERAPY IN HEAD AND NECK CANCERS
Avoid
apoptosis
Reprogrammed
energy metabolism
Figure 73.1 Hallmarks of cancer.
Oncogenes are mutated versions of normal cellular genes (called proto-oncogenes) encoding
proteins that control cell proliferation, survival, and spread. Abnormalities in proto-oncogenes
cause uncontrolled cell division, enhanced cell survival, and dissemination. A single mutated
copy can promote cancer. Oncogenes are activated in three ways to cause cancer: mutation,
amplication, and translocation.
TSGs are genes whose normal function inhibits cell proliferation and survival. The
function of both copies of a TSG must be lost in order to promote cancer (so-called
phenotypic recessiveness). Mutated TSGs are responsible for the majority of inherited
cancer syndromes, although such syndromes are not a significant cause of head and
neck cancers.
Hallmarks of Cancer
Eight key transformations that drive malignant processes, termed the ‘hallmarks of cancer’,
are summarised in Figure 73.1. ese properties underpin immunotherapy, which exploits
fundamental biological dierences between normal and malignant cells.
Evade immune
destruction
Hallmarks of cancer (8)
Sustained
angiogenesis
Growth factor
independence
Tissue invasion
& metastasis
Insensitivity to
anti-growth signals
Cellular
immortality
Biological Targeting
Improvements in our knowledge of cancer biology have enabled development of novel targeted therapies against cancers. is chapter focuses on three specic themes that appear
most promising:
Targeting growth factor independence
•
Radiosensitisers
•
Enhancing antitumor immune responses
•
Targeting Growth Factor Independence
Squamous cell carcinoma of the head and neck (HNSCC) frequently displays upregulated
epidermal growth factor receptor (EGFR) signalling. EGFR (a.k.a. HER1) is a member of
the c-erb family of transmembrane type I receptor tyrosine kinases, which has four members (HER1–4). Binding to EGFR leads to a cascade of intracellular second messengers that
subsequently alter gene expression, which means that a protein binding on the cell surface
inuences cell behaviour.
Growth factor independence can lead to sustained signalling in pathways that control
essential functions: growth, apoptosis, angiogenesis, invasion, and DNA damage repair.
Monoclonal antibodies (MAbs) and tyrosine kinase inhibitors (TKI) block these pathways
by acting on dierent aspects of the receptor signalling pathway.
Curative Anti-EGFR MAbs
Several EGFR-targeted MAbs have been tested in clinical practice. Clinical trials conrmed
the ecacy of cetuximab in combination with chemotherapy or radiotherapy. Subsequently,
376 Head and Neck
IMMUNOTHERAPY IN HEAD AND NECK CANCERS
Table 73.1 Clinical trials of anti-EGFR MAbs
Trial Study info Summary
RTOG-0522
(Ang 2014)
CONCERT-1
(Mesia 2015)
CONCERT-2
(Giralt 2015)
De-ESCALaTE HPV
(Mehanna 2019)
Locally advanced disease; radiation plus
cisplatin ± concurrent cetuximab
Untreated stage III–IVb disease;
chemoradiotherapy (CRT) ± concurrent
panitumumab
Unresected stage III–IVb disease;
platinum-based CRT vs. radiation plus
panitumumab only
HPV+ oropharyngeal cancers; patients
randomised to radiotherapy with either
cisplatin or Cetuximab
No difference in LRC or OS
No benet for LRC or OS
Panitumumab had greater
toxicity
No benet for LRC or OS
Panitumumab had greater
toxicity
Cetuximab was deleterious for
both OS and recurrence rate
research in locally/regionally advanced HNSCC demonstrated that patients receiving radiotherapy and cetuximab have prolonged locoregional control (LRC) and overall survival
(OS) when compared to patients receiving radiotherapy alone (Bonner 2006). Cetuximab
was associated with a higher incidence of rash and infusion reactions, but supplementary
analysis demonstrated that skin reactions represented a biomarker of favourable outcome.
Further trials (Table 73.1) have not shown improved outcomes. e data indicate that, in the
curative setting, anti-EGFR MAb therapy should be restricted to the use of cetuximab plus
radiotherapy.
Palliative Anti-EGFR MAbs
e EXTREME study treated patients with untreated recurrent/metastatic HNSCC with
cisplatin or carboplatin plus 5-uorouracil. Patients were then randomised to receive cetuximab; the cetuximab arm had prolonged median OS and median progression-free survival,
as well as improved response.
erefore, it appears that triple-agent therapy with platin/5-uorouracil and cetuximab may
be benecial for patients as rst-line therapy for relapsed/metastatic disease. In practice, this
regimen is oen not used due to concerns about additional toxicity from adding cetuximab
to standard treatment.
Curative TKI
Currently, there is no clear indication for the use of TKI in the treatment of newly diagnosed
HNSCC. Trials that substantiate this are shown in Table 73.2.
Table 73.2 Clinical trials of tyrosine kinase inhibitors (TKI)
Treatment/
Trial Study info Summary
Getinib
(Saarilahti 2010)
(Cohen 2010)
Erlotinib
(Martins 2013)
Lapatinib
(Harrington
2015)
Afatinib
(Burtness 2019)
CRT ± concurrent getinib
Chemotherapy ± concurrent
getinib
CRT ± concurrent erlotinib No improvement in outcomes and
CRT ± concurrent lapatinib and
maintenance in high-risk surgically
treated HNSCC (stage III–IVa)
Radiotherapy with either cisplatin or
carboplatin ± concurrent afatinib
Can be safely combined with CRT
(either standard cisplatin-based CRT or
unconventional split-course schedule
of 5-uorouracil and hydroxyurea)
increased toxicity
Lapatinib did not offer any efcacy/
safety benet when compared to
placebo
Addition of afatinib did not improve
disease-free survival and increased toxicity
Head and Neck 377
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