Post-therapeutic surveillance strategies in head and neck squamous cell carcinoma

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European Archives of Oto-Rhino-Laryngologyand Head & Neck ISSN 0937-4477 Eur Arch OtorhinolaryngolDOI 10.1007/s00405-012-2172-7

Post-therapeutic surveillance strategies inhead and neck squamous cell carcinoma

Antoine Digonnet, Marc Hamoir,Guy Andry, Missak Haigentz, RobertP. Takes, Carl E. Silver, Dana M. Hartl,Primož Strojan, et al.

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REVIEW ARTICLE

Post-therapeutic surveillance strategies in head and necksquamous cell carcinoma

Antoine Digonnet • Marc Hamoir • Guy Andry • Missak Haigentz Jr. • Robert P. Takes • Carl E. Silver •

Dana M. Hartl • Primoz Strojan • Alessandra Rinaldo • Remco de Bree • Andreas Dietz • Vincent Gregoire •

Vinidh Paleri • Johannes A. Langendijk • Vincent Vander Poorten • Michael L. Hinni • Juan P. Rodrigo •

Carlos Suarez • William M. Mendenhall • Jochen A. Werner • Eric M. Genden • Alfio Ferlito

Received: 15 July 2012 / Accepted: 15 August 2012

� Springer-Verlag 2012

Abstract The management of head and neck squamous

cell carcinomas does not end with the completion of

ablative therapy. The oncologic objectives of post-treat-

ment follow-up are to detect recurrences and second pri-

mary tumors; beyond that, follow-up should evaluate acute

and chronic treatment-related side effects, guide the reha-

bilitation process, alleviate functional loss, manage pain,

restore nutritional status and assess psychosocial factors. In

this structured review, we address the questions of timing

and the tools required to achieve a complete and coherent

routine surveillance. Several guidelines and consensus

statements recommend clinical examination as the cor-

nerstone of follow-up which should be performed for at

least 5 years, although there are no data in favor of any one

particular follow-up program, and only low-level evidence

suggests an improvement in oncologic outcomes by close

follow-up. Baseline imaging (computed tomography andThis paper was written by members and invitees of the International

Head and Neck Scientific Group (http://www.IHNSG.com).

A. Digonnet � G. Andry

Department of Head and Neck and Thoracic Surgery,

Institut Jules Bordet, Brussels, Belgium

M. Hamoir

Department of Head and Neck Surgery,

Cancer Center, St. Luc University Hospital, Brussels, Belgium

M. Haigentz Jr.

Division of Oncology, Department of Medicine,

Montefiore Medical Center, Albert Einstein College

of Medicine, Bronx, NY, USA

R. P. Takes

Department of Otolaryngology-Head and Neck Surgery,

Nijmegen Medical Center, Radboud University,

Nijmegen, The Netherlands

C. E. Silver

Departments of Surgery and Otolaryngology-Head

and Neck Surgery, Montefiore Medical Center,

Albert Einstein College of Medicine, Bronx, NY, USA

D. M. Hartl


Institut Gustave Roussy, Villejuif Cedex, France

D. M. Hartl

Laboratoire de Phonetique et de Phonologie,

Sorbonne Nouvelle, Paris, France

P. Strojan

Department of Radiation Oncology,

Institute of Oncology, Ljubljana, Slovenia

A. Rinaldo � A. Ferlito (&)

ENT Clinic, University of Udine,

Piazzale S. Maria della Misericordia, 33100 Udine, Italy

e-mail: [email protected]

R. de Bree


VU University Medical Center, Amsterdam, The Netherlands

A. Dietz

Department of Otorhinolaryngology,

University of Leipzig, Leipzig, Germany

V. Gregoire

Radiation Oncology Department and Center for Molecular

Imaging and Experimental Radiotherapy, Universite Catholique

de Louvain, St-Luc University Hospital, Brussels, Belgium

V. Paleri


Newcastle upon Tyne Foundation Hospitals NHS Trust,

Newcastle upon Tyne, UK

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Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-012-2172-7

Author's personal copy

http://www.IHNSG.com

magnetic resonance imaging) should be obtained within

2–6 months after definitive therapy if used for treatment

response evaluation. Metabolic response, if indicated,

should be assessed preferably after 3 months in patients

who undergo curative-intent therapy with (chemo)-radio-

therapy. Chest computed tomography is more sensitive

than plain radiography, if used in follow-up, but the benefit

and cost-effectiveness of routine chest computed tomog-

raphy has not been demonstrated. There are no current data

supporting modifications specific to the surveillance plan

of patients with human papillomavirus-associated disease.

Keywords Head and neck cancer � Surveillance strategy �Recurrence � HPV � Distant metastasis

Introduction

The care of patients with head and neck squamous cell

carcinoma (HNSCC) does not end with the completion of

definitive treatment and requires a period of post-thera-

peutic follow-up with three main objectives.

The first objective is to detect as soon as possible

recurrences, whether local, regional, and/or at distant sites.

It is widely accepted that patients who have received

potentially curative treatment for HNSCC are at risk for

loco-regional recurrences and second primary tumors.

Recurrence rates vary from \10 to 48 %, depending on

initial stage and primary tumor site [1, 2]. A prospective

study by Boysen et al. [3] published in 1992 found that

76 % of recurrences (all head and neck sites combined)

occurred in the first 2 years following treatment, with

another 11 % detected during the third year. de Visscher

and Manni [4] found that 76 % of recurrences, second

primary tumors or metastases (cancer-related ‘‘events’’)

occurred within 3 years of initial treatment. Similarly,

prospectively collected data analyzed by Lester and Wight

[5] found that 95 % of recurrences or second primaries

occurred within 2.7 years for oropharyngeal primaries,

2.3 years for hypopharyngeal primaries and 4.7 years for

laryngeal primaries. Wensing et al. [6] reported that 83 %

of recurrent disease in a series of 197 oral cavity squamous

cell cancer occurred within 2 years. Although early

detection of local and/or regional recurrence can offer the

possibility of successful salvage treatment with curative

intent [7], the early detection of distant metastasis is of

uncertain benefit to patients, as it implies incurable disease,

and in most cases treatment will be guided by symptoms in

a palliative setting [8]. Therapeutic options for locore-

gional recurrence continue to evolve. Recent demonstration

of promising new options such as re-irradiation [9, 10] with

or without targeted therapy and photodynamic therapy [11]

decrease the number of patients ‘‘without therapeutic

options.’’

The second objective of post-treatment surveillance lies

in the detection of second primary malignancies outside of

the head and neck region. In patients with primary tumors of

the upper aerodigestive tract (UADT), the reported rates of

second primary tumors in the esophagus or lung vary from 10

to 20 % [12, 13], depending on duration of follow-up.

The other objectives of surveillance are to evaluate

acute and chronic treatment-related side effects, guide the

rehabilitation process, alleviate functional loss, manage

pain, restore nutritional status, and assess the psychosocial

consequences of all these factors. The optimal surveillance

strategy for HNSCC patients who have undergone poten-

tially curative treatment is not clearly defined and varies

widely among practitioners [14–16].

J. A. Langendijk

Department of Radiation Oncology,

University Medical Center Groningen,

University of Groningen, Groningen,

The Netherlands

V. Vander Poorten

Department of Otorhinolaryngology-Head

and Neck Surgery and Leuven Cancer Institute,

University Hospitals Leuven,

Leuven, Belgium

M. L. Hinni


Mayo Clinic, Phoenix, AZ, USA

J. P. Rodrigo � C. Suarez

Department of Otolaryngology,

Hospital Universitario Central de Asturias,

Oviedo, Spain

J. P. Rodrigo � C. Suarez

Instituto Universitario de Oncologıa del

Principado de Asturias, Oviedo, Spain

W. M. Mendenhall

Department of Radiation Oncology, University of Florida,

Gainesville, FL, USA

J. A. Werner


Philipp University, Marburg, Germany

E. M. Genden


The Mount Sinai Medical Center, New York, NY, USA


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Recently, the link between HNSCC, especially oropha-

ryngeal cancer (OPC), and human papillomavirus (HPV)

has been established [17]. HPV 16 is the most common

oncogenic genotype in these tumors. Patients with HPV-

associated HNSCC who are non-smokers seem to have a

better prognosis after completion of treatment [18]. Con-

versely, patients who have HPV-negative disease or those

who continue to smoke and drink after completion of

treatment are at high risk for recurrences. Guidelines for

surveillance stratified for HPV status are not well estab-

lished since epidemiological data in comparison with dif-

ferent continents (USA vs. Europe) and the individual mix

of risk factors are still confusing due to high heterogeneity.

In this structured review, we discuss the optimal timing for

visits and the tools required for surveillance.

Methods

A comprehensive literature search on PubMed/MEDLINE,

EMBASE and Cumulative index to Nursing and Allied

Health Science Literature (CINAHL) was performed dur-

ing the period of 1980–2011 for follow-up strategies in

patients with HNSCC. Keywords included head and neck

cancer, surveillance strategy, recurrence, and HPV. Selec-

ted articles fulfilled criteria of post-therapeutic surveillance

in HNSCC and use of any modality for surveillance of

HNSCC. Articles published in a language other than

English were not included. The reference list of the rele-

vant articles was analyzed and any other pertinent articles

were added to the review.

Results

Surveillance plan

There are several recommendations in the literature

regarding the post-treatment follow-up of HNSCC patients.

In their recent review, Manikantan et al. [19] concluded

that no one specific surveillance program is more efficient

in detecting recurrences or improving quality of life. Fur-

thermore, there is conflicting evidence as to whether

recurrences detected by the patient or those by routine

surveillance confer a survival advantage [2, 4]. Some

authors suggest that good patient education is important

and encourage patients to self-present at the first sign of

suspicious symptoms. In 2010, Flynn et al. [20] conducted

a study of 223 patients with locoregionally advanced (stage

III–IV) HNSCC to evaluate the utility of the follow-up

regimen used in their center. The recurrences were cate-

gorized into two groups: patient-detected cases were

defined as those for which the patients were symptomatic at

the time of the visit or were self-referred for pain or wor-

risome symptoms, and physician-detected cases were

defined as those for which patients had an asymptomatic

recurrence identified during follow-up consultation. The

authors found no improvement in disease-free or overall

survival in the physician-detected recurrence group when

compared with the patient-detected recurrence group. In

another study reported by Boysen et al. [3] which included

661 HNSCC patients considered free of disease at 6 weeks

after completion of therapy, the patients were seen every

2–3 months for the first 2 years and every 3–4 months for

the following 3 years. The authors found that the survival

rate was better in patients where recurrence was detected

through symptoms when compared with survival in

asymptomatic patients where recurrence was detected

through physical examination (PE). The majority of

recurrences (61 %) were diagnosed after self-referral for

specific symptoms. In this series, the authors did not

observe any recurrence after 3 years.

In a study on early stage (I and II) floor of mouth and

tongue cancer the effectiveness of a 10-year routine follow-

up was found to be limited, suggesting that visits on routine

basis can be stopped after 5 years [21]. In a study on lar-

yngeal carcinoma, a routine follow-up program did not lead

to survival benefit for asymptomatic patients with tumor

recurrence [22]. It was suggested that after the third year of

follow-up screening for recurrent tumor can be stopped [23]

and that an intensive and long follow-up schedule had lim-

ited influence on life expectancy in elderly people. The lack

of benefit of post-treatment oncologic surveillance programs

as compared with nationwide primary screening programs

may be explained by the fact that patients who have already

received oncologic treatment but develop a recurrence have a

worse prognosis compared with patients who have initial

malignancies. Other factors may be the limited therapeutic

options in the event of cancer recurrence, the detection of

slow-growing tumors (length–time bias) and the magnitude

and adjustment of lead time [23]. Also, for second primary

tumors, treatment options may be limited due to previous

treatments in the same anatomical site.

In contrast, Kissun et al. [24] retrospectively studied 278

patients treated for oral and OPC and reported that 54

patients (19.5 %) developed a recurrence within a median

of 8 months. Among them, only 20 patients were aware of

recurrent disease. Patients were considered aware of their

recurrence if they were experiencing new symptoms

defined by pain, lump, ulcer or swallowing difficulties. The

authors concluded that close clinical follow-up is needed

after treatment.

A study by de Visscher and Manni [4] of 428 patients

assessed whether curative treatment was possible in

patients in whom early recurrence, metastasis or second

primary tumors was detected by routine follow-up. The


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authors found that the mean survival of patients with

recurrences detected on routine follow-up was 58 months

while it was only 32 months in patients with recurrence

detected after self-referral.

These observed differences in the results of follow-up

strategies may reflect [25] that geographical and socio-

economic factors account for some of the variation in the

use of surveillance method. Lester and Wight [5] added

that routine follow-up must be planned with reference to

the local population.

Other authors propose a strict follow-up regimen during

the first 3 years only in patients where a salvage treatment

option could exist [26]. For patients without any potential

therapeutic option, follow-up should be focused more on

providing care and support than on detecting recurrence.

For other tumors resectability can only be determined after

restaging of the recurrent tumor.

In 2001, the British Association of Head and Neck On-

cologists (BAHNO) [27] advised a 4- to 6-week follow-up

schedule for the first 2 years, 3-month follow-up visits during

the third year, 6-month follow-up for the fourth and the fifth

years and annual visits thereafter. More recently, the National

Comprehensive Cancer Network (NCCN) [28] recom-

mended 1- to 3-month follow-up for the first year, 2- to

4-month follow-up for the second year, 4- to 6-month follow-

up for years 3 to 5 and every 6–12 months thereafter. The

most relevant schedules of follow-up visits reported in the

literature are summarized in Table 1 [5, 14, 16, 27, 28].

Some authors have proposed tailoring the frequency of

visits according to factors such as the primary tumor site and

stage of the disease [4, 29]. Although it would be reasonable

to tailor follow-up depending on risk-stratification for loco-

regional recurrences in particular, this could be difficult to

implement in clinical practice. Similarly, it may be argued

that the design of screening programs for distant metastasis

should be tailored to the risk of recurrence by identifying

those patients at highest risk for distant metastasis [30].

However, assessment of risk of recurrence would be more

relevant concerning locoregional recurrences, as patients will

only benefit if there are potentially curative treatment options

left for them. The presence of distant metastasis usually

implies incurable disease with the rare exception of oligo-

metastatic disease managed with locoregional therapy, and

management is often guided towards symptom control [8,

31]. The early detection of distant metastasis will not always

serve sensible purposes.

In our opinion, scheduled visits are still the best way to

offer an adequate follow-up to patients treated for HNSCC

as they address several purposes which are mentioned

above and not just for early detection of recurrence or

second primaries. Self-presentation at the first sign of

suspicious symptoms or other problems related to onco-

logical treatment must be used in combination with plan-

ned surveillance but should not replace it.

Surveillance tools

Physical examination

PE remains the cornerstone for detection of potential

recurrence. It is the most easily available and reliable

method for assessing superficial mucosal tumors and/or the

extent of mucosal involvement of other tumors [32]. Cur-

rent studies justify the need for PE in the routine follow-up,

but never provide exact details [15, 16, 19, 33]. As PE

should be easily standardized and reproducible, we propose

to present it as a checklist (Table 2) derived from the lit-

erature [27, 28]. In this proposal, PE should include cranial

nerve examination, an assessment of vocal, breathing and

swallowing functions, and a systematic pain evaluation

using a visual analogic scale (VAS). A complaint of new or

worsening pain should alert the physician to potential

disease recurrence. Flexible fiberoptic endoscopy is para-

mount for a comprehensive examination of the UADT [27]

as well as direct laryngoscopy when indicated.

Improvements in endoscopic evaluation for detection of

early recurrences or second primary tumors include tech-

niques like high-definition digital video endoscopy with

Table 1 Scheduled visits in the literature

Frequency of the visits

BAHNO [27] NCCN [28] ASHNS [16] SHNS [16] Lester and Wight [5] DHNS [14]

Year 1 4–6 weeks 1–3 months 1–3 months 1–3 months 1 month 2 months

Year 2 4–6 weeks 2–4 months 2–4 months 2–4 months 2 months 3 months

Year 3 3 months 4–6 months 3–6 months 3–6 months 3 months 4 months



[Year 6 1 year 6–12 months 1 year 1 year 1 year None


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narrow band imaging [34, 35] or laser-induced fluores-

cence endoscopy [36].

The weight of the patient should be noted at each visit, and

any unexplained weight loss should alert the physician.

Detection of functional outcomes remains a critical issue; in

2001, the World Health Organization (WHO) adopted the

International Classification of Functioning, Disability and

Health (ICF). The ICF has been tailored specifically for head

and neck cancer (ICF-HNC). The ICF core sets for head and

neck cancer are divided into four items: bodily functions, body

structures, participation in activities and environmental factors.

The ICF-HNC can be used routinely to provide a clear estimate

of early and late functional outcome measures [37, 38].

Dental status is an important and often overlooked aspect

of the clinical follow-up. Adequate evaluation and pre-

ventive periodontal care prior to treatment should be coupled

with a rigorous continued assessment of oral health during

follow-up visits, given the importance of oral health to self-

rated quality of life and to the potential complications arising

from failure to follow-up this aspect [39, 40].

Radiation-induced toxicity should also be objectively

monitored during follow-up evaluations. Toxicity reporting

systems such as the Common Terminology Criteria for

Adverse Events (CTCAE) scales, Late Effects of Normal

Tissues (LENT) and Subjective, Objective, Management

and Analytic (SOMA) scales have been shown to be a valid

measure of head and neck radiotherapy toxicity [41].

Bronchoscopy, esophagoscopy and panendoscopy

Historically, bronchoscopy and esophagoscopy have been

performed during initial evaluations of patients with

Table 2 Checklist for head and neck examination

Nodes Mass Ulceration

External fields

Nodes Level I-VIParotid gland

Examination-palpation

ThyroidOccipital fieldScalpFacial pedicles

Upper aerodigestive tract (UADT)

Oral cavity-oropharynxBispatulate examinationBimanual palpation

Nasal cavity

Flexible fiberoptic endoscopy

NasopharynxOropharynx

Hypopharynx, base of the tongue Rigid endoscopyLarynx

Functional outcomes

Weight (kg)Pain (VAS)Cranial nerve dysfunctionSwallowing disorder on indicationVoice assessment on indicationBreathing assessment on indication


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HNSCC to rule out the presence of synchronous second

primary tumors [42]. With regard to follow-up of patients

after definitive therapy, some authors have recommended

routine panendoscopy within 2 years of completion of

treatment [43], while others, despite high accuracy of the

procedure, do not support it, arguing that it is an aggressive

and unpleasant procedure [44]. Moreover, the yield is too

low to justify these invasive procedures. The use of routine

screening during follow-up for distant metastases and/or

second primary tumors in the esophagus and lower airway

in particular is questionable and, if indicated, is currently

often achieved with positron emission computed tomog-

raphy (PET-CT) (see below).

Another recent technique for close surveillance is the

use of autofluorescence bronchoscopy and esophagoscopy

that may detect bronchogenic and esophageal carcinoma at

an early stage in high-risk patients [45].

Thyroid function testing

Even the most modern techniques for delivery of curative

head and neck radiation therapy (RT) will inevitably

cause incidental exposure of non-target tissues and organs.

When conventional, non-intensity modulated radiation

therapy (IMRT) techniques were used, the prevalence of

radiation-induced hypothyroidism (RIHT) was reported to

range from 10 to 45 % among patients receiving RT to

the neck and its dose-dependent fields. The mean radia-

tion dose at which 50 % of patients will experience

hypothyroidism was estimated to be approximately 44 Gy

[46]. The risk is significantly higher in patients with lar-

yngeal cancer, especially those undergoing laryngectomy,

and does not seem to be associated with chemotherapy or

age [47].

Half of these events will appear within 5 years, with a

peak incidence after 2–3 years [48]. While surgery

including partial thyroidectomy is associated with an

increased risk of hypothyroidism in patients treated with

RT, even surgery sparing the thyroid gland is associated

with an increased risk of hypothyroidism when combined

with RT, possibly due to an increased risk of vascular

damage [49]. In a study dealing with 504 patients [50] in

which neck RT was part of the treatment for HNSCC, the

absence of hypothyroidism was 78 % at 5 years and 51 %

at 10 years. The authors concluded that serum thyroid

stimulating hormone (TSH) should be checked at 6-month

intervals for the first 5 years and yearly thereafter. The

NCCN [28] proposed TSH evaluations every 6–12 months

for the first 5 years. However, these recommendations are

just ‘‘guidelines’’ and are not applicable in patients that do

not have surgery in the thyroid bed or if no radiation has

been given. The point of initiating hormone replacement

therapy was proposed at a TSH value reaching 4.5 mIU/L.

Imaging studies

Computed tomography (CT) and magnetic resonance

imaging (MRI) A baseline imaging study is often recom-

mended after completion of therapy, allowing a compari-

son with subsequent images for earlier detection of lesions

[7]. These baseline studies could be particularly useful for

patients treated by (chemo)radiotherapy and for patients

treated with primary surgery for tumors in anatomical

regions difficult to evaluate on PE, such as the paranasal

sinuses and skull base. Accurate interpretation of imaging

is crucial to differentiate between post-treatment changes

and residual disease or recurrence. It is generally recom-

mended that the post-treatment ‘‘baseline’’ CT/MRI should

be performed 3-6 months after treatment [28, 32], and

subsequent imaging should be with the same modality.

Hermans et al. [51] reviewed the clinical records of 66

patients who underwent radiotherapy for laryngeal and

hypopharyngeal cancers. Twenty-nine patients experienced

local failure; in 12 patients suspicious CT findings were

apparent prior to physical findings and were confirmed by

biopsy. The authors concluded that imaging was necessary

for routine follow-up and recommended an interval of

3–4 months between studies for a duration of 2 years. Use

of imaging-based information could lead to earlier diag-

nosis of recurrence, allowing more efficient salvage sur-

gery and could improve the survival rate of these patients,

but this remains to be demonstrated with higher level

evidence (prospective randomized studies) and whether

this also applies to only surgically treated patients.

The aforementioned studies addressed either all sites

and stages of HNSCC or were limited to laryngeal and

hypopharyngeal cancers. Our review found no study

reporting the utility of imaging follow-up for early stage

oral carcinoma, the most common site of HNSCC. In the

particular subgroup of patients with carcinoma of the oral

cavity as well of the larynx and other sites easily accessible

for clinical examination, it may be appropriate to monitor

by PE alone. In 2011, the NCCN recommendations pro-

posed further reimaging based only on clinical signs and

symptoms. Routine imaging was not recommended for

asymptomatic patients [28].

There are no data suggesting the superiority of con-

ventional MRI over CT scan for follow-up assessment. It

appears logical, at least after radiotherapy or chemoradio-

therapy, to use the same imaging modality as the pre-

treatment study. Typically, MRI is recommended for

patients with sinonasal, skull base and nasopharyngeal

tumors and when there is suspicion of perineural or intra-

cranial spread [19]. Diffusion-weighted MRI (DW-MRI)

measures the diffusivity of water molecules in biologic

tissues and has been demonstrated to be effective in

detecting recurrences after completion of RT [52]. In this


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setting it has been shown to be superior to anatomical

imaging [53]. DW-MRI also shows promise for assessing

treatment response immediately after completion of che-

moradiotherapy at 3 weeks [54], whereas the window of

opportunity for PET-CT is only at 3 months after com-

pletion (see below).

Chest CT/chest X-ray The lungs are the most common

site of distant metastasis [55], and primary lung cancer

accounts for 23 % of metachronous second primaries in

HNSCC patients [55, 56]. Traditionally, conventional chest

radiography has been part of the follow-up. However, chest

X-ray has been reported as inadequate for the early

detection of synchronous and metachronous neoplasms at a

curative stage [57, 58].

In a recent study, only 33 % of intrathoracic lesions

picked up by CT were also detected by chest X-ray alone

[51]. In a retrospective study [59] of 26 patients undergoing

treatment for HNSCC, it was observed that 4 patients with

a normal chest X-ray had an abnormal CT. Similarly, in a

series of 102 with newly diagnosed mucosal head and neck

cancer patients, 11 were proven to have pulmonary

metastasis or primary lung tumor, and 7 had normal chest

X-rays. The authors concluded that chest CT should be

used rather than chest X-ray for the follow-up of HNSCC

patients. Notably, radiation doses delivered by CT have

decreased with the latest generation of CT scans [60].

However, in developing countries the availability of CT for

routine screening in asymptomatic patients remains a

limiting factor.

Aside from the question of which technique is best, the

question remains as to how effective is routine screening

for lung metastases or second primary lung cancer.

According to Hsu et al. [61] chest CT should be mandatory

in follow-up and is recommended every 6 months during

the first 2 years in high-risk (stage III–IV) patients. On the

other hand, screening by chest X-ray to detect lung cancer

in an asymptomatic stage after curative treatment for

squamous cell laryngeal cancer was reported to not

improve survival for patients who develop lung cancer

[62]. As only a limited number of patients with second

primary lung cancer were detected by annual radiography,

of which only a small percentage was eligible for curative

surgical treatment, screening by annual chest X-ray has

been reported to be of little benefit [63].

In summary, there is currently no high-level evidence to

support routine plain chest radiography, either for

improved oncologic outcomes or from a cost-benefit

standpoint.

Neck ultrasonography The accuracy of ultrasound (US)

and CT for detection of neck lymph node metastasis is

comparable [64–66]. Table 3 [64–66] reports the sensitiv-

ity and specificity of neck US and CT reported in the lit-

erature. With the use of color duplex ultrasonography,

Leuwer et al. [67] achieved a sensitivity of 90 % in

detecting neck metastasis. Neck US is frequently included

in the routine surveillance of patients treated for HNSCC,

avoiding radiation exposure and allowing fine needle

aspiration of suspicious lesions under US guidance (US-

gFNA). US-guided cytology of metastatic lymph nodes

that have been irradiated is less reliable than when applied

in the pre-treatment setting [68]. Park et al. [69] retro-

spectively reviewed the medical records of 140 HNSCC

patients followed at least for 5 years after completion of

definitive therapy. Patients were seen every month during

the first year, every 2 months during the second year, every

3 months during the third year, every 4 months during the

fourth year and every 6 months thereafter. Each visit

included medical history, PE, indirect or direct endoscopy

and neck US. A chest X-ray was taken every 6–12 months.

The authors reported that regional recurrences were diag-

nosed earlier than local failure (9 vs. 19 months after

completion of therapy), suggesting earlier detection of

small-sized nodal metastasis by neck ultrasonography. The

same authors concluded that neck ultrasonography has no

impact on the detection rate of nodal metastases but allows

earlier detection resulting in more rapid treatment. This

would allow, when suitable, less morbid neck dissection

with more favorable oncologic outcome as compared with

delayed diagnosis and more extended regional recurrence.

Nieuwenhuis et al. [70] reported a high salvage rate (79 %)

if delayed metastases are detected earlier by routine sur-

veillance USgFNA (each 3 months) in the previously

untreated neck. There is currently no high-level evidence,

however, regarding improvement in survival or cost-

effectiveness of routine follow-up neck screening using US

or neck CT to detect regional recurrences.

Finally, concerning the monitoring of treatment-related

morbidities, screening for extra-cranial carotid artery dis-

ease by specific US examination might be considered, as

patients with HNSCC treated with radiotherapy are at an

increased risk for this condition [71, 72]. Furthermore, the

physician should be aware that in this setting, the risk of

internal carotid stenosis increases following treatment.18Fluorodeoxyglucose (FDG)-PET-CT FDG-PET-CT

has been widely employed for the staging of HNSCC due

to the avidity of FDG for these tumors [73]. According to

Schoder et al. [74], one of the main applications of PET-CT

is the detection of residual disease in lymph nodes after

(chemo)radiotherapy. They found a high negative predic-

tive value (NPV [95 %) suggesting that planned neck

dissection could be avoided in many cases. Several post-

treatment studies [75–78] have reported that FDG-PET-CT

is very accurate for detection of locoregional and distant

recurrence of HNSCC. Gupta et al. [79] performed a sys-

tematic review and meta-analysis on the diagnostic per-

formance of post-treatment FDG-PET or FDG-PET-CT


123


imaging in head and neck cancer. A total of 51 studies

involving 2,335 patients were included. The weighted

mean pooled sensitivity, specificity, positive predictive

value (PPV) and NPV for the primary site were 79.9, 87.5,

58.6 and 95.1 % and for the neck 72.2, 87.6, 52.1 and

94.5 %, respectively. These latter figures are also depen-

dent on the incidence of the disease, which may differ in

the different study populations. Meta-regression analysis

showed no significant difference between stand-alone PET

and integrated PET/CT, suggesting lack of impact of

technological and methodological advancements in PET

imaging on diagnostic performance in the post-treatment

setting [79].

The optimal timing for response assessment reported in

the literature ranges from 8 to 12 weeks [80], with most

authors agreeing that waiting at least 12 weeks allows one

to be sure that a negative result is truly negative [81–83].

Gupta et al. [79] found in a meta-analysis that scans done at

12 weeks or more after completion of definitive therapy

had a moderately higher diagnostic accuracy on meta-

regression analysis using time as covariate. The optimal

timing of post-treatment FDG-PET is still a subject of

debate [84].

Recently, Haerle et al. [83] studied the accuracy of

PET-CT in detecting distant metastasis in HNSCC

patients. This study retrospectively reviewed 299 patients

who underwent PET-CT imaging 3 months after com-

pletion of therapy and then every 6 months for 2 years.

The authors reported an NPV of 99.6 % and a PPV of

67.4 %. Although this study showed a high accuracy in

detecting distant metastasis, the drawback of using PET-

CT routinely in follow-up is the high number of false

positives resulting in increased emotional burden and

costs associated with follow-up and verification of all

suspicious lesions. Nevertheless, the authors recom-

mended screening for distant metastases with PET-CT at

least annually during the first 2 years after treatment [83].

However, it must be noted that in contrast to screening for

locoregional recurrences, screening for distant metastases

during follow-up remains debatable if no beneficial

treatment options for (asymptomatic) distant metastases

are available.

Lee et al. [85] tried to reach a consensus regarding the

interval and frequency of PET-CT for surveillance of

HNSCC patients. A review of 189 patients after completion

of treatment to detect residual cancer or recurrence was

performed. Twelve patients with inadequate clinical follow-

up or metastatic work up as well as 18 patients who under-

went PET-CT within 2 months to determine metabolic

response were excluded. A total of 159 charts of HNSCC

patients with a median follow-up of 24 months (3–65

months) were reviewed. One hundred twelve patients had

one PET-CT, 33 had 2 studies, 12 had 3 studies and 2 had 4

studies. The PET-CTs were divided into four groups

according to time after completion of treatment: 2–6 months

(group 1), 6–12 months (group 2), 12–24 months (group 3)

and [24 months (group 4). Each group was further subdi-

vided by indication: suspicion of recurrence versus ‘‘rou-

tine’’ PET-CT. The NPV for locoregional recurrence was 97

and 100 % for distant metastasis or second primary cancer.

The PPV for locoregional recurrence was 72 and 66 % for

distant metastasis and second primary cancer. Based on their

data, the authors concluded that routine PET-CT performed

within 2–6 months was highly accurate for detecting early

recurrences. However, most agree that it should not be

employed during the first 12 weeks after completion of

therapy [86]. In addition, of 106 patients who had a true

negative PET-CT, 37 (35 %) patients were in group 1, 27

(25 %) in group 2, 29 (27 %) in group 3 and 13 (12 %) in

group 4. Long-term follow-up of these patients suggested

that locoregional recurrence was unlikely for at least 1 year

after initial negative PET scans, suggesting that for patients

with negative PET-CT studies, conventional evaluation may

be sufficient for post-treatment surveillance during the next

year, unless obvious suspicious signs appear. The authors

concluded that initial PET-CT should be performed within

6 months after treatment and that the next routine PET-CT

should be performed 1 year later.

In summary, FDG PET-CT is highly effective for

assessing recurrence in patients treated for HNSCC.

However, cost effectiveness, impact on management and

survival impact remain to be evaluated more thoroughly.

No prospective trial comparing PET-CT to other imaging

modalities for follow-up has been conducted.

Patients with HPV-associated HNSCC

It is now widely acknowledged that a growing proportion

of HNSCC, particularly OPC, results from an infection by

HPV [6]. HPV 16 is the most common genotype of all HPV

DNA-positive cancers, accounting for 87 % of HPV-rela-

ted OPCs. HPV 18 is the second common genotype of

HPV-related cancer, occurring in 1 % of OPCs. HPV DNA

infection increases the relative risk of HPV-associated

HNSCC by 15- to 200-fold compared with the risk without

Table 3 Studies comparing accuracy of CT and US

Timing of

imaging

CT US

Di Martino

et al. [64]

Pre- and post-

treatment

Sens: 84 %

Spe: 91 %

Sens: 84 %

Spe: 87 %

Yoon et al.

[65]

Post-treatment Sens: 77 %

Spe: 99.4 %

Sens: 78.5 %

Spe: 98.5 %

Adams et al.

[66]

Post-treatment Sens: 82 % Sens: 72 %


123


HPV infection [87]. Three types of tumors have been

defined: HPV-negative/p16-negative, HPV-negative/p16-

positive and HPV-positive/p16-positive. In a study dealing

with 323 patients, the authors reported the effect of tumor

HPV status on survival among patients with HNSCC [18].

The authors found 3-year overall survival of 82.4 % in the

HPV-positive group and 57.1 % in the HPV-negative

group. The 3-year progression-free survival was 73.7 % in

the HPV-positive group and 43.4 % in the HPV-negative

group. The authors also found that patients with HPV-

positive tumors had a 58 % reduction in the risk of death as

compared with patients with HPV-negative tumors.

Outcomes were also evaluated according to the

expression of p16 protein, associated with oncogenically

active HPV infection. P16 expression was associated with a

3-year overall survival of 83.6 % while the absence of p16

protein was associated with a 3-year overall survival of

51.3 %. This study provided strong evidence that tumor

HPV status was an independent prognostic factor for

overall and progression-free survival among patients with

HNSCC. Patients with HPV-positive tumors also have a

lower risk of developing metachronous second primaries

[88, 89]. According to our review, there are no data indi-

cating that the surveillance plan of patients with HPV-

positive disease should different than the follow-up of

patients with HPV-negative disease. However, HPV status,

in non-smokers particularly, is important information that

could be used by the clinicians to provide reassurance to

patients regarding prognosis. Notably, p16 status is an

independent predictor of outcome regardless of HPV status

and is generally much cheaper and easier to perform [90].

Conclusions

According to this literature review and from our own

experience, it is recommended that patients be followed in

the clinic every 2–3 months for the first 2 years, every

3–6 months for years three and four, every 6 months dur-

ing the fifth year and annually thereafter. However, other

frequencies and durations of follow-up may be followed

according to the literature [5, 16, 27–29]. An important

issue is which items are important to evaluate during these

visits. In our opinion, each visit should comprise a thor-

ough clinical history of symptoms and PE (Table 2).

Toxicity evaluation, rehabilitation of functional loss, pain

management, nutritional support and psychological support

including tobacco cessation should be addressed during

each of the visits. Weight should be assessed at each visit.

Systematic evaluation of radiation-induced late toxicity

should also be performed using published criteria.

Patients should be educated about relevant symptoms

and the need for additional visits if new symptoms appear.

In addition to palpation of the neck and direct visual

examination of the oral cavity, oropharynx and dental

status, flexible fiberoptic endoscopy of the UADT, should

be performed at each PE. A baseline post-treatment

imaging study (CT or MRI) should be performed within

3–6 months after completion of primary therapy in patients

treated for locoregionally advanced stage HNSCC in sites

not easily accessible to physical or fiberoptic examination

or when evaluating treatment response. Additional imaging

modalities should be performed based on clinical signs

and symptoms. In case of suspicious lymph nodes found

at clinical examination, ultrasonography can be performed

with fine needle aspiration biopsy. PET-CT provides high

accuracy for detecting residual disease and should be

performed at 12 weeks after treatment of patients who

have undergone definitive chemoradiotherapy. The value

of additional PET-CT evaluations for detection of loco-

regional and distant recurrences is debatable as its impact

on survival remains to be evaluated. Screening of distant

lung lesions may be performed by CT scan annually for

the first 2 years in high-risk patients. Serum TSH levels

should be checked at 6 monthly intervals for the first

5 years and yearly thereafter in patients treated with neck

radiotherapy.

Although non-smoking patients with HPV-positive

tumors have a better prognosis, they should have the same

routine follow-up plans as patients with HPV-negative

tumors, as there is no evidence to support other follow-up

regimens.

In the future, new modalities including biomarkers to

identify patients with low risk of developing distant

metastasis, molecular techniques for early detection of

recurrence, patient-based saliva proteomics and artificial

‘‘noses’’ (nanoparticle sensors for testing breath samples)

could lead to the development of cost-effective, fast, and

reliable methods for early detection of primary head and

neck cancer, recurrences or second primary tumors.

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Post-therapeutic surveillance strategies in head and neck squamous cell carcinoma

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