Journal of the Egyptian National Cancer Institute (2017) 29, 1–9

Cairo University

Journal of the Egyptian National Cancer Institute

www.elsevier.com/locate/jnci
www.sciencedirect.com

Review

Re-irradiation for head and neck squamous cell

carcinoma
Rony Benson, Prashant Giridhar, Bhanu Prasad Venkatesulu, Supriya Mallick *,
Mohd Waseem Raza, Goura Kishor Rath

Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India

Received 29 April 2016; revised 22 July 2016; accepted 24 July 2016

Available online 29 August 2016

KEYWORDS Abstract Introduction: Local recurrences after curative treatment have a potential for cure with
Squamous cell carcinoma; salvage surgery or with re-irradiation.
Recurrent; Methods: We reviewed the PubMed for articles published in English with key words squamous cell
Re-irradiation; carcinoma, recurrent, re-irradiation, prognostic factors to find relevant articles describing prognos-
Toxicity tic factors, re-irradiation, and outcome for recurrent head and neck squamous cell carcinoma.
Results: Various factors including age, performance status, time for recurrence, previous radiation
dose volume and site of recurrence, previous use of chemotherapy are all prognostic factors in
recurrent head and neck squamous cell carcinoma. Surgery is feasible in very select subgroup of
patients and must be done when feasible. Re-irradiation with the aid of modern sophisticated tech-
nology is safe and confers durable and clinically meaningful survival benefit. Re-irradiation in head
and neck recurrent squamous cell carcinoma may provide an expected median survival of 10–
12 months. Chemotherapy may be added along with radiation in the recurrent setting.
Conclusion: Treatment approaches may have to be personalized. Re surgery must be done in all
patients in whom it is feasible. In patients in whom surgery is not feasible, re-irradiation must be
evaluated as a therapeutic option especially in patients with limited volume recurrence.
Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Search methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Prognostic factors in recurrent Head and neck squamous cell carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
General treatment approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Re-irradiation in recurrent/second head and neck cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

* Corresponding author. Fax: +91 11 26589243.

E-mail address: [email protected] (S. Mallick).
Peer review under responsibility of The National Cancer Institute, Cairo University.
http://dx.doi.org/10.1016/j.jnci.2016.07.002
1110-0362 Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
2 R. Benson et al.

Patient selection criteria for re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Dose fractionations for re-irradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Target volume definition for re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Technique for re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Dose constrains for the organs at risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Brachytherapy for re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Post-operative reirradiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Systemic therapy with re-irradiation – feasibility and outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Toxicity with re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Expected outcome with re-irradiation in head and neck cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Meeting presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Financial support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Introduction search of the references in the available article to retrieve miss-

ing articles and conducted a hand search in Google to find any
Head and neck squamous cell carcinoma (HNSCC) is the sixth possible publication. After a thorough search the duplicates
most common cancer globally [1]. The advances in surgical and were removed and the remaining articles were looked into
radiotherapy techniques have contributed tremendously detail.
toward improved outcome with less morbidity in these patients
[2]. Despite the advances in the last two decades, 35–40% of Investigations
patients recurs locally or loco-regionally and poses a signifi-
cant health burden. Second primary cancers in the head and As patients with local or nodal recurrence would undergo a
cancer region further add to this burden, which can be as high salvage surgery or salvage re-irradiation it is important to rule
as 20–25% in a long term [3]. The treatment of recurrent/sec- out any other site of disease that is not evident clinically. An
ond primary HNSCC is always challenging and is associated indirect laryngoscopy and upper gastrointestinal endoscopy
with significant morbidity [4]. A balance has to be achieved must be done in all patients and suspected abnormal areas
between local control and treatment related morbidity and must be biopsied. A contrast enhanced magnetic resonance
mortality. Salvage surgery alone has yielded dismal results as imaging (MRI) of the head and neck may be superior to con-
has systemic chemotherapy alone [4,5–8]. Median survival with trast enhanced computed tomography (CT) depending on the
both these approaches has ranged from 5 to 9 months. In addi- tumor subsite and tumor extensions. Soft tissue delineation
tion, many patients are found unsuitable for surgery because of the disease may be better appreciated in an MRI than a
of disease extent or morbidity associated with such approach. CT. In addition the perfusion and diffusion-weighted MRI
Re-irradiation of such cases has been tried in the recent prac- helps in differentiating recurrent cancer from post radiation
tice with promising results. Understanding of the molecular changes [9]. PET scan also is of great help in this scenario
biology and genetic aberrations has paved for newer targeted and is associated with a high predictive value in patients with
drugs and are being increasingly tried for the treatment of such recurrence post chemoradiation [10].
cases. However, there is limited prospective data about the The need for a re-biopsy is sometimes debated in a recur-
management of recurrent/second primary HNSCC rent head and neck cancer patient. It may be avoided in some
(rHNSCC). Hence, management of these tumors varies widely patients in whom recurrence occurred early and have a diffuse
across institutes and based on local perception, available metastatic disease that is clinically correlating with the natural
resource. The non-availability of prospective data also pre- course of the disease. This is particularly important in these
cludes comparing one modality to the other and finds the opti- patients due to the field cancerization phenomenon that occurs
mum based treatment option. In this review we intend to look in head and neck cancers [11]. It is also of significance as the
into current status of re-irradiation for the treatment of recur- patient might have developed a radiation induced second pri-
rent/second primary HNSCC (rHNSCC). mary which is usually a sarcoma, which should be salvaged
surgically [12,13].
Search methodology
Prognostic factors in recurrent Head and neck squamous cell
We performed a comprehensive search of the PubMed, SCO- carcinoma
PUS and Google Scholar with the following MesH terms:
‘‘reirradiation in head and neck cancer, radiation in recurrent Prognosis with salvage treatment depends on disease related
head and neck cancer, reirradiation AND recurrent head and factors or treatment related factors. Balancing toxicity and dis-
neck cancer AND treatment, survival” to find all possible pub- ease control becomes an important issue in re-irradiation.
lications pertaining to rHNSCC. We also conducted a detail Disease related factors are site of recurrence, previous response
Re-irradiation for head and neck squamous cell carcinoma 3

to radiation therapy, time from previous radiation and human evaluated with special consideration to factors like perfor-
papilloma virus (HPV) status [5,6]. Treatment related factors mance status, age of the patient, site of recurrence, volume of
include usage of conformal radiation therapy, dose of reirradi- recurrence, disease free interval, and presence of severe co-
ation, concurrent chemotherapy usage, salvage surgery and morbidity. The sub-sites like oral cavity and limited nodal
radiation volume [7,8,14]. Patient related factors include age, recurrence are ideal candidates for a surgical salvage. Specific
performance status, comorbidities, organ dysfunction from issues related to surgery in recurrent setting like wound healing,
previous treatment, feeding tube dependency, tracheostomy organ dysfunction, dependency on feeding tube and increased
and soft tissue defect [15–18]. blood loss during surgery must also be kept in mind before tak-
Tanvetyanon et al. in a retrospective series of 103 patients ing a patient for salvage surgery. Post radiation fibrosis in the
found comorbidity and organ dysfunction as independent pre- neck also makes surgical salvage difficult in some cases.
dictors of survival. Reasons attributed were both factors may The availability of modern surgical techniques like trans-
lead to suboptimal cancer directed therapy and increase risk oral robotic surgery (TORS), trans-oral microsurgical
of death from cancer related causes and may cause death approaches have made surgery a viable option in oropharyn-
due to non-cancer related causes as well. Other factors that geal cancers with small disease volume. Those patients who
had prognostic implications were T stage, tumor bulk, re- are found not suitable for surgery may be evaluated for
irradiation dose, time interval between previous radiation re-irradiation. But here also careful patient selection is the
and current. [19]. In a similar series of 79 patients aged less key to optimize outcomes. Those who are not suitable for
than 50 years, a disease free interval of two years or more pos- either may be given systemic chemotherapy with a palliative
itively influenced survival [20]. Choe et al. evaluated phase 1 intent. A treatment approach to a patient with localized recur-
and phase 2 protocols of 166 patients who underwent chemo rent HNSCC is given in Fig. 1.
radiation in recurrence. Prognostic factors for overall survival
were previous chemoradiotherapy (CTRT), surgery before Re-irradiation in recurrent/second head and neck cancers
CTRT, re-irradiation and RT interval. Patient who had previ-
ously received CTRT had dismal outcomes. Reason attributed Re-irradiation has long remained an unpopular treatment
was aggressive tumor biology and resistant clonogens [21]. option because of variety of reason including fear of excessive
toxicity, unpredictable dose delivery beyond the normal tissue
General treatment approach tolerance and non-availability of imaging modality. With
advent of sophisticated radiotherapy techniques like stereotac-
Various available treatment options should be discussed with tic radiotherapy, image guided radiotherapy and intensity
the patients with particular emphasis of treatment outcome modulated radiotherapy, re-irradiation rHNSCC has gained
and toxicity. Surgical salvage should be attempted whenever momentum. Re-irradiation alone or in combination with
possible as surgical salvage in recurrent setting has been found chemotherapy can be offered in patients not suitable for sur-
to be an independent prognostic factor [4]. The patients must be gery. In addition, reirradiation can also be offered for patients

Figure 1 Proposed treatment approach for a recurrent head and neck cancer.
4 R. Benson et al.

with adverse pathologic feature after salvage surgery. In the tion, whereas, accelerated radiation aims to complete the
subsequent segments we will discuss about patient selection scheduled radiation before the accelerated repopulation kicks
criteria for re-irradiation, the acceptable dose fractionations, off following a lag phase of nearly 4 weeks. An incremental
role of brachytherapy, target volume definitions, the role of dose of 0.6 Gy is required after this to counter the accelerated
concurrent chemotherapy, toxicity prediction, prevention, mit- repopulation to achieve tumor control. Based on these princi-
igation and treatment of radiation toxicity. ples, hyper fractionation would be the preferred approach for
re-irradiation because of improved sparing of late responding
Patient selection criteria for re-irradiation tissues with equal total dose. There is a considerable debate
regarding the optimal dose fractionation in re-irradiation. A
There are a number of patient related, tumors related and pre- dose of >72 Gy biological equivalent dose (BED) or equiva-
vious treatment related factors that predict prognosis after lent dose 2 Gy (EQD2) of 60 Gy has been shown to have
re-irradiation. Charlson co-morbidity index, ACE grading – favorable OS in certain series compared to less than 72 Gy
27 [19], feeding tube dependency, presence of tracheostomy, [22]. The incidence of carotid blowout was higher when
presence of skin necrosis, Karnofsky performance status 1.5 Gy twice daily fractionation five days a week on alternate
(KPS) and age [22] are patient related factors that define prog- weeks or delayed accelerated hyper fractionation was used
nosis and help in selecting patients for re-irradiation. compared to 2 Gy daily or 1.2 Gy twice daily five days a week
Smaller tumor volume(<221 ml), nasopharyngeal and [26]. Hypo-fractionation 48 Gy BED in five fractions has pro-
laryngeal recurrence, longer time interval of recurrence vided comparable results in terms of PFS and OS in a small
(>16 months) are some of the tumor related factors that pre- series but with increased late toxicity. Certain criteria like
dict favorable prognosis compared to patients with larger vol- CBOS index have been created to define suitable patients for
ume, non-laryngeal primary, and early recurrence [20,22]. hypo fractionation [23]. So the most acceptable and effective
Patients treated with conformal techniques and for smaller vol- dose fractionation seems to be 60 Gy in 30 fractions over six
umes in initial treatment are expected to fare better with lesser weeks or 64 Gy in 54 fractions twice daily over 5.5 weeks.
toxicity compared to conventional treatment [20,22]. Patients The final dose prescribed must also take into account the tech-
treated with conformal techniques and for smaller volumes nique used, volume of recurrence, dose received by vital struc-
in initial treatment are expected to fare better with lesser tox- tures during previous irradiation. Hypo-fractionation can be
icity compared to patients treated with conventional tech- considered with the caveat of increased risk of late toxicity.
nique. Patients who received chemotherapy as part of initial Hypo-fractionation is useful in small volume recurrence far
treatment are associated with increased toxicity [21]. Not many from the spinal cord and carotids.
molecular factors have been validated for selecting patients for
re-irradiation. While treating patients with hypofractionated Target volume definition for re-irradiation
radiation, the risk of carotid blow out should be considered.
Only patients with <180 degree encasement of carotid artery After radiation and surgery, normal lymphatic flow gets dis-
on imaging and absence of ulceration can be taken up [23]. rupted. So, in recurrent tumors of head and neck lymph node
A carotid blow-out syndrome (CBOS) index has been con- metastases do not follow the expected pattern based on loca-
structed by a retrospective analysis of cases receiving hypofrac- tion and size of primary. Lymphoscintigraphy studies have
tionated RT to help select patients. shown that in around two thirds of cases the lymph flow is
In the post-operative setting patients with margin positive altered post-radiation [27]. Irradiating uninvolved nodal
disease, extracapsular nodal spread, deeply infiltrating tumors region leads to increased volume of irradiation and higher tox-
(>1 cm), rT4 disease in larynx and nodes >3 cm in size are to icity. Recurrence can occur only in primary, only in nodes or in
be considered for re-irradiation [24,25]. Point should be made both nodes and primary. If recurrence is only in the primary,
that the indications of postoperative re-irradiation are less dis- the target volume is defined as gross tumor plus a 0.5–1 cm
cussed. Janot et al. did not include patients with R1 resection. margin to form clinical target volume (CTV). If only in nodes,
However, from all other series it appears that re-irradiation the target volume will include the involved nodal level or in few
should be delivered for margin positive resection and ECE. cases only the gross node with a 0.5–1 cm margin [20]. The
Rest of the factors should play an important role to tradeoff need to use a margin to account for microscopic disease has
between toxicity and benefit of re-irradiation. been questioned as most recurrences that have occurred after
re-irradiation have been in field recurrences [28].
Dose fractionations for re-irradiation The target delineation should include the use of imaging
modalities of MRI and PET. PET integration in planning
Dose fractionation is critical in eradiating the tumor cells. has demonstrated to shift the location of GTV when compared
There are different radiation schedules-hyper fractionation, to CT alone because of clearer differentiation with fibrosis and
accelerated fractionation and hypo fractionation. Radiation post treatment changes [29,30]. MRI will help in identifying
in hyper fractionation is delivered in small dose per fraction fibrosis and identifying carotid vessel ulceration and encase-
with two or three fractions delivered every day to achieve a ment. It is difficult to comment on volumes to be treated when
higher biologically effective dose to the tumor when the a/b both primary and nodes are involved and should be left to the
ratio for tumor cells is greater than that for the dose- physician’s discretion. The re-recurrence is most commonly
limiting, late-responding normal tissue. Hyper fractionation seen in the areas of initial GTV. Hence, elective local or nodal
also induces radio-sensitization through cell-cycle redistribu- irradiation is not beneficial [20].
Re-irradiation for head and neck squamous cell carcinoma 5

Technique for re-irradiation 7% and 25% grade III toxicity at 6 and 12 months [39]. But
the final dose constrain for an IMRT must be personalized
As re-irradiation may be associated with higher toxicity, more on a patient to patient basis.
so with concurrent chemotherapy it is advisable to use the best
conformal technique. Compared to conventional technique Brachytherapy for re-irradiation
intensity modulated radiotherapy (IMRT) enables delivery of
conformal dose to the target, but at the risk of increased inte- Brachytherapy allows for a very conformal radiation if recur-
gral dose. Lee et al. reported higher loco regional failure with rence is confined to primary or single lymph node. But per-
non-intensity modulated techniques [8]. The use of image guid- forming brachytherapy may be difficult in a re-irradiation
ance during radiation delivery help in reducing the margins setting. Fibrosis of neck may make placement of needles diffi-
given for the planning target volume and thus must be used. cult. Often the location of recurrence like larynx and
Proton therapy also needs to be evaluated due to its physical hypopharynx is inaccessible to brachytherapy. Trismus due
property of the Bragg peak. Point should be made that proton to prior radiation and disease per se makes placement of nee-
therapy is not necessarily superior in all patients [31]. But, for dles difficult in anterior and base of tongue. If recurrence is
eligible patients proton therapy may impart long term disease close to bones like mandible, the high dose per fraction and
control. Hayashi et al. in a series of 34 patients combined dose rate in HDR brachytherapy may lead to osteoradionecro-
intra-arterial chemotherapy with proton therapy. They sis. The risks may thus outweigh the benefits of the procedure
reported encouraging 1-year and 2-year LC rates of 77% and in a patient who has limited survival.
60% [32]. In another recent report Romesser et al. reported lim- There are very few studies that have used brachytherapy in
ited toxicity with proton beam reirradiation. The authors a reirradiation setting. In a phase I/II reirradiation study by
reported acute grade 3 or greater toxicity in the form of mucosi- Martinez–Monge et al. 25 patients were treated with peri-
tis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermati- operative high dose rate brachytherapy (4 Gy twice daily  8
tis (3.3%) [33]. Thus the best conformal technique available (32 Gy) for R0 resections and 4 Gy twice daily  10 (40 Gy)
must be used for re-irradiation with the use of image guidance. for R1 resections) [40]. The authors reported a 4 year local
control rate of 85.6% and OS of 46.4%. However 40%
Dose constrains for the organs at risk (n = 10) developed RTOG grade 3 or higher toxicity. Strnad
et al. evaluated pulsed dose rate brachytherapy with
There is paucity of data regarding optimum dose constraints chemotherapy or hyperthermia for rHNSCC [41]. The authors
for re-irradiation. So, whenever dose constraints are discussed reported improved local control when PDR brachytherapy
it is based on some retrospective literature only discussing tox- was used in combination with systemic chemotherapy.
icity profile for a given set of patients. Dose constrains for re-
irradiation must be individualized on a case to case basis Post-operative reirradiation
depending on the previous dose fractionation used, and time
since previous irradiation. In a study by Zwiker et al. the risk
for xerostomia was significantly higher for cumulative mean Re-irradiation after salvage surgery is required for patients
doses of P45 Gy to parotid glands [34]. Spinal cord is one with adverse pathological features. Indications for reirradia-
of the most critical organs at risk during radiation. As these tion after salvage surgery are extra nodal spread, positive sur-
patients already have radiation up to 70 Gy the spinal cord gical margins, and/or other risk factors like close margin,
receives up to the maximum tolerable dose by then and limits lymphovascular space invasion [24,42]. Kasperts et al. in a
the further option of dose delivery. In this context Schultheiss prospective study of 39 patients reported 3 year loco regional
et al. made an import revelation that after an initial dose of control and overall survival 74%, 44%respectively, however
45 Gy, 50% recovery happens for an elapsed period of two at the cost of higher toxicity [42]. Janot et al. randomly
years [35]. Nieder et al. in a literature review found small risk assigned 130 patients with head and neck cancer treated with
of myelopathy after 6135.5 Gy [BED] when the interval is not salvage surgery to full-dose reirradiation combined with
shorter than 6 months and the dose of each course is 698 Gy chemotherapy or to observation. The authors reported signif-
[36]. Sminia et al. also shared similar view of spinal cord recov- icantly improved disease free survival but OS was not different
ery after primary radiation and cumulative irradiation dose between two arms. The authors also report higher rate of treat-
applied to the spinal cord can vary between 125 and 172% ment related toxicity. Unfortunately, the authors do not men-
of the BED tolerance [37]. They also found that keeping cumu- tion about techniques of radiation. Radiation technique would
lative maximum dose to the spinal cord of 53 Gy and 63 Gy to be of importance in such cases for limiting the toxicity. Inter-
the brain stem is safe in patients with re-irradiation. Similarly a estingly, 37% patients in the reirradiation arm had P3 node
study by Yamasaki et al. had found that re-irradiation dose to positive compared to 12% in the observation arm. It appears
spinal cord and brainstem, below 60 Gy was safe without any such high risk patients may have contributed to larger volume
long term neurological complications [28]. The cumulative of radiation and death secondary to toxicity [24].
mandible below 70 Gy, and two-thirds laryngeal dose below
50 Gy may be safe [38]. Chua et al. in a phase II study for Systemic therapy with re-irradiation – feasibility and outcomes
recurrent nasopharyngeal carcinoma used the following dose
constraints: 10 Gy 6 10% for brainstem, 4 Gy 6 5% for spinal A number of systemic agents like paclitaxel, carboplatin, doc-
cord, 8 Gy 6 5% for optic nerve and chiasm, 10 Gy 6 5% for etaxel, erlotinib, cisplatin, hydroxyurea and adenoviral vector
orbit, and 10 Gy 6 10% for temporal lobe. The authors expressing TNF alpha have been integrated with re- irradia-
reported modest late toxicity with these dose constraints of tion [42–48]. The logic is to eradicate microscopic disease that
6 R. Benson et al.

may be left out as the irradiation is to a limited region and also

Grade 3 or higher late toxicity-29%

to act as a radio sensitizer. The use of chemotherapy has not

Grade 3 or 4 acute toxicity-28%

Acute Grade III mucositis-30%

prolonged survival significantly in many series of reirradiation.

Grade 3 or 4 late toxicity-39%

Acute Grade III toxicity 30%
Acute grade 3-4 toxicity-23%
 Carotid hemorrhage 5.2%
A large number of patients receiving re-irradiation would have

 Osteoradionecrosis-11.3%
also received chemotherapy either concurrently or in the

Osteoradionecrosis-8%
Mucosal necrosis-21%
neoadjuvant setting for the primary disease. The use of

Late grade 3-4 -15%

Severe toxicity 20%

Neck fibrosis-41%
chemotherapy in the primary setting may have led to resistance

Grade 4 or higher
by increased efflux of drugs by tumor cells, improved DNA

Trismus-30%.
repair mechanisms and increased glutathione production
(GSH). All these may contribute to decreased effectiveness of

Toxicity
chemotherapy along with radiation in the recurrent setting.
Also drugs like cisplatin may also lead to cumulative toxicity
mainly the neuropathy. The specific issue whether addition
of chemotherapy adds to survival in patients undergoing re-

2-year loco-regional progression-free survival-42%

However, OS was not different between two arms

Significantly better DFS, LRC favoring RT arm.
irradiation for head and neck cancer is not well addressed in

Median progression-free survival-15.0 months

studies. But, it would be logical to use a chemotherapy which
has a different mechanism of action and minimal cross resis-
tance with the drug used in the primary disease while treating
recurrent disease. A summary of various chemo-re-irradiation

Median overall survival 11 months

Median overall survival 10 months

2-year loco-regional control-64%
trials are summarized in Table 2 [25,42–47].

Overall survival at 2 years 40%

2-year overall survival-37%

2-year overall survival-58%

Toxicity with re-irradiation

Survival outcomes
Toxicity is one of the main concerns during re-irradiation for
a recurrent HNSCC. Acute mucositis is the predominant
Summary of various trials that have evaluated re-irradiation in recurrent head and neck cancers.

adverse reaction during radiation which may be more severe

with addition of chemotherapy. This can be reduced to a
great extent using more conformal techniques for re-
irradiation thus reducing the amount of mucosa coming in
the radiation field. Usually the acute mucositis subsides and
RT dose median

is manageable. But what is more worrisome is the late toxic-

ity. The late toxicity ranges from the dreaded carotid blow
64.8 Gy

59.4 Gy

out to the chronic xerostomia. In our experience 30% patients

60 Gy

45 Gy

60 Gy

68 Gy

60 Gy
suffered from acute grade 3 or worse toxicity. In our series 7
patients suffered from grade 3 skin toxicity, 12 patients suf-
fered from grade 3 mucosal toxicity, and 5 patients had grade
Intensity modulated radiation therapy-70%

3 laryngitis. However, there was no death because of toxicity

or carotid blow out. However, point should be made nearly Intensity modulated radiation therapy or
Intensity modulated radiotherapy-7.6%
Intensity modulated radiation therapy

50% patients receive re-irradiation by conventional technique

[20].
Conventional or 3D conformal

Conventional or 3D conformal

The incidence of carotid blow out may be as high as 5%

[6]. This is a life threatening complication and can be
Technique of radiotherapy

avoided to a great extent by careful patient selection and

3D conformal-43.3%
Conventional-46.8%

selecting suitable fractionation schedules. Similarly the inci-

dence of osteoradionecrosis has ranged in literature from
8% to 11% [5,6]. Other severe toxicities associated may be
3D conformal
Conventional

mucosal necrosis, chronic xerostomia, brachial plexopathy,

subcutaneous fibrosis and hypothyroidism. Accelerated caro-
tid artery stenosis, and increased incidence of second malig-
nancy may be seen in such cases. Hoebers et al. in a
retrospective data of 58 reported 43% serious (late) toxicity
n = 130 [65 patients received

PGrade 3. This categorically points to the fact that a deli-

De Crevoisier et al. (1999)

cate balance between effectiveness and toxicity is required

Popovtzer et al. (2009)

for the practice of reirradiation [49]. However, we must

Mallick et al. (2014)
Sulman et al. (2009)
Salama et al. (2006)

emphasize that most of the literature present limited absolute

re-irradiation] [24]
Janot et al. (2008)
Lee et al. (2007)

data which must be considered a limitation compared to

actuarial rate and perhaps underestimate the true incidence
n = 105 [14]

n = 79 [20]

n = 66 [28]
n = 115 [6]

n = 105 [8]

n = 169 [5]

of toxicity. A summary of various trials that have evaluated

Table 1

re-irradiation in recurrent head and neck cancers is given in

Trial

Table 1.
Re-irradiation for head and neck squamous cell carcinoma 7

Expected outcome with re-irradiation in head and neck cancers

The median overall survival expected from re-irradiation may

Monitoring for thrombotic events necessary but

Functional outcomes declined with addition of
vary from 10 to 12 month, with a 2 year overall survival rang-

One patient had Grade 5 carotid hemorrhage

ing from 37% to 58% in various reported trials [6,8,14]. The
overall survival may be slightly higher for patients who under-
went re-irradiation in the postoperative setting with a range of
Severe late toxicity in 33% patients 12–16 months [25,34,35]. The 2 year local control that may be
One toxic death by hemorrhage

Gastrostomy tube need = 68%

Acute Grade 3 toxicity in 69%

expected from re-irradiation may be in the range 40–64%
Osteoradionecrosis 3 patients
Grade 3 neutropenia = 15%

[8,14]. Thus a good survival can be achieved along with good

local control in selected patients of head and neck cancer trea-
ted with re-irradiation.

integration feasible
chemotherapy
Conclusion
Toxicity

The recurrent head and neck cancer has always been consid-
ered a poor prognostic subgroup. Little effort has been made
to look into these patients separately. Hence, the treatment
Median follow-up was 8.4 months overall

of these cases has always been made with a palliative intent

and 15.1 months for surviving patients

and salvage with curative option has rarely been made espe-
cially those with limited volume recurrence occurring after a
long disease free interval. In patients with local recurrence or
loco-regional recurrence surgery should be attempted for best
Median OS = 13.4 months

Median OS = 12.5 months

Median OS = 9.6 months

Median OS = 16 months

cure. In cases with high risk feature (margin positive/Extra

5 year survival = 20%

capsular extension) consolidation should be done with post-

(95% CI = 30–62%)
1 year OS = 47.5%

operative re-irradiation alone or with chemotherapy. Patients

Survival outcome
Summary of various trials that have used concurrent chemotherapy in Re-irradiation setting.

deemed inoperable/unresectable should be considered for re-

irradiation alone or with concurrent chemotherapy with an
expected median survival of 10–12 months.

Disclosures
per fraction with concurrent weekly Paclitaxel and

Re-irradiation 40 Gy split course alternating with

Re-irradiation of 36 Gy in six fractions by SBRT

concurrent and maintenance Erlotinib of 150 mg

Re-irradiation to median dose 60 Gy at 2 Gray

adenoviral vector expressing TNF alpha with 5

The authors have nothing to disclose.

Dose escalation study of replication deficient
Re-irradiation 66 Gy in 2.2 Gy fraction with

Postoperative re-irradiation with concurrent

Dose escalation trial for concurrent and
RT Dose and concurrent chemotherapy

Meeting presentation
3 cycles Docetaxel and Cisplatin

FU, Hydroxyurea and radiation

Not presented.
with five doses of cetuximab

Financial support
maintenance Erlotinib

No financial support received.

daily feasible
carboplatin

Conflicts of interest
Cisplatin

The authors have no conflict of interest.

Phase I trial

Phase I trial

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