Abstract: Objectives: to assess patient’s loco-regional control rates, associated
toxicity rates and related prognostic factors as a consequence of reirradiation
of recurrent head and neck cancer with intensity modulated radiotherapy (IMRT)
or volumetric arc therapy (VMAT).

Data Sources: Medline databases (PubMed, MedScape, ScienceDirect. EMF-Portal) and all materials available in the Internet from 2007
to 2017.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

Study Selection: The initial search presented 50 articles of which 33 met the
inclusion criteria. The articles studied the relation between re-irradiation of
recurrent head and neck cancer with IMRT or VMAT and loco-regional control
rate, associated toxicity rate and related prognostic factors that affected
outcomes.

Data Extraction: If the studies did not fulfill the inclusion criteria, they were excluded.
Study quality assessment included whether ethical approval was gained,
eligibility criteria specified, appropriate controls, adequate information and
defined assessment measures.

Data Synthesis: Comparisons were made by structured review with the results
tabulated.

Findings: In
total 33 potentially relevant publications were included. The studies indicated an association
between re-irradiation of recurrent head and neck cancer with IMRT or VMAT and good
response rates, whereas re-irradiation toxicity rate had controversial results,
Some reported accepted low toxicity rates, while others reported high rates. We
found that good performance status, re-irradiation dose more than 60 Gy, small
tumor volume and disease free interval more than 12 months were associated with
better outcomes.

Conclusion: We found better
loco-regional control rates with accepted associated toxicity after
reirradiation of recurrent HNC with IMRT or VMAT especially for patients with
favorable selection criteria.

Key words: Head and neck
cancer, Re-irradiation,
Recurrent, toxicity.

 

Introduction

Local recurrence is the most common cause of death among patients
with recurrent head and neck cancer, acquiring local control may have direct effect
on their survival and quality of life. 1 Management of recurrent head and neck cancer (HNC) is difficult,
although surgery offers the best local control; it is only feasible in minority
of patients. Moreover, systemic chemotherapy failed to exhibit any curability
chance with poor survival benefit. 2 Reirradiation
is the alternative best option when surgery is not possible with the aim of obtaining
local control and improving survival benefit with accepted toxicity; which is ranging
from acute to late toxicity and cumulative radiation doses to normal nearby
organs should respect different tissue constrains. 3 Recently, Intensity-modulated radiation therapy (IMRT) and
Volumetric modulated arc therapy (VMAT) help use of higher dose to local tumor
recurrence and lower dose to nearby organ at risk which result in better local control and more
survival benefit. However,
prospective studies about using IMRT and VMAT in re-irradiation setting of
recurrent head and neck cancer (HNC) are rare. 4 reirradiation
of recurrent HNC is challenging and finding the most optimal plan in sparing
the different normal nearby organs at risk(OAR) is difficult, Also the best
selection criteria for the patients associated with better outcomes is widely advisable.
5 Few
prospective studies have been published for the role of IMRT and VMAT in
recurrent HNC, while many retrospective studies observed good tumor control and
survival benefit with accepted toxicity rate. 6 The aim of this study
was assessing the response rate of re-irradiation with modern techniques in
recurrent HNC and
determining associated toxicity rates and better prognostic factors.

MATERIALS AND METHODS

Search Strategy: We reviewed papers on the role of IMRT and VMAT on re-irradiation
of recurrent head and neck cancer from Medline databases which are (PubMed, MedScape, Science Direct) and also materials
available in the Internet. We used recurrent/ head and neck/ re-irradiation and
IMRT/response/ toxicity/ VMAT/survival as searching terms. In addition, we
examined references from the specialist databases EMF-Portal
(http://www.emf-portal.de), reference lists in relevant publications and
published reports from different re-irradiation research journals. The search
was performed in the electronic databases from 2007 to 2017. Study Selection: All the studies were individually assessed for inclusion. They were
included if they fulfilled the following criteria: Inclusion
criteria of the published studies: -Published in English language. -Published
in peer-reviewed journals. -Focused on re-irradiation with IMRT or VMAT of
recurrent HNC.        -Discussed the
relation between re-irradiation, response rates and toxicity. -If a study had
several publications on certain aspects we used the latest publication giving
the most relevant data. Data Extraction: If the studies did not fulfill the above
criteria, they were excluded such as, Studies on re-irradiation with
conventional techniques, report without peer-review, not within national
research programmes, letters/comments/editorials/news and studies not focused
on re-irradiation with IMRT or VMAT.  The
analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of
the U.S. Preventive Services Task Force & UK National Health Service
protocol for EBM in addition to the Evidence Pyramid (Fig 1).

U.S. Preventive Services
Task Force: Level I: Evidence reported from at
least one efficiently designed randomized controlled trial. Level II-1: Evidence obtained from properly designed controlled
trials with no randomization. Level
II-2: Evidence obtained from properly designed cohort or case-control
analytic studies, better from more than one center or research group. Level
II-3: Evidence achieved from multiple time series with or without the intervention.
Unexpected results in uncontrolled trials might also be regarded as this type
of evidence. Level III: considerations of respected authorities, based on
clinical experience, descriptive trials, or reports of expert committees. Quality
Assessment: The quality of all the studies was evaluated. Considerable
factors included, study design, fulfillment of ethical approval, evidence of a
power calculation, defining eligibility criteria, appropriate controls, sufficient
information and specified assessment tools. Confounding factors were reported
and controlled, suitable data analyses were verified in addition to an
explanation of missing data. Data Synthesis: A structured systematic
review was performed with the results tabulated. Study selection and characteristics: In total 50 potentially relevant publications were identified, 17 articles
were excluded as they did not meet our inclusion criteria. A total of 33
studies were included and the majority of the studies examined the role of
re-irradiation with IMRT or VMAT on recurrent head and neck cancer patients and
the risk of toxicity. The studies were analyzed with respect to the study
design using the classification of the U.S. Preventive Services Task Force
& UK National Health Service protocol for EBM.

RESULTS

Regarding loco-regional control rate, Re-irradiation of recurrent head
and neck cancer with IMRT or VMAT was investigated in 20 studies. There were
different results with 14 studies reported better locoregional response
rate more than 40% and 2 year survival benefit rate more than 40%. However, six
studies reported that there was mild response rates as regard loco-regional
control and minimal or no survival benefit.
Regarding re-irradiation dose, it was investigated in 20 studies. Most of
them were retrospective studies, 12 studies reported that better response rates
were correlated with higher doses more than 60 Gy, 6 studies reported that
doses more than 50 Gy was associated with survival benefit while only two
studies showed that doses with a mean of 45Gy had a good results with accepted
toxicity. As regard toxicity, we
identified 10 studies that published the associated toxicity outcome after re-irradiation
with IMRT or VMAT of recurrent HNC and we found that 6 studies reported toxicity
rate of 20% to 30% However, two studies represented high rates of toxicity more
than 30%. Also two studies reported lower toxicity rates of less than 20% (Tab
1). Selection criteria correlated with better response outcome were
investigated in 7 studies. There were 5 studies that reported multiple factors
like advanced techniques, free disease interval, low tumor volume, reirradiation
dose more than 60, early nodal recurrence and post operative re-irradiation were
associated with better outcome. While 2 studies reported that time interval
between primary and re-irradiation was the only factor associated with better
outcome and survival benefit.

DISCUSSION

Research into the re-irradiation of recurrent HNC is an area in
which there are a limited number of scientific studies with no randomized
prospective studies and majority of retrospective nature. These studies cover
the role of advanced radiotherapy techniques in reirradiation era as regarding
response and toxicity rates. Both IMRT and VMAT had been conducted in recent investigations,
and include studies measuring the loco-regional control and toxicity. Most of
the studies reported better loco-regional control and survival benefit over
conventional reirradiation. However, because of the nature of retrospective and
rare prospective studies, it can be some difficult to provide the exact role of
IMRT or VMAT in re-irradiation of recurrent HNC as regard not only therapy
response but also therapy related toxicity. This can result in the
misinterpretation of results or false impression about scientific findings. So
this study tried to provide an updated analysis that describe recent studies,
classify and evaluate them according to evidence-based medicine (EBM) criteria.
Reviewing the recent studies about the role
of IMRT or VMAT in re-irradiation of recurrent HNC, we found majority with 14 studies 7, 10, 11, 14,
17 reported better response rate more than 40% and 2 year survival benefit
rate more than 40%. Confirming that advanced techniques can improve loco-regional control
and survival rates, Re-irradiation with IMRT or VMAT techniques provide higher
doses to gross tumor and lower doses to nearby organs which was associated with
better loco-regional control and progression free survival. 3 In our review,
6 studies reported toxicity rate that had ranged from 20% to 30% which was less
than that expressed by conventional re-irradiation. 7, 8, 9 However,
two studies represented high rates of associated toxicity more than 30%. 10,
18 Also two studies reported lower toxicity rates of less than 20%. 12,
19 Some studies on re-irradiation with IMRT or
VMAT had suggested a decreased risk of reirradiation toxicity, but
others had not. The studies to date have been conflicting about toxicity rates
with IMRT or VMAT. But most of
the studies showed well tolerability and
better quality of life. 4 In a study by Lee et al. which was a
retrospective one From July 1996 to September 2005 included 105 patients 70% of
them received IMRT reported loco-regional control of 45% and survival benefit
of 40%. On multivariate analysis, IMRT was associated with better local
response rate and Radiation dose more than 50 Gy was associated with improved
OS. Severe toxicity was seen in 11% of patients. None had a carotid rupture.
This study showed significant improvement in survival for those patients who acquired
good local control rate. 9 Duprez et al.
which was a retrospective study between 1997 and 2008 that included 84 patients
showed that IMRT in re irradiation of recurrent HNC was associated with local
control of 48% with adverse events of about 11%. Also on multivariate analysis they
found advanced stage, short time interval between two radiations, absence of
surgery, and hypo-pharyngeal cancer were considered bad prognostic factors. 12
Popovtzer et al. which was a retrospective study on 66 patients reported 71% of
good response rate and adverse events rate was 19%. This study informed that a
prophylactic field is not needed in reirradiation era at present. 13 Reirradiation dose is individualized
according to age, performance status and radiotherapy equipments, duration and
timing of re-irradiation. we found 12 studies 1, 2, 5, 6 reported that better
locoregional control was associated with higher doses more than 60 Gy, also 6
studies 9, 16 reported that reirradiation doses more than 50 Gy were correlated
with survival benefit while only two studies 8, 14 showed that doses
with a mean of 45 Gy had a good results with accepted toxicity. Malik
et al. which was a trial with a retrospective nature on 79 patients from year
of 1999 to 2011 used a dose of re irradiation with a mean of 45 Gy and found
that progression free survival benefit was 35% and adverse events was 30% and reported
that Reirradiation of recurrent HNC with moderate radiation doses achieved
acceptable progression-free survival and toxicity rates. 14 Valez et
al. which was a retrospective trial between 1998 and 2015 on 80 patients. IMRT
was used in 71 patients (93.4%) with a median dose of 60 Gy and found that local
control rate was 36%, overall survival 51% and associated toxicity was 32.8%
denoted good response rates but related toxicity was challenging and needed
more selection criteria. 15 Karakia et al. which was a retrospective
study from year of 2007 to 2012 on 31 patients. Reported locoregional control
of 40%, overall survival of 40% and toxicity rate of 28%. Also he noted some
prognostic factors correlated with better outcome based on patient’s
performance status (PS) and tumor characteristics. 20 Many selection criteria that might be correlated
with better results have been used like advanced techniques, free disease
interval, low tumor volume, reirradiation dose more than 60 Gy, early nodal
recurrence and post operative reirradiation. Those multiple selection criteria
were widely shown by 5 studies 20, 22, 23. While 2 studies 7, 21
reported that time interval between primary and re-irradiation was the only
factor associated with survival benefit. On the other hand, two studies 5,
24 failed to show any criteria that correlated with better results. In study by Bots et al which was a retrospective study between year
of 1986 and 2013 on 137 patients, he found better outcome as regard loco-regional
control 46% and disease free survival 30% also he showed accepted toxicity rate
of 28% and noticed that higher radiation doses and postoperative re-irradiation
were  associated with better results.
17

Conclusion:

Re-irradiation of recurrent head and neck cancer with
IMRT or VMAT is feasible and provides a chance for not only better loco-regional
control and survival benefit but also curability chance with low toxicity rate
which is of major concern as it has a direct impact on quality of life. For
better results it is advised to reirradiate patients with small tumor recurrence,
longer disease free interval, higher reirradiation doses in respect to tissue
constrains and advanced radiotherapy techniques.