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Purpose of review
The treatment of locally advanced squamous cell carcinoma of the head and neck has
improved with the addition of chemotherapy to radiotherapy. Other approaches are
being investigated to improve the clinical benefit at an acceptable level of toxicity.
Recent findings
The present review summarizes recently published data on the treatment of locally
advanced squamous cell carcinoma of the head and neck. Altered radiation
fractionation regimens have been shown to increase efficacy, and induction
chemotherapy may offer clinical benefits. One of the most important advances in this
setting has been the demonstration that addition of the epidermal growth factor
receptor-targeted monoclonal antibody, cetuximab, to radiotherapy improves
locoregional control and overall survival compared with radiotherapy alone. The survival
benefit of this combination appears to be of at least the same magnitude as that seen
with chemoradiotherapy, but the combination is not associated with the high level of
toxicity that characterizes chemoradiotherapy . The use of more sensitive instruments for
adverse event recording may provide a better picture of the toxicity burden.
Summary
Although the further modification of radiotherapy and chemotherapy within
chemoradiotherapy regimens is unlikely to offer major clinical benefits, it is likely that any
significant advances will be made with the incorporation of novel agents into treatment
regimens. The combination of cetuximab and radiotherapy forms a new standard for the
treatment of locally advanced squamous cell carcinoma of the head and neck.
Keywords
cetuximab, chemoradiotherapy, epidermal growth factor receptor, locally advanced
squamous cell carcinoma of the head and neck, radiotherapy
Curr Opin Oncol 20:249255
2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8746
Introduction
Until the turn of the century, the treatment of locally
advanced head and neck cancer has improved with the
use of altered radiation fractionation regimens, better
radiation delivery techniques to minimize healthy tissue
exposure, and the addition of concurrent chemotherapy
to radiotherapy (chemoradiotherapy, CRT). Within the
past 2 years, further treatment developments have been
made in this area, some of which have had important
implications for treatment practice.
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Chemoradiotherapy
CRT is a standard treatment option for medically fit
patients with locally advanced SCCHN. The contribution
of chemotherapy to the clinical efficacy of CRT was
quantified by Kasibhatla et al. [5] using data from the
RTOG 90-03 trial together with those from a number of
studies using CRT for the treatment of locally advanced
disease. These investigators calculated that the addition of
chemotherapy to radiotherapy increased the biologic
equivalent dose by approximately 10 Gy in standard fractionated radiotherapy [5]. Such a dose escalation could not
be achieved safely by increasing the dose of radiation
alone. An update of the MACH-NC demonstrated an
absolute survival benefit of between 6.5 and 8% at 5 years
(depending on the analysis methodology used) with the
addition of chemotherapy to radiotherapy [2]. A more
recent meta-analysis of 32 randomized trials comparing
radiotherapy with CRT, both administered with curative
intent to patients with locally advanced SCCHN, was
conducted by Budach et al. [3]. To increase the relevance
of the results to current treatment practices, the analysis
excluded information from trials using chemotherapy no
longer considered to be the standard treatment and those
using subcurative radiation schedules. The analysis
demonstrated a significant overall survival benefit of
12 months for the addition of chemotherapy to radiotherapy delivered by conventional or accelerated fractionation
or hyperfractionation. Combination of radiotherapy with
5-fluorouracil (5-FU) alone, cisplatin alone, mitomycin C
alone, or 5-FU and cisplatin yielded the best overall
survival data. Updated results of a phase III trial using
hyperfractionated and accelerated radiotherapy in combination with carboplatin and 5-FU [6] demonstrated a
significant survival advantage in favor of CRT [7]. In a
review published in 2005, we had also showed that the
addition of chemotherapy to altered fractionation regimens yielded a clear increase in tumor control above
the clavicles [8].
Induction chemotherapy
The clinical benefit of induction chemotherapy in the
treatment of locally advanced disease is hotly contested
[9]. Although no consistent survival advantage of induction therapy over concomitant chemotherapy has been
demonstrated [2], this approach has its advocates. A
number of trials have looked at the relevant benefits of
modifying what is regarded as the standard platinum/
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Grade 2/Grade 3
Grade 4
CRT; chemoradiotherapy; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events, v3.0. Reproduced with
permission [13].
Cisplatin1
93%
71%
Cycles on weeks 1, 3, and 6
98% /98%
Carboplatin/5-FU2
66% /67%
86% /87%
Cisplatin/5-FU/FA3
46% /47% /59%
0
10
20
30
40
50
60
70
90
100
first cycle;
second cycle;
third cycle.
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individualized treatment based on indicators predicting efficacy, there is a need to identify indicators
that predict an individual patients susceptibility for
toxicity.
Quality of life
Quality of life (QoL) is an important factor for consideration in the treatment of patients with head and neck
cancer, and the negative effect of a poor baseline QoL on
treatment outcome should not be underestimated [24].
The baseline QoL of cancer patients is worse among
patients with lower Karnofsky performance status
(KPS), younger patients (55 years), patients with lower
incomes and the less well educated [25]. A recent multivariate analysis of data from two randomized RTOG trials
confirmed previous findings that baseline health-related
QoL [recorded using the Functional Assessment of Cancer
Therapy-Head and Neck (FACT-H&N) questionnaire] is
a significant and independent predictor of locoregional
control in locally advanced head and neck cancer [26].
The most significant predictor of locoregional control was
the functional well being component of the questionnaire.
Neither baseline QoL [26] nor emotional well being [27]
was predictive for overall survival. Despite the side effects
associated with CRT, studies [28] in patients with
advanced head and neck cancers reported that there was
no difference in global QoL between patients receiving
CRT and those receiving surgery followed by postoperative radiotherapy. With both treatment approaches,
patients developing complications following treatment
commonly recorded lower QoL scores, increased anxiety
and depression [29].
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Cetuximab + RT6
20
Cisplatin + HFX-RT5
18
14
7
0
10
15
20
Figure 3 Cetuximab and radiotherapy versus radiotherapy alone in locally advanced SCCHN
(ns)
Social
functioning
(ns)
Cognitive
functioning
(ns)
(ns)
Emotional
functioning
(ns)
Role
functioning
(ns)
(ns)
(ns)
Physical
functioning
60
P = 0.0281
Global health
status
(ns)
80
(ns)
40
20
(ns)
20
Cetuximab + RT
RT
40
60
80
100
Comparison of mean best and worse postbaseline QoL scores for five functional scales and global health status [39]. RT, radiotherapy.
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Conclusion
Steady progress is made in the treatment of locally
advanced SCCHN. Further modifications to current
radiotherapy schedules and chemotherapy regimens
within the CRT approach are, however, unlikely to offer
additional major improvements in efficacy. One of the
most important advances made in the treatment of
locally advanced disease in the past 2 years has been
the demonstration that the EGFR-targeted MAb,
cetuximab, is able to potentiate the effects of radiotherapy
and to improve locoregional control and overall survival,
without increasing the side effects of radiotherapy or
compromising patients QoL. Whether the additional
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In this paper, the authors calculated that the addition of chemotherapy to radiotherapy increased the biologic equivalent dose by around 10 Gy, more than could
safely be achieved with radiotherapy alone.
5
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A US randomized, phase III trial demonstrating that the addition of docetaxel to
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13 Bernier J, Bonner J, Vermorken J, et al. Consensus guidelines for the manage ment of radiation dermatitis and coexisting acne-like rash in patients receiving
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The first international consensus guidelines produced for the treatment of radiation
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14 Macmillan MS, Wells M, MacBride S, et al. Randomized comparison of dry
dressings versus hydrogel in management of radiation-induced moist desquamation. Int J Radiat Oncol Biol Phys 2007; 68:864872.
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27 Coyne JC, Pajak TF, Harris J, et al. Emotional well being does not predict
survival in head and neck cancer patients: a radiation therapy oncology group
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Analysis of data from two randomized RTOG trials demonstrated that emotional
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32 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for
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33 Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated
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This QoL analysis of the randomized, phase III study of radiotherapy and cetuximab
versus radiotherapy alone demonstrates that the addition of cetuximab has no
negative impact on patients QoL. Of note, the rash associated with EGFR
inhibitors did not have a negative effect on social functioning.
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