A multidisciplinary approach to squamous cell carcinomas of the

head and neck: an update

Jacques Bernier
Department of Radiation Oncology, Genolier Swiss
Medical Network, Genolier, Switzerland
Correspondence to Dr Jacques Bernier PD,
Department of Radiation Oncology, Genolier Swiss
Medical Network, CH-1272 Genolier, Switzerland
Tel: +41 22 366 9959; fax: +41 22 366 9961;
e-mail: jbernier@genolier.net

Current Opinion in Oncology 2008, 20:249255

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.

Altered radiation fractionation schedules

The RTOG 90-03 study published by Fu et al. [1] in 2000
provided the first real proof that the use of accelerated
or hyperfractionated radiation schedules improved
locoregional control in locally advanced squamous cell
carcinoma of the head and neck (SCCHN) over that
achieved with conventionally fractionated schedules.

An updated Meta-Analysis of Chemotherapy in Head &

Neck Cancer (MACH-NC) report, involving 15 randomized trials comparing standard and altered fractionation
regimens, showed an absolute survival benefit of over 3%
at 5 years, the greatest benefit being realized with hyperfractionated radiation [2
]. The significant survival benefit
of hyperfractionation over conventional fractionation has
also been confirmed in another recent meta-analysis of
randomized trials, which showed no survival benefit for
accelerated fractionation over conventional fractionation
[3]. Prolonged overall treatment time, reduced overall
radiation dose or split course radiotherapy does not
improve tumor control. The 5-year results of a randomized,
phase III trial investigating continuous accelerated 7 days/
week radiotherapy have also been published recently [4].
Patients with moderately advanced disease (T24, N01,
M0) received 1.82.0 Gy/day (total dose 6672 Gy,
depending on tumor stage) delivered either 5 days/week
or 7 days/week. Disease-free and overall survival were

1040-8746 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

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250 Head and neck

significantly improved in the 7 days/week arm. Confluent

mucositis was the main toxicity, and radiation necrosis
developed as a consequential late effect in patients receiving a radiation dose of 2.0 Gy/fraction as part of the
accelerated regimen. Further cases of radiation necrosis
were prevented by reducing the dose per fraction to 1.8 Gy.

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/

5-FU induction regimen. Two randomized, phase III

trials have recently shown a survival advantage of adding
docetaxel to induction chemotherapy with platinum,
followed by either CRT [10

] or radiotherapy alone
[11

] in locally advanced SCCHN (either unresectable
disease or disease in patients who were candidates for
organ preservation). In another trial, the addition of uracil
tegafur and vinorelbine to platinum improved survival
over platinum/5-FU alone [12]. Although, until a survival
benefit of induction chemotherapy followed by CRT
versus CRT alone is proven, investigation of the relative
merits of different induction chemotherapy regimens
remains debatable, the exact role of neoadjuvant
approaches in the global strategy of treatment for patients
with high-risk and very high-risk tumors is worth revisiting.

Adverse events associated with radiotherapy

and chemoradiotherapy
Most patients will be affected to some degree by the acute
side effects of radiotherapy, including mucositis (stomatitis), dysphagia and skin toxicity (radiation dermatitis),
and adequate (and often aggressive) management is
required to minimize treatment disruptions. Recently
published guidelines provide grade-specific (Table 1)
and general management strategies for radiation dermatitis
[13

]. One of the most important, but simplest, general
measures is to ensure that the skin in the radiation field,
even when ulcerated, is clean and dry prior to radiotherapy.
Drying pastes, gels and creams may all offer relief from
symptoms when applied after radiotherapy [13

].
Although hydrogel dressings are considered by some to
provide symptomatic relief for patients with radiationinduced moist desquamation, a recently published
randomized trial actually showed that there was no statistically significant improvement in the symptomatic
benefit of hydrogel dressings over dry dressings in patients
with a variety of solid tumors, including head and neck
malignancies [14]. Further, the use of hydrogels was
associated with a significant increase in healing times.
Although it is well documented that modifying fractionation to intensify radiation treatment increases the incidence and degree of acute radiation-induced side effects,
the impact on late effects has remained unclear. The
long-term follow-up of a randomized trial has now shown
that the increase in 5-year disease-free and overall survival
achieved with hyperfractionated radiotherapy (58 Gy in
40 fractions) compared with conventional fractionation
(51 Gy in 20 fractions) is not accompanied by a significant
increase in late toxicities: the rates of grade 3/4 late
toxicities were 10.5% in the conventional fractionation
arm and 7.7% in the hyperfractionation arm [15
].
CRT is associated with a higher incidence of severe (grade
3/4) acute adverse events compared with radiotherapy

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Multidisciplinary approach to carcinomas Bernier 251

Table 1 Grade-specific management of radiation dermatitis
Grade 1

Grade 2/Grade 3

Grade 4

NCI-CTCAE v3.0, grade of radiation dermatitis

Moisturizers (optional)
Noninfected; use 1 topical approaches
Antibacterial moisturizers (occasionally)
Drying gels (topical antiseptic)
Anti-inflammatory emulsion
Hyaluronic acid cream
Hydrophilic dressings
Zinc oxide paste (if easily removed)
Silver sulfadiazine or b-glucan cream
Where infection is suspected
Try to identify infectious agent
Topical antibiotics
Doxycycline is not recommended
Check blood granulocyte counts (particularly with CRT)
Carry out blood cultures if there are additional signs of
sepsis and/or fever

Verify radiation dose/distribution

Requires specialized wound care

CRT; chemoradiotherapy; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events, v3.0. Reproduced with
permission [13

].

alone [1619]. In addition, it has been estimated that 15%

of deaths in patients receiving CRT are due to early or late
treatment-related complications [20]. The increase in
toxicity associated with this treatment approach leads to
chemotherapy compliance problems: around one-third of
patients in clinical trials do not receive the planned number of cisplatin cycles [18,19,21] (Fig. 1), and the number of
patients receiving cisplatin as scheduled decreases over
time [17]. As a consequence of the chemotherapy schedule
modifications, CRT can be associated with a significantly
prolonged treatment time and more frequent and prolonged treatment interruptions than radiotherapy alone
[18,19,21].
The recording and analyzing of early and late adverse
events associated with radiotherapy and CRT is beset by
problems. In a recently published review of data from five
clinical trials, Trotti et al. [22

] illustrated that traditional
reporting methods such as the use of maximum grade
adverse events can markedly underestimate the burden

of acute toxicity and, to a lesser extent, late toxicities.

They suggest that aggressive treatment schedules may
appear less toxic than they really are. Reliable, reproducible and consistently applied methods of reporting
relevant adverse events are required, if we are to make
meaningful comparisons of data between clinical studies.
For that purpose, Trotti et al. [22

] proposed a new
recording system (TAME) which takes into account
the acute toxicities (T), late effects (A) and mortality
risk (M) associated with treatment (E). In view of the
impact of severe adverse events on morbidity and
treatment compliance, and thus potentially treatment
outcome, a better clinical or pharmacogenetic understanding of a patients toxicity susceptibility profile
would contribute considerably to enabling the tailoring
of treatment. Bentzen and Trotti [23] suggest that
streaming patients according to risk might enable more
intensive treatment schedules to be used for patients
with relatively low normal tissue sensitivity, thus offering
the potential for improved outcome. Analogous to

Figure 1 Scheduled chemotherapy administration may be compromised in patients receiving chemoradiotherapy

Cycles on weeks 1 and 5

Cisplatin1

93%
71%
Cycles on weeks 1, 3, and 6
98% /98%

Carboplatin/5-FU2
66% /67%

86% /87%

Cycles on weeks 1, 3, and 6

100% for all

Cisplatin/5-FU/FA3
46% /47% /59%
0

10

20

30

40

50

60

70

75% /72% /78%

80

90

100

Patients receiving all planned doses (%)

FA, folinic acid; 5-FU, 5-fluorouracil. 1Huguenin et al. [21]; 2Calais et al. [18];3 Wendt et al. [19].

first cycle;

second cycle;

third cycle.

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252 Head and neck

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].

Cetuximab and radiotherapy: from robust

preclinical data to a new standard of care?
Epidermal growth factor receptor (EGFR) is detectable
in nearly all head and neck cancers, and high levels of
EGFR are associated with a reduction in overall survival
and a higher risk of locoregional relapse, compared with
lower EGFR levels, in head and neck cancer patients
receiving radiotherapy [30]. This, together with a number
of inspiring preclinical studies on the interaction between
EGFR inhibitors and ionizing radiation [31], led to
launch a number of prospective clinical investigations
on targeted therapies.
One of the most significant findings in the treatment of
locally advanced SCCHN in the past 2 years has been the
demonstration by Bonner et al. [32] that the addition of the
EGFR-targeted immunoglobulin G1 (IgG1) monoclonal
antibody (MAb), cetuximab (Merck Serono, a division of
Merck KGaA, Darmstadt, Germany), to radiotherapy
improved locoregional control and overall survival over
radiotherapy alone.

Bonner et al. reported results of a phase III study in which

424 patients received radiotherapy alone or in combination with cetuximab (400 mg/m2 initial dose followed
by subsequent weekly doses of 250 mg/m2). Basically,
three radiotherapy regimens were administered at the
investigators discretion: once daily (70 Gy in 35 fractions), twice daily (7276.8 Gy in 6064 fractions) or
concomitant boost (72 Gy in 42 fractions). Randomization
was stratified by KPS, nodal involvement, tumor stage
and radiation fractionation.
In contrast to what we often experience when adding
chemotherapy to radiotherapy, the vast majority of
patients in the cetuximab arm (90%) were able to receive
cetuximab according to protocol specifications, that is,
without dose reduction or delay. In addition, radiation
exposure was similar in the treatment arms indicating
that cetuximab did not interfere with the radiotherapy
schedule.
Adding cetuximab to radiotherapy significantly reduced
the risk of locoregional progression or death (hazard ratio
0.68, P 0.005) and led to a 10-month increase in the
median duration of locoregional control, from 14.9 to 24.4
months. The 2-year rates of locoregional control were 50%
for cetuximab and radiotherapy and 41% with radiotherapy
alone. Patients in the cetuximab arm also had a significantly reduced risk of death (hazard ratio 0.74, P 0.03)
and disease progression or death (hazard ratio 0.70,
P 0.006). The 2-year progression-free survival (PFS)
rates were 46 and 37% for cetuximab and radiotherapy
and radiotherapy alone, respectively. Corresponding
3-year overall survival rates were 55 and 45%. Sixty
percent of patients randomized to treatment, in whom
the primary tumor site was the oropharynx, appeared to
derive the greatest survival benefit from cetuximab-based
treatment. This reflects findings reported for CRT, which
is particularly active in patients with oropharyngeal, compared with hypopharyngeal, tumors [6,7].
Much has been made of the fact that CRT is frequently the
treatment approach of choice for patients with locally
advanced disease. In this respect, the Bonner study may
be considered to have used a comparator arm not representative of treatment approaches for all patients, although
when the study was originated, radiotherapy was the
standard treatment choice. To put the results of
the Bonner study into context with CRT, we can compare
the survival time advantage (i.e. the period of time by
which investigational therapy prolonged survival over that
observed with radiotherapy alone) in the Bonner study
with that observed in the CRT arms of large, randomized
phase III trials comparing CRT with radiotherapy
[7,19,21,3134] (Fig. 2). Although this is a cross trial
comparison, the 20-month survival time advantage seen
with cetuximab is greater than that seen with CRT in any

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Multidisciplinary approach to carcinomas Bernier 253

Figure 2 Cetuximab and radiotherapy compared with chemoradiotherapy: survival time advantage

Cetuximab + RT6

20

Cisplatin + HFX-RT5

18

Cisplatin + 5-FU/FA + accelerated RT4

14

Carboplatin + 5-FU + conventional RT3

Carboplatin + 5-FU + HFX-RT (CB)2

Mitomycin C + 5-FU + HFX-RT (CB)1

7
0

10

15

20

Median survival advantage (months)

Reviewed by Bernier and Schneider [31]; 1Budach et al. [33]; 2Semrau et al. [7]; 3Denis et al. [34]; 4Wendt et al. [19]; 5Huguenin et al. [21]; 6Bonner
et al. [32]. CB, concomitant boost; FA, folinic acid; 5-FU, 5-fluorouracil; HFX-RT, hyperfractionated radiotherapy; RT, radiotherapy.

of the five trials investigated. A randomized, phase III

RTOG study (www.cancer.gov) is now comparing the use
of platinum-based CRT alone or in combination with
cetuximab in locally advanced SCCHN.
A major advantage of adding cetuximab, compared with
traditional cytotoxic chemotherapy, to radiotherapy is the
good tolerability of this monoclonal antibody. In the
Bonner study, there were no statistically significant
differences in the incidence of most of the grade 3/4

adverse events between the radiotherapy and the

cetuximab and radiotherapy arms, including mucositis,
dysphagia and radiation dermatitis [32]. Only grade 3/4
acne-like rash (17 versus 1%, P < 0.001) and infusionrelated reactions (3 versus 0%, P < 0.01) were significantly more common in the cetuximab and radiotherapy
compared with the radiotherapy arm. These findings
were not unexpected, as acne-like rash is a characteristic
side effect of treatment with most EGFR-targeted agents
and infusion-related reactions can be associated with the

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

Mean worst score

20

(ns)
20

Cetuximab + RT
RT

40

60

80

100

Mean best score

Comparison of mean best and worse postbaseline QoL scores for five functional scales and global health status [39]. RT, radiotherapy.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

254 Head and neck

use of monoclonal antibodies, as well as other anticancer

therapies. There have recently been some isolated
reports of severe skin reactions within the irradiated field
of patients receiving EGFR inhibitors concomitantly
with radiotherapy [3537]. Although data from the large,
randomized, controlled trial of Bonner et al. [32] showed
no statistically significant increase in radiation dermatitis
with EGFR inhibition, the incidence and severity of
radiation dermatitis should continue to be monitored
in randomized trials.

benefit conferred by cetuximab is maintained when it is

combined with CRT is currently under investigation.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:


of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 329331).
1

Curran et al. [38 ] conducted a QoL analysis on the data

from the Bonner trial and showed that the addition of
cetuximab to radiotherapy did not adversely affect patient
QoL. In line with previous reports, global health status/
QoL was identified in a multivariate analysis as being a
significant independent prognostic indicator. Adding
cetuximab to radiotherapy had no negative impact on
the mean best and worst postbaseline QoL scores for
the different functional scales and for the global health
status/QoL, compared with radiotherapy alone [38

]
(Fig. 3). It is notable that there was also no significant
difference between the treatment arms in the results
generated from the social functioning scale of the European Organization for Research and Treatment of Cancer
(EORTC) QLQ-C30 instrument (Pharmacia & Upjohn
Company, Kalamazoo, Michigan, USA) used: it was
expected that any negative effect of cetuximab-associated
acne-like rash on QoL would be detected by this scale.
Although adding cetuximab to radiotherapy undoubtedly
improves the survival prospects for patients compared
with radiotherapy alone, the cost of including this
monoclonal antibody into treatment strategies has to
be considered. According to the recently published findings of an economic evaluation, based on data from the
Bonner study, the combination of cetuximab and
radiotherapy may be considered to be a cost-effective
option in five European countries (Belgium, France,
Italy, Switzerland, UK) in patients with locally advanced
SCCHN, who are not amenable to CRT [39].

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

Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG)
phase III randomized study to compare hyperfractionation and two variants of
accelerated fractionation to standard fractionation radiotherapy for head and
neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat
Oncol Biol Phys 2000; 48:716.

Pignon JP, Le Matre A, Bourhis J. Meta-analyses of Chemotherapy in Head

and Neck Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys 2007;
69:S112114.
This updated meta-analysis confirmed a survival benefit of CRT over radiotherapy
alone but showed no survival advantage for induction chemotherapy.

2

Budach W, Hehr T, Budach V, et al. A meta-analysis of hyperfractionated and

accelerated radiotherapy and combined chemotherapy and radiotherapy
regimens in unresected locally advanced squamous cell carcinoma of the
head and neck. BMC Cancer 2006; 6:28.

Skladowski K, Maciejewski B, Golen M, et al. Continuous accelerated 7-daysa-week radiotherapy for head-and-neck cancer: long-term results of phase III
clinical trial. Int J Radiat Oncol Biol Phys 2006; 66:706713.

Kasibhatla M, Kirkpatrick JP, Brizel DM. How much radiation is the chemotherapy worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys
2007; 68:14911495.
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

Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated

radiotherapy limits the additional benefit of simultaneous chemotherapy:
results of a multicentric randomized German trial in advanced head-and-neck
cancer. Int J Radiat Oncol Biol Phys 2001; 50:11611171.

Semrau R, Mueller RP, Stuetzer H, et al. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with
carboplatin and 5-fluorouracil: updated results of a randomized multicentric
trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2006;
64:13081316.

Bernier J. Alteration of radiotherapy fractionation and concurrent chemotherapy: a new frontier in head and neck oncology? Nat Clin Pract Oncol 2005;
2:305314.

Eisbruch A. Commentary: induction chemotherapy for head and neck cancer:

hypothesis-based rather than evidence-based medicine. Oncologist 2007;
12:975977.

10 Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone


or with docetaxel in head and neck cancer. N Engl J Med 2007; 357:1705
1715.
A US randomized, phase III trial demonstrating that the addition of docetaxel to
induction therapy with cisplatin and 5-FU, prior to CRT, improves survival compared
with cisplatin and 5-FU alone.
11 Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and


docetaxel in unresectable head and neck cancer. N Engl J Med 2007;
357:16951704.
A European randomized, phase III trial demonstrating that the addition of docetaxel
to induction therapy with cisplatin and 5-FU improves survival compared with
cisplatin and 5-FU alone.
12 Rivera F, Vega-Villegas ME, Lopez-Brea M, et al. Randomized phase II study of
cisplatin and 5-FU continuous infusion (PF) versus cisplatin, UFT and vinorelbine (UFTVP) as induction chemotherapy in locally advanced squamous cell
head and neck cancer (LA-SCHNC). Cancer Chemother Pharmacol 2007
[Epub ahead of print].
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
radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck. Ann Oncol 2008; 19:142149.
The first international consensus guidelines produced for the treatment of radiation
dermatitis.
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.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Multidisciplinary approach to carcinomas Bernier 255

15 Cummings B, Keane T, Pintilie M, et al. Five year results of a randomized


trial comparing hyperfractionated to conventional radiotherapy over four
weeks in locally advanced head and neck cancer. Radiother Oncol 2007;
85:716.
Long-term follow-up of a randomized trial demonstrating that treatment with
hyperfractionated radiation does not increase the incidence of late, severe
toxicities compared with conventionally fractionated radiation.
16 Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of
standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin
Oncol 2003; 21:9298.
17 Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or
without concomitant chemotherapy for locally advanced head and neck
cancer. N Engl J Med 2004; 350:19451952.
18 Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy
versus concomitant chemotherapy and radiation therapy for advanced-stage
oropharynx carcinoma. J Natl Cancer Inst 1999; 91:20812086.
19 Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer:
a randomized multicenter study. J Clin Oncol 1998; 16:13181324.
20 Argiris A, Li Y, Forastiere A. Prognostic factors and long-term survivorship in
patients with recurrent or metastatic carcinoma of the head and neck. Cancer
2004; 101:22222229.
21 Huguenin P, Beer KT, Allal A, et al. Concomitant cisplatin significantly
improves locoregional control in advanced head and neck cancers treated
with hyperfractionated radiotherapy. J Clin Oncol 2004; 22:46654673.
22 Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for


summarising adverse events of cancer treatment by the Radiation Therapy
Oncology Group. Lancet Oncol 2007; 8:613624.
Proposal for a new method for recording adverse events to better appreciate the
toxicity burden of radiotherapy/CRT. The authors suggest that there is considerable under reporting of adverse events and that this is particularly marked with
more intense treatment regimens.
23 Bentzen SM, Trotti A. Evaluation of early and late toxicities in chemoradiation
trials. J Clin Oncol 2007; 25:40964103.
24 de Graeff A, de Leeuw JR, Ros WJ, et al. Sociodemographic factors and
quality of life as prognostic indicators in head and neck cancer. Eur J Cancer
2001; 37:332339.
25 Movsas B, Scott C, Watkins-Bruner D. Pretreatment factors significantly
influence quality of life in cancer patients: a Radiation Therapy Oncology
Group (RTOG) analysis. Int J Radiat Oncol Biol Phys 2006; 65:830835.
26 Siddiqui F, Pajak TF, Watkins-Bruner D, et al. Pretreatment quality of life


predicts for locoregional control in head and neck cancer patients: a Radiation
Therapy Oncology Group analysis. Int J Radiat Oncol Biol Phys 2008;
70:353360.
In what the authors consider to be the largest analysis of its kind, analysis of data
from two randomized RTOG trials showed health-related QoL to be a significant
and independent predictor of locoregional control in locally advanced head and
neck cancer.

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
study. Cancer 2007; 110:25682575.
Analysis of data from two randomized RTOG trials demonstrated that emotional
functioning was not an independent predictor of survival in patients with cancer.
28 Mowry SE, Ho A, Lotempio MM, et al. Quality of life in advanced oropharyngeal
carcinoma after chemoradiation versus surgery and radiation. Laryngoscope
2006; 116:15891593.
29 Nguyen NP, Vos P, Karlsson U, et al. Quality of life following chemoradiation
and postoperative radiation for locally advanced head and neck cancer. ORL J
Otorhinolaryngol Relat Spec 2007; 69:271276.
30 Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor
expression on survival and pattern of relapse in patients with advanced head
and neck carcinoma. Cancer Res 2002; 62:73507356.
31 Bernier J, Schneider D. Cetuximab combined with radiotherapy: an alternative
to chemoradiotherapy for patients with locally advanced squamous cell
carcinomas of the head and neck? Eur J Cancer 2007; 43:3545.
32 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for
squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354:
567578.
33 Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated
chemoradiation with concurrent fluorouracil-mitomycin is more effective than
dose-escalated hyperfractionated accelerated radiation therapy alone in
locally advanced head and neck cancer: final results of the radiotherapy
cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial. J Clin Oncol 2005; 23:11251135.
34 Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and
Neck Oncology and Radiotherapy Group randomized trial comparing
radiotherapy alone with concomitant radiochemotherapy in advanced-stage
oropharynx carcinoma. J Clin Oncol 2004; 22:6976.
35 Budach W, Bolke E, Homey B. Severe cutaneous reaction during radiation
therapy with concurrent cetuximab. N Engl J Med 2007; 357:514515.
36 Herchenhorn D, Dias FL, Pineda RM, et al. Phase II study of erlotinib
combined with cisplatin and radiotherapy for locally advanced squamous
cell carcinoma of the head and neck (SCCHN) [Abstract]. J Clin Oncol 2007;
25:6033.
37 Lord HK, Junor E, Ironside J. Cetuximab is effective, but more toxic than
reported in the Bonner trial. Clin Oncol (R Coll Radiol) 2008; 20:96.
38 Curran D, Giralt J, Harari PM, et al. Quality of life in head and neck cancer


patients after treatment with high-dose radiotherapy alone or in combination
with cetuximab. J Clin Oncol 2007; 25:21912197.
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.
39 Brown B, Diamantopoulos A, Bernier J, et al. An economic evaluation of
cetuximab combined with radiotherapy for patients with locally advanced
head and neck cancer in Belgium, France, Italy, Switzerland and the United
Kingdom. Value Health 2007 [Epub ahead of print].

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