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Supportive care in head and neck oncology

ARTICLE in CURRENT OPINION IN ONCOLOGY · FEBRUARY 2010

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Supportive care in head and neck oncology
Gilberto de Castro Jr and Rodrigo S.C. Guindalini
Department of Clinical Oncology, Instituto do Câncer
do Estado de São Paulo, Faculdade de Medicina da
Universidade de São Paulo, São Paulo, Brazil
Correspondence to Gilberto de Castro Jr, MD, PhD,
Department of Clinical Oncology, Instituto do Câncer
do Estado de São Paulo, Faculdade de Medicina da
Universidade de São Paulo, Av. Dr Arnaldo, 251 – 5th
Floor, São Paulo, SP 01246-000, Brazil
Tel: +55 11 3893 2686; fax: +55 11 3083 1746;
e-mail: gilberto.castro@usp.br
Current Opinion in Oncology 2010, 22:221–225
Introduction
Head and neck cancer (HNC) accounts for around
645 000 new cases each year, worldwide, 75% of them
with stages III and IV disease, causing more than
350 000 deaths yearly [1]. Patients diagnosed with head
and neck squamous cell carcinoma (HNSCC), by far the
most common histological type of HNC, must ideally be
treated in accordance to multidisciplinary guidelines.
Briefly, the adjuvant treatment of patients submitted to
surgery with curative intent and presenting with risk
features (e.g., positive margins and extracapsular spread
of nodal disease) must include adjuvant cisplatin-based
concurrent chemoradiation, and overall survival (OS)
gains are seen in some subgroups [2–5]. For those
patients with unresectable tumors, the recently updated
results of the Meta Analysis of Chemotherapy on Head
and Neck Cancer (MACH-NC), including 93 studies
and 17 346 patients, do confirm the absolute survival
benefit for chemotherapy of 4.5% at 5 years in HNSCC
(hazard ratio of death 0.88, P < 0.0001) and, for concur-
rent chemoradiation, the hazard ratio was 0.81
(P < 0.0001) and the absolute survival benefit 6.5% at
1040-8746 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
Survival gains were achieved in head and neck cancer patients treated with a
multidisciplinary approach, including platinum-based concurrent chemoradiation, with a
substantial increase in toxicity. The prompt diagnosis and treatment of these toxicities –
the focus of this review – are essential aspects in the daily care of head and neck
squamous cell carcinoma patients.
Recent findings
Low-level laser is a promising therapy for prevention and treatment of mucositis.
Amifostine, as an acute and late xerostomia-preventive agent, may be considered in
patients undergoing fractionated radiation therapy alone. The incidence of xerostomia
was significantly reduced in patients treated with intensity-modulated radiation therapy.
Severe cutaneous reactions can occur when epidermal growth factor receptor-
targeting agents are administered concurrently to radiation therapy. Erythropoiesis-
stimulating agents should not be administered to head and neck cancer patients under
radiation therapy or chemotherapy outside of the context of clinical trials.
Summary
The best outcomes in head and neck squamous cell carcinoma patients treated in the
multidisciplinary context can only be achieved with an adequate patient selection, an
experienced and motivated team and if the best possible supportive care is offered.
Randomized studies on promising supportive therapies must be encouraged.
Keywords
dermatitis, erythropoiesis-stimulating agents, head and neck cancer, intensity-
modulated radiation therapy, low-level laser, mucositis, xerostomia
Curr Opin Oncol 22:221–225
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8746
5 years. In those patients treated with concurrent
platinum-based chemoradiation, the observed survival
benefit was more pronounced (hazard ratio 0.75 versus
0.86, P < 0.01) [6

].
These survival gains were achieved with a substantial
increase in toxicity. In the above-mentioned RTOG
95-01 adjuvant chemoradiation study [2], the frequency
of acute grade 3 (or more severe) toxicities reached
77% in patients submitted to chemoradiation versus
34% in those patients submitted to radiation therapy
alone (P < 0.0001). Mucositis, dermatitis and hemato-
logical toxicities are some of the most common acute
toxicities observed in these HNSCC patients treated
with chemoradiation and can negatively impact survival
rates and quality of life, as well as diminishing treat-
ment efficacy, due to unplanned radiation therapy
breaks.
In this scenario, supportive care plays a crucial role. To be
familiar with these toxicities, and their prompt diagnosis
and treatment – the focus of this review – are essential
aspects in the daily care of HNSCC patients.
DOI:10.1097/CCO.0b013e32833818ff
 222 Head and neck
Supportive care: essential aspects in head
and neck squamous cell carcinoma patients
The most frequent acute adverse effects observed in
HNSCC patients treated with chemoradiation include
mucositis, dysphagia, dermatitis and anemia, which will
be discussed below. In addition, xerostomia as a late
toxicity will also be presented.
Mucositis and dysphagia
Oral mucositis is a major treatment-related complication
of concurrent chemoradiation in HNSCC patients. It
affects nutrition, pain control, quality of life and adequate
treatment delivery, as it may lead to unplanned radiation
therapy breaks, thus compromising treatment efficacy
[7,8
].
Several measures have been studied to prevent or treat
oral mucositis induced by chemotherapy or radiation
therapy, but efficacy has not been consistently shown
for any. A recent Cochrane systematic review [9] on the
prevention of oral mucositis in cancer patients concluded
that the strength of the evidence was variable among
many interventions and that there is a need for well
designed trials on this issue.
Low-level laser (LLL) is a promising preventive therapy.
It has been used in the prevention and treatment of oral
mucositis in several clinical settings, including radiation
therapy in HNSCC patients and high-dose chemotherapy
with hematopoietic stem cell transplantation [10–13].
These studies, in general, show that LLL treatment is
well tolerated and there is some benefit for LLL-treated
patients, but high-quality evidence is missing, mostly in
the HNSCC patients under chemoradiation. In addition
to this, the best LLL treatment schedule still needs to be
defined. Our group has recently presented the results of a
phase III, randomized, double-blind study to evaluate
the efficacy of LLL to prevent or delay the appearance of
severe oral mucositis induced by chemoradiation in
HNSCC patients and its impact on unplanned radiation
therapy interruptions in 75 patients treated with either
daily He–Ne LLL 2.5 J/cm2 or placebo laser, before each
fraction of radiation therapy. In both groups, it was
allowed to receive basic oral care and analgesics. The
number of patients diagnosed with grade 3 or 4 oral
mucositis treated with LLL was significantly lower in
week 4 (P ¼ 0.04) and more patients treated with placebo
had radiation therapy interruptions due to mucositis
(6 versus 0, P ¼ 0.02), which may translate in better
chemoradiation efficacy and tolerability [14].
To reduce the extent of mucositis, special attention to
radiation therapy planning techniques, allied to adequate
oral care, are strongly recommended as preventive strat-
egies. Systemic opioids to effectively treat mucositis-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
associated pain and close monitoring to nutrition and
hydration must be offered. Hospitalization for intra-
venous analgesics, nutrition and hydration is sometimes
necessary, as well as in those patients who developed
secondary infection.
As a consequence of mucositis, dysphagia and odyno-
phagia are commonly seen in HNSCC patients treated
with radiation therapy. The use of prophylactic feeding
tubes is controversial, but it may be necessary in some
high-risk patients (e.g., large radiation therapy fields,
previous severe weight loss) [15]. A recently published
randomized trial [16
] evaluating prophylactic gastro-
stomy in unresectable HNSCC treated with chemoradia-
tion demonstrated higher posttreatment quality of life
in those patients receiving systematic prophylactic gas-
trostomy, after adjusting for other potential predictive
quality of life factors. Swallowing (at least liquids) and
swallowing exercises must be always encouraged, even in
those patients having a feeding tube.
Xerostomia
Xerostomia is highly prevalent among HNC patients
treated with radiation therapy, with a significant negative
impact in terms of quality of life. Wijers et al. [17] reported
that 64% of long-term HNC survivors after conventio-
nal radiation therapy experienced a moderate-to-severe
degree of permanent xerostomia. It increases the risk for
developing dental caries and compromises oral mucosal
integrity, resulting in oral pain, loss of taste, difficulties
with swallowing and chewing, sleep disorders and oral
infections. Ultimately, this can lead to decreased nutri-
tional intake and weight loss.
Xerostomia is the result of radiosensitivity of salivary
glands, occurring during the first few days of radiation
therapy, when the radiation damage on plasma mem-
brane causes a signal transduction disturbance that
affects the watery secretion mediated through muscarine
receptor stimulation. A late damage seems to occur after
death of progenitor cells caused by radiation therapy,
thus preventing cell replacement. Extracellular micro-
environment changes after radiation therapy may also
play a role [18]. The severity of salivary dysfunction
depends on the dose received by salivary glands, the
irradiated volume and time elapsed after radiation
therapy. Braam et al. [19] reported an improvement of
32% in the salivary flow rate at 5 years after radiation
therapy, in comparison with 12 months after radia-
tion therapy, but other authors failed to demonstrate it
[20].
A recently published guideline by the American Society of
Clinical Oncology (ASCO) [21

] on the use of chemother-
apy and radiation therapy protectants recommended that
amifostine, as an acute and late xerostomia-preventive
 Supportive care in head and neck oncology de Castro and Guindalini
agent, may be considered in patients undergoing fractio-
nated radiation therapy alone, but not in those treated with
concurrent platinum-based chemoradiation. Three studies
[22–24] showed significant reductions in grade 2 or greater
acute or late xerostomia, but they were not placebo-con-
trolled. On the contrary, in the setting of platinum-based
chemoradiation, a placebo-controlled study [25] did not
show significant reductions in grade 2 or greater acute or
late xerostomia in 132 patients. No effect on tumor control
has been suggested for amifostine [26].
As the incidence of xerostomia is directly related to the
cumulative radiation dose in parotid glands, intensity-
modulated radiation therapy (IMRT) as a strategy to
sparing parotid glands is being studied to decrease both
occurrence and severity of xerostomia. Delivered doses
lower than 24–26 Gy seem to be crucial to preserve
salivary flow rates after radiation therapy [27]. The PASS-
PORT phase III study [28] included 94 patients with
T1–4 N0–3 oropharynx or hypopharynx SCC that were
randomly assigned to 65 Gy delivered in 30 fractions
(over 6 weeks) either conventionally or using IMRT.
The incidence of xerostomia at 12 months after radiation
therapy was the primary endpoint, measured by late
effects in normal tissues subjective, objective, manage-
ment and analytic (LENT-SOMA) and Radiation
Therapy Oncology Group (RTOG) scales. After a median
follow-up of 31.9 months, the incidence of grade 2
xerostomia at 12 months was 74 versus 40% (P ¼ 0.005,
LENT-SOMA) and 64 versus 41% (P ¼ 0.06, RTOG) for
those patients treated with conventionally delivered or
with IMRT, respectively, with no differences in terms of
progression-free survival, OS or other late toxicities rates
[28].
Pilocarpine is the only drug approved by U.S. Food and
Drug Administration for the treatment of radiotherapy-
induced xerostomia, and may be considered during
conventional radiotherapy in order to preserve parotid
function, but a phase III study [29] designed to assess
quality of life in patients receiving pilocarpine as a
hyposalivation-preventive agent failed to achieve any
difference on patients’ assessment of salivary function,
or quality of life, in those patients treated with pilocar-
pine, despite an objective preservation of salivary func-
tion. Many saliva substitutes may be useful to relieve
xerostomia-related symptoms. A phase I/II clinical trial
[30
], using a recombinant adenoviral vector to mediate
gene transfer, employing the aquaporin-1 cDNA to treat
patients with existing radiation-induced salivary hypo-
function is currently underway.
Skin toxicity, radiation dermatitis and epidermal growth
factor receptor-targeting agents
Radiation dermatitis occurs in the majority of patients
undergoing radiation therapy, and approximately 20–
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
223
25% develop severe skin toxicity [31]. This toxicity is
related to the total radiation therapy dose, the dose per
fraction, the overall treatment time, the beam type and
energy, the planned treatment area and concurrent thera-
pies such as conventional cytotoxic (platinum deriva-
tives) or molecular-targeted agents.
In addition to the well described acneiform rash associ-
ated with the epidermal growth factor receptor (EGFR)
inhibitors, many reports have indicated that these agents
may develop severe cutaneous reactions when admi-
nistered concurrently to radiation therapy [32,33]. Irradia-
tion of the skin leads to a complex pattern of direct
tissue injury and inflammatory cell recruitment, after
damage to epidermal basal cells and endothelial cells,
with a reduction in Langerhans cell population [34]. The
increased expression of EGFR in keratinocytes then
occurs, possibly as a mechanism for repopulating irra-
diated areas [35]. At the same time, EGFR-targeting
agents can inhibit basal keratinocytes and hair follicle
cell proliferation, leading to growth arrest and subsequent
inflammation [36]. It could explain the possible interplay
between radiation and EGFR-targeting agents in those
patients presenting severe and sometimes life-threaten-
ing skin toxicities when treated with radiation therapy
and concurrent EGFR-targeting agents such as cetuxi-
mab. Interestingly, there are some differences in terms of
incidence of the acneiform rash among the different anti-
EGFR antibodies. It seems to be less frequent and less
severe in those patients treated with nimotuzumab,
probably due to a different mechanism of EGFR inhi-
bition, determined by the way in which the antibody
binds to the receptor [37].
The first consensus guidelines [38

] on radiation derma-
titis and coexisting acne-like rash in patients receiving
radiation therapy and EGFR-targeting agents was pub-
lished in 2008. All patients should be encouraged to
maintain the irradiated area clean and dry, to minimize
the risk of infection. Sunlight exposure and skin irritants,
such as alcohol-based lotions, must be avoided. Topical
treatment for palliation of symptoms and to induce skin
healing may be helpful: drying paste for moist areas, gels
in seborrhoeic areas and creams outside skin folds and
seborrhoeic areas may be considered. The use of topical
corticosteroids is not contraindicated but the overall
treatment time should be as short as possible.
For mild reactions related to EGFR-targeting agents,
topical treatment with antiacne or antirosacea can be
used such as clindamycin or erythromycin gel. For mod-
erated reactions, topical treatment can be used in associ-
ation with an oral antihistamine (loratadine and hydroxy-
zine), when itching is present, and an oral tetracycline
(doxycycline 10 mg/day, minocycline 100 mg/day or
lymecycline 300 mg/day) [39].
 224 Head and neck
When grades 2 and 3 radiation therapy dermatitis devel-
ops in these patients receiving the EGFR-targeting
agents, antiseptic creams (chlorhexidine-based cream),
hydrophilic dressing, anti-inflammatory emulsion (e.g.,
trolamine, and hyaluronic acid cream) and zinc oxide
paste are useful. Medical judgment for management is
important in case of infection. Systemic antibiotics may
be necessary. Grade 4 radiation dermatitis, although
extremely rare, should be treated under the supervision
of wound care experts and sometimes need to stay in burn
care unit.
Anemia
Anemia occurs frequently in cancer patients and, as a
consequence, fatigue and compromised performance
and quality of life develop. Anemia has been demonstrated
to be a negative prognostic factor in HNSCC patients
treated with chemoradiation [40]. Red blood cells transfu-
sions are often prescribed to treat cancer-related anemia.
The use of erythropoiesis-stimulating agents (ESAs) in
HNSCC patients under radiation therapy or chemother-
apy is a matter of debate. Despite a clear improvement in
hemoglobin levels in those patients treated with ESAs,
worse survival outcomes, or neutral effects, were
observed [41–43]. More recently, Hoskin et al. [44
]
published a randomized trial on 301 HNSCC patients
treated with radiation therapy along with epoietin alfa or
radiation therapy alone. No difference was observed in
terms of disease-free survival or OS, tumor control, cancer
treatment-related anemia or fatigue.
In addition, a Cochrane systematic review [45] conducted
on five randomized controlled trials (RCTs) and 1397
patients showed a significantly worse OS (Peto odds ratio
0.73, P ¼ 0.005) and nonsignificantly worse local regional
tumor control (relative risk 0.92, P ¼ 0.15) in those
patients treated with ESAs. However, the target hemo-
globin concentration, which was higher than recom-
mended in four RCTs, may have had a significant role.
On the basis of these findings, ESAs should not be
administered to HNSCC patients under radiation
therapy or chemotherapy outside of the context of clinical
trials.
Conclusion
The best outcomes in HNSCC patients treated in the
multidisciplinary context can only be achieved with an
adequate patient selection, an experienced and motiv-
ated team and if the best possible supportive care is
offered. Suboptimal supportive care allied to poor nutri-
tional status, comorbidities and adverse social aspects
such as low income and low educational level, commonly
observed in patients diagnosed with HNSCC, are among
the most probable underlying causes of the low long-term
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
survival rates presented by HNSCC patients who are
candidates to aggressive therapies in the community
setting. The search for new prognostic and predictive
factors that will emerge from translational studies, and
adequately powered randomized studies on many prom-
ising supportive therapies must be encouraged in HNC
patients worldwide.
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
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