Critical Reviews in Oncology/Hematology 53 (2005) 7180

Treatment of head and neck cancer in elderly patients:

state of the art and guidelines
Daniele Bernardia, , Luigi Barzand , Giovanni Franchinb , Roberta Cinellia ,
Luca Balestreric , Umberto Tirellia , Emanuela Vacchera
a

Division of Medical Oncology A, National Cancer Institute, Aviano (PN), Italy

b Division of Radiotherapy, National Cancer Institute, Aviano (PN), Italy
c Department of Radiology, National Cancer Institute, Aviano (PN), Italy
d ENT Division, Ospedale S. Maria Degli Angeli, Pordenone, Italy
Accepted 5 August 2004

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72

2.

Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Standard radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Unconventional fractionation radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73
73
74

3.

Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

4.

Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76

5.

Combined modality treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

6.

General conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78

Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79

Abstract
Although the majority of head and neck cancers occur between the fifth and sixth decade, their onset in patients older than 60 years is not
a rare event.
A peculiar characteristic of almost all case series is the lower prevalence of radical treatments among elderly as compared to younger
patients, in particular surgery and combined treatment of surgery plus radiation therapy or chemotherapy and radiation therapy.
Radiotherapy is a feasible treatment in elderly patients, also in very advanced age groups and, in the era of organ preservation, chemotherapy
combined with RT has a paramount importance. Therapeutical planning must be based not only on tumor characteristics, but also on the
physiological, rather than the chronological age the patient. The main clinical problem is, therefore, the selection of patients to be administered
anticancer treatment. In patients aged 70 or older, complete geriatric assessment and a multidisciplinary approach are the crucial points.
2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Head and neck; Cancer; Elderly; Review

Corresponding author. Tel.: +39 0434659284; fax: +39 0434659531.

E-mail address: oma@cro.it (D. Bernardi).

1040-8428/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2004.08.001

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D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

1. Introduction
In western countries cancer-related morbidity and mortality increase progressively with age. About 60% of all tumors
arise in patients older than 65 years and 70% of all deaths
due to cancer occur in this age [14]. The majority of head
and neck (HN) cancers occur between the fifth and sixth
decade. Nevertheless, the onset of tumors in patients older
than 60 years is not a rare event. In a retrospective study conducted by the Italian Geriatric Radiation Oncology Group
(GROG), HN cancers were present in 12% (1112/9422)
of patients older than 70 years with different tumors, referred to 37 radiation therapy centers located in the whole
Italian territory [5]. In mono-institutional case series, mostly
European, elderly patients with an age between 70 and 75
years represent 632% of all patient with HN cancers. The
most frequent histologic type is squamous cell carcinoma and
the most frequent sites of disease are larynx and oral cavity
and, less frequently, oropharynx and hypopharynx. The distribution of stages is more or less superimposable to that of
the younger patients, with the exception of some case series
where a prevalence of stage N0 is present in elderly patients
(Table 1). A peculiar characteristic of almost all case series
is the lower prevalence of radical treatments among elderly
patients as compared to younger patients (3074% versus
6791%, P 0.001), in particular surgery and combined
treatment of surgery plus radiation therapy or chemotherapy
and radiation therapy. Overall survival is significantly lower
in elderly patients, with an actuarial rate at 5 years of 1731%
versus 3044% (P 0.001) in younger patients in the same
case series [511]. However, these differences tend to become
smaller and, sometimes to disappear, in the case series where
cancer-specific survival is analyzed and/or the groups of pa-

tients are homogeneous in terms of radicality of treatment

[11,12]. When considering cancer-specific overall survival,
the difference between the two groups was at borderline statistical level, being at 5-year 55% versus 59%, respectively,
P = 0.008). Cancer-specific overall survival was similar between the two groups for oral cavity and oropharynx cancer
(at 5-year 37% versus 50%, P = 0.4 and 44% versus 44%, P
= 0.5, respectively), whereas elderly patients with larynx and
hypopharynx cancer had a significantly worse 5-year cancerspecific overall survival than the younger counterpart (71%
versus 78%, P = 0.02 and 30% versus 42%, P = 0.05, respectively).
In the casecontrol study by the surveillance, epidemiology and result data base (SEER) of Baltimore, on 2508
cases of carcinoma of the larynx, tongue and tonsil in patients older than 50 years, cancer-specific survival of patients
older than 70 years has been shown to be superimposable to
that of patients of 5069 years, with the exception of stage
I and IV glottic carcinoma and stage III tonsil carcinoma,
whose cancer-specific prognosis has been demonstrated to
be worse and better in elderly patients, respectively (Table 2)
[12]. Noteworthy is the fact that both groups were homogeneous according to sex, year of diagnosis, tumor characteristics (all of them M0 ) and type of treatment. According to
the same group, the overall medical morbidity and mortality
rates were 5.65 and 2.98%, respectively. The presence of a
major medical complication increased the odds of death by
5.65 (P < 0.001). Post-operative pneumonia was the most
common medical complication (3.26%) and was associated
with a mortality rate of 10.94% (odds ratio for mortality, 4.4).
Acute myocardial infarction and stroke were rare (combined
incidence, 1.86%) and were not statistically associated with
increased mortality. Procedures that involved the esophagus

Table 1
Clinical characteristics of HN cancers in elderly patients
OLMI [7] (%)

Hirano [8] (%)

Sarini [9] (%)

Seer [10] (%)

Vaccher [11] (%)

Total
Age (years)
Year of diagnosis

365/1114 (32%)
70
19601992

751/2508 (30%)
70
19711995

273/4610 (6%)
75
19741983

9386/?
65
19851993

181/2143 (8%)
19751998

Site of disease
Oral cavity
Oropharynx
Larynx
Hypopharynx

32
28
40

12
17
22
25

40
29
25
9

39
20
42

23
17
49
10

61
39
72
13
14
2

TNM stage
T1 T2
T3 T4
N0
N1
N2 N3
M1
UICCb

62
38
81a
19

40
60
60

stage

I
III
Main case series from literature.
a N +N .
0
1
b UICC = Union Internationale Contre le Cancer.

31
69

52
48

D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

73

Table 2
Cancer-specific survival (CSS) in cancer of the larynx, tongue, tonsil in 2508
patients 70 years compared with 2508 patients <70 years

Table 3
Locoregional control (LRC) in 331 patients 70 years with HN tumorsa
treated with radiotherapy and stratified by stage (TNM)

Stage

Median CSS (months)

Stage

LRC at 3 years (%)

Larynx

8966
4741
88
71
46

<70

70

<70

70

<70

70

Primary tumor
T1 T2
T3 T 4

I
II
III
IV

118.5
96.1
95.0
101.4

109.4**
93.8
73.6
69.6*

105.3
94.2
52.3
60.9

97.8
78.3
45.4
45.3

102.7
80.0
36.2
57.8

62.2
88.6
71.2**
56.9

Nodal disease
N0
N1 N 2
N3

Total

114.1

105.9**

93.6

81.6*

70.7

71.5

From Lusinchi et al., modified, Int J Radiol O.B.P. (1990).

a Oropharynx 30%, larynx 28%.

Tongue

Tonsil

From Bhattacharyya et al., modified, The Laryngoscope (2003).

P 0.05.
P 0.01.

carried the highest mortality rate (8.38%). The overall mean

length of stay was 6.15 days. This increased to 17.7 days
when a major medical complication occurred (P < 0.001).
Nevertheless, in the analysis of the prognostic factors for
overall survival performed on the whole case-series in the
SEER elderly patients, constituted by 9386 patients older
than 65 years with the same type of HN tumor but not selected by stage and/or therapy, the main prognostic factor has
been shown to be comorbidity, as evaluated according to the
Charlson score. The risk of death correlates with the presence
of associated comorbidities, with a doseresponse relationship. The hazard ratio (HR) for patients with a Charlson score
of 1 is 1.33 (95% confidence interval [CI] 1.211.47) as compared to that of patients without comorbiditiy and the excess
rises up to 1.83 (95% CI: 1.642.05) if the morbidity score
is 2 (P 0.001). The presence of one comorbidity whatsoever is prognostically more important in patients with an
age between 65 and 74 years as compared to those older than
85 years, probably due to the lower life expectancy of the
latter group (HR 1.53, 95% CI 1.381.69 versus 1.32, 95%
CI 1.091.84) [10].
Aging is always associated with a multiorgan functional
decline, an increase in comorbidity and a decline of cognitive
functions [24]. The presence of these failures is very heterogeneous in the population of elderly patients and anagraphic
age by itself cannot be the only criterion for the therapeutic
planning.

2. Radiotherapy
2.1. Standard radiotherapy
External beam radiotherapy with conventional fractionation (180200 cGy/day for 5 days/week) (standard-RT) represents the most widely diffused form of treatment in HN
tumors in elderly patients. The biggest case series has been
published by the University of Florence, Italy, on 446 cases
of carcinoma of the larynx, oropharynx and oral cavity in patients older than 70 years, treated exclusively with RT with
curative intent, whose outcome has been compared to that of

patients <70 years with the same type and stage of tumor. In
this case series, laryngeal cancers were, in more than 90% of
cases, at early stage (T1T2), while in both groups the other
neoplasias were mostly in advanced locoregional stage. No
differences in 5-year actuarial local control (LC) or survival
with no evidence of disease (NED) were seen between the
two age groups for laryngeal and oropharyngeal cancer. For
patients with cancer of the oral cavity, LC was better in the
younger patients than in those aged 70 years and older (50%
versus 28%, P = 0.04). There was no statistically significant
difference in the NED survival between the two groups. Acute
or late reactions from RT in older patients were not different
from those observed in the younger patients [7].
Lusinchi and co-workers reported the Gustave Roussy experience on 331 elderly patients with an age 70 years affected by carcinoma of the larynx (28%), oropharynx (27%)
and oral cavity (16%) treated with radical RT (6570 Gy) in
84% of cases and with palliative RT (30 Gy) in the remaining 16% in poor general conditions. Overall, the treatment
was well tolerated with a grade 34 toxicity according to the
radiation therapy and oncology group (RTOG) score as follows: cutaneous 1%, mucositis only in 17%, but naso-enteral
feeding was required in 54% of cases. A reduced psychological tolerance due to depression, confusion or inability to
cooperate, affected the feasibility of RT in 6% of patients,
with a heterogeneous distribution in the age groups (5% in
patients 7075 years old, 9 and 21%, respectively, in patients
7580 years and 8085 years). Overall, the LC at 3 years was
71% for patients treated with radical dose and 19% for those
treated with a palliative dose. The analysis of the LC by stage
of disease showed similar data to those of historical control
groups with an age lower than 70 years (Table 3). Five-year
survival rates of 30, 27, 21 and 0% were observed for the
7075, 7579, 8085 and over 84 age groups, respectively.
In patients treated with palliative dose, the survival rate at 5
years was only 5% [13].
Thompson and co-workers reported 2 case series in patients older than 75 years, 68 of whom had laryngeal carcinoma, treated with radical RT in 59% of cases and 33 patients
with carcinoma of the hypopharynx, treated with curative intent in 52% of cases. The 3-year actuarial survival was 57%
in the group of patients with laryngeal carcinoma and 22%

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D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

Table 4
EORTC radiation trials in HN cancers (1589 patients): evaluation ad impact
of age on acute toxicity
Acute toxicity

Age
<70 years (%)

70 years (%)

Pa

G0
G1G2
G3

1
48
51

2
41
58

NS

Functionalc
G0
G1G2
G3G4

2
49
49

0
34
67

0.001

Objectiveb

From Pignon et al., modified, Eur J Cancer (1996).

a X2 test.
b One thousand three hundred and seven evaluable patients.
c Eight hundred and sixty eight evaluable patients.

in the group of patients with carcinoma of the hypopharynx

[14].
The GROG evaluated prospectively the feasibility of radical radiotherapy (mean dose 63.4 Gy) in 91 elderly patients
(age 7088 years) with laryngeal carcinoma, mainly (56%)
in stage III. Overall, the treatment was well tolerated, with
a mild (G2 according to RTOG) cutaneous and mucosal toxicity, respectively, in 11 and 38%, and severe (G3G4) in
1 and 5% [7]. The impact of age on the development of an
acute or chronic toxicity was evaluated by Pignon and coworkers on 589 patients with HN carcinoma treated with
radical RT in 5 protocols of the EORTC, activated between
1980 and 1995. The acute normal tissue reactions (mucositis
and weight loss) in elderly patients (70 years) was superimposable to that of younger patients, but, considering the
same objective damage, the severe subjective intolerance, defined as G3G4 functional acute toxicity, was significantly
more frequent in elderly patients (Table 4). No difference
was shown in the analysis of the late toxicity, whose latency
and severity were similar in the different age groups. In these
studies, where usually patients in very good general conditions and without important comorbidities were enrolled, the
loco-regional control (LRC) and the cancer-specific survival
were similar in all age groups [15].
Data on the use of RT in very old patients (8090 years)
are limited to few case series and have mostly been reported
together with other tumors [1618]. In the case-series of
Zachariah, on 203 patients older than 80 years, 50 patients
(25%) had HN cancer in different sites and stage of disease. Thirty-five of them (70%) were treated with radical RT
(median dose 65.9 Gy) and 15 (30%) with palliative RT (median 36.3 Gy). In the group treated with higher dose, 51%
of patients developed a mild mucositis (G1G2 according
to RTOG), 29% a moderatesevere mucositis (G3) and only
3% a severe hemorrhagic mucositis (G4). With supportive
therapy, mucositis disappeared in 46 weeks. In the group
treated with palliative RT, G1G2 mucositis was demonstrated in only 13% of patients. The objective response rate
was 86%, with 66% complete remission (CR) in the radically

treated group, while a palliation of the symptoms of the disease was obtained in 67% of patients treated with low dose
RT. Noteworthy is the fact that, overall, patients achieving a
CR presented a longer median survival of 25 months [16].
Mitsuhashi reported on 32 patients older than 90 years, 14 of
whom (44%) affected by HN tumors, 11 (79%) treated with
radical RT (median dose 61.2 Gy) and 3 (21%) with palliative
RT (40 Gy), discontinued for 23 weeks in 4 (36%) patients
of the first group due to G2G3 mucositis. The median survival in the radically treated patients was 8 months (range
355) while that of patients treated with palliative intent was
6 months [17].
2.2. Unconventional fractionation radiotherapy
Accelerated RT (fraction size of daily dose > 200 cGy)
and hyperfractionated RT (more than one fraction per day),
often used in combination, represent a promising method to
improve the treatment outcome in patients with HN carcinoma. Elderly patients, in general, are excluded from protocols with unconventional fractionated RT, due to the fear
of an increased toxicity, sometimes relevant also in younger
patients. A Swiss group recently published the first study
with an unconventional RT regimen (accelerated concomitant boost RT schedule), in a group of 39 patients older than
70 years with carcinoma of the hypopharynxlarynx (49%)
and of the oral cavityoropharynx (46%), compared with 81
patients <70 years. Elderly patients were in 79% of cases in
good general conditions (performance status, PS, 01) and,
in comparison with younger patients, had a more advanced
T stage (T3T4, 54% versus 30%, P = 0.01) but a less advanced N stage (N0 , 46% versus 72%, P = 0.01). The first
volume (the primary tumor area and both sides of the neck
down to the clavicles) received a dose of 50.4 Gy over 5.5
weeks given daily fractions of 1.8 Gy, 5 times a week. The
boost to the initial involved sites comprised of 13 fractions of
1.5 Gy (total 19.5 Gy) given as a second daily fraction beginning the last day of the second week. Withdrawal of treatment
due to toxicity occurred in only 8% of elderly patients and in
none of the younger patients. The median dose administered
(69.9 Gy, range 6773) and the median treatment time (41
days, range 3760) were similar in the two groups. Acute
and late toxicities were similar in the two age groups, as well
as LRC and overall survival (Table 5) [18].
In conclusion, RT is a feasible treatment in elderly patients, also in very advanced age groups and even with innovative schedules with unconventional fractionation. With
radical doses, it provides an LRC almost superimposable to
that obtained in younger patients with the same type of neoplasia. Although it could seem likely that equivalent results
can be obtained when the target volume is small, like in early
stages for larynx, oral cavity and oropharynx as compared to
more advanced stages, like in most hypopharingeal tumors
and N+ patients, in our experience, the irradiated volume is
not relevant in the comparative outcome of elderly versus
younger patients.

D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

Table 5
Severe toxicity and outcome of 120 patients with HN cancers treated with
accelerated radiotherapy, stratified by age

Table 6
Surgical treatment and post-operative complications in a case series of 438
patients with HN cancers, stratified by age

Patients
70 years (n = 39) (%)
Toxicitya
Acute
G3
G4
NET/PEGb
Chronic
Outcome at 3 years
Locoregional control
Overall survival

64
3
26
3
73
68

75

Age (years)
59 (%)

6069 (%)

70 (%)

Surgery
Resection En bloc

48***
47***

33***
35***

19***
20***

Complications
Local
Systemic

25
25

25
25

40
27

<70 years (n = 81) (%)

71

23
10
68
62

From Allal et al., modified, Cancer (2000).

a According to RTOG.
b Naso-enteral tube/percutaneous endoscopic gastrostomy.

Acute and chronic toxicities are similar to those showed

in younger patients, but subjective tolerance and sometimes
compliance are significantly lower as compared to the other
age groups. Therefore, this data show the need to increase
supportive medical and psychological therapy always during
and after treatment. Fragile patients seem to tolerate well
palliative radiation treatment, but the data from the literature
are at the moment too unclear to provide treatment guidelines
in this subset of patients. Finally, the fact that in certain stages
or sites of disease, in patients treated with radical therapy, the
outcome in elderly patients is more unfavorable as compared
to the younger ones prompts the activation of studies aimed
at evaluating the impact of age on the tumor biology.

3. Surgery
Surgery is still the most important treatment for solid tumors, including HN cancers, irrespective of age. Nevertheless, elderly patients have a higher potential operative risk
of morbidity and mortality due to the presence of comorbidity and physiologic reduction of functional reserve connected to aging. For example, elderly patients are more sensitive than younger patients to the volume depletions that
are often associated to wide resections and/or longer surgical
procedures typical of surgical oncology, and less resistant to
post-operative infections due to the progressive impairment
of the immune system [24,19]. The first studies on demolitive surgery in HN cancers in elderly patients date back to the
1970s and 1980s and show a significant increase in mortality
in patients older than 6570 years with a rate ranging from 3.5
to 7.4% versus 0.81.4% in younger patients [20,21]. The first
study of the 1990s was published by Barzan and co-workers
and evaluated the impact of demolitive surgery on a group of
107 patients older than 70 years, compared with 135 patients
aged 6069 years and 196 patients younger than 59 years.
As predictable, systemic contraindications to surgery and/or
refusal of surgery were more frequent in elderly patients as
compared to other patients. The number of patients under-

From Barzan et al., modified, J Laryngol Otol (1990).

P 0.001.

going en-bloc surgery was higher in the group of younger

patients, but post-operative local or systemic complications
were similar in all age groups (Table 6). Moreover, no difference was shown in LRC and cancer-specific survival among
the age groups. PS and stage of disease, but not age, were the
main prognostic factors for survival [22].
Clayman and co-worker in a group of 43 patients older
than 80 years, compared with 79 patients younger than 65
years, demonstrated the feasibility of demolitive surgery even
in very old patients. Although 93% of elderly patients fit in
the high anesthesiologic risk category (Group 34 according
the American Society of Anesthesiology [ASA]) classification) versus 63% of other patients (P 0.001), the complications were superimposable in the two groups, with a rate of
major complication in 23% in elderly patients versus 20% in
younger patients and of minor complications, respectively, in
28 and 23% of cases. The type of complications was different among the groups, with a higher prevalence of systemic
complications, in particular cardiovascular and pulmonary,
in the first group and a higher prevalence of local complications in the second group. Post-operative mortality was 2% in
the elderly and absent in the younger patients. Loco-regional
control at 2 and 5 years in patients stratified by stage of disease was similar in the two groups, whereas overall survival
was lower in elderly patients as compared to the control group
(at 5 years 33% versus 63%, P 0.001), but similar to that
of the population of the same age group [23]. According to
Mc Guirt and Davis, patients older than 75 years with locally
advanced stage of disease have a higher operative morbidity
and mortality risk as compared to the other age groups [24].
Conservation surgery, such as supraglottic laryngectomy,
reconstructive subtotal laryngectomy, conservation surgery
of base of tongue and hypopharynx, showed a moderate mortality rate in elderly patients (07%). The diffusion of conservation surgery in this population is mainly limited by the
scarce feasibility of a program of feeding and phonatory rehabilitation in the post-operative period. The low compliance to
rehabilitation in elderly patient, due to refusal and/or the lack
of an adequate familial and social support, seriously affects
the functional outcome of surgery and is frequently associated
with an increased risk of aspiration pneumonia [6]. According to Laccourreye, supracricoid partial laryngectomy, one of
the surgical treatments with a higher risk of inhalation of food

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D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

in the airways, is feasible in cooperative elderly patients. In

his series of 69 patients older than 65 years (median age 71
years), with a carcinoma of the glottic and supraglottic larynx (stage III 61%), mortality was shown to be absent and
the rate of surgical complications (13%) and medical complications (10%) during the operative procedure and in the
immediate post-operative period was similar to that reported
in younger patients. Twenty-two percent of patients showed
an inhalation pneumonitis in the first 6 months of follow-up
and 1% died after 3 years, due to pulmonary complications.
Nutritional rehabilitation after this surgical procedure must
therefore be continued for a long period of time [25].
Age does not affect the outcome of reconstructive surgery
with free flaps, whose engraftment occurs overall in 95100%
of elderly patients [2631]. Nevertheless, patients older than
70 years, with important comorbidities, show a rate of local complications, such as ischemic necrosis, significantly
higher as compared to younger patients without comorbidities (12% versus 8% in the case series of Pompei) [30].
Patients older than 80 years examined by Blackwell, 92 %
with ASA 34 class, have a rate of medical intra- and postsurgical complications higher than that of younger patients
(62% versus 15%, P = 0.02), after reconstructive surgery with
free flaps. Considering the same ASA class, the incidence of
complications is still higher in patients older than 80 years
and is correlated with the duration of the surgical procedure
[31].
The advances in anesthesiology techniques, in perioperative monitoring and in post-operative support allow now
to face with lower risks surgical procedures in older patients
as well. In general, in tumors of the oral cavity, surgical procedures including wide reconstructions (skinbonemucosa)
and revascularized flaps are more difficult to be performed.
In the carcinoma of the oropharynx, wide resections of base
of tongue or of the lateral wall more easily can lead to chronic
inhalation and therefore should not be performed. In the carcinoma of the larynx and hypopharynx, conservation surgical
procedures must be weighted in relation to the entity of the
predictable resection, the patients respiratory function and
his/her possibility to cooperate in a post-operative rehabilitation program.
Chronological age should not be considered a limit for
neck dissection. Appropriate surgery treatment should be offered to elderly patients with N0 disease but at high risk of
relapse/distant metastases. The deterioration of the general
conditions, that inevitably occurs as time goes by, and the
diagnostic delay following the impossibility of an adequate
follow-up, can often render non-feasible the salvage surgery
in elderly patients [6]. In this setting, despite advances in conservative laryngeal surgery and radiotherapy, total laryngectomy remains a valuable and reliable treatment for advancer
pharyngo-laryngeal cancers in elderly patients
The classification of the operative risk according to the
ASA score does not seem to have a predictive value in elderly patients. An integration of a comprehensive geriatric
assessment (CGA) is needed.

Transoral laser surgery has achieved a key position in minimally invasive treatment concepts in the ears, nose and throat
area, especially for the treatment of malignancies of the upper
aerodigestive tract. The CO2 laser is the approach most commonly used. In the hands of experienced surgeons it remains
a valuable option for elderly patients since it is a minimally
invasive, functional and rapidly performed treatment [32].

4. Chemotherapy
Elderly patients are often excluded from chemotherapy
clinical trials, because they are considered subjects at high
risk for toxicity from cytotoxic drugs [1]. A theoretical background exists for an increase in toxicity, but clinical studies, aimed at evaluating the relationship between toxicity
from chemotherapy and age, are very few [33]. Standard
chemotherapy for HN carcinomas is the Al-Sarraf regimen, a sequential combination of cisplatin and infusional
5-fluorouracil (5-FU) that, in the treatment of locoregional recurrences and/or distant metastases achieves a response rate
of 4050% (CR 510%) and in neoadjuvant setting (CTRT)
for organ preservation of 7088% (CR 4060%) [34]. The
reduced functional reserve of elderly patients can potentially
alter the pharmacokinetic of cytotoxic drugs and reduce the
capacity of healthy tissues to recuperate. Moreover, polypharmacy, typical of the older age can be responsible for pharmacokinetic and pharmacodynamic interactions between the
different types of drugs. Table 7 reports data on toxicity of cisplatin and 5-FU in elderly patients with miscellaneous solid
tumors [24,33,35]. Cisplatin is associated with an increase
in peripheral neuropathy, anemia, and nephropathy. Generally, sensory-motor peripheral neuropathy initially arises
with paresthesia, loss of deep tendinous reflex and tactile
sensitivity and then with muscular weakness that sometimes
severely affects patients autonomy [33,35]. In vitro studies
have demonstrated that elderly patients have a reduced capacity to repair cisplatin-induced DNA damages. The inter-chain
bindings that are present on the monocytes of young subjects
treated with cisplatin, are almost completely eliminated afTable 7
Acute toxicity related to cisplatin and 5-fluorouracil in elderly patients
Toxicity
Cisplatin
Peripheral neuropathy
Anemia
Nefrotoxicity
5-Fluorouracil
Cardiotoxicity
Mucositis

Leukopenia

Cause
Reduced capacity of DNA-damage
reparation
Pharmacokinetic alterations
Multiorgan functional reduction
Reduced glomerular filtration rate
Cardiomiopathy
Pharmacokinetic alterations
Reduced intracellular concentration of
dihydropirimidine carboxylase
Reduced bone marrow reserve

D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

ter 2448 h from the exposure to the drug. In the monocytes

from elderly patients, the capacity to repair after 48 h is significantly lower and has a higher degree of inter-individual variability as compared to younger patients [36]. Treatment with
5-FU, mostly administered in continuous infusion at high
dose, determines in elderly patients a potential increase in
cardiotoxicity, mucositis and leukopenia. Cardiotoxicity has
its main cause in the frequent co-existence of a cardiomyopathy and/or alterations in electrolytes that occur during treatment. Mucositis is in general more severe than in younger
patients and requires significantly longer time to recuperate.
One the main risk factors is the physiologic decline in aging
of the intracellular concentration of the dehydropirimidine
decarboxylase, the main enzyme involved in the catabolism
of the drug. Leukopenia is mostly determined by a reduction in the bone marrow functional reserve and its severity is
strictly related to the age of the patient [33,35,37].
Schneider reported on 71 patients aged 70 or older treated
with cisplatin and 5-FU, with an age-adjusted dose regimen.
Patients aged 7079 years were treated with standard-dosage
of cisplatin 100 mg/m2 /day 1 and 5-FU 1000 mg/m2 /day continuous infusion for 5 days, while those aged 8084 years
with a reduction of the dosage by 20% and those older than
85 years with a reduction of the dosage of 30%. The objective
response rate was 79% (CR 52%) among the 54 patients aged
7079 years and only 31% (CR 6%) among the 17 patients
aged 80 or older. In the group of patient older than 80 years,
patients responsive to chemotherapy were in better general
conditions as compared to the non-responsive patients. Myocardial ischemia, the only form of cardiotoxicity that was
examined in this study, was very low and superimposable in
the two age groups, with a rate of 2% in the first group and 3%
in the second [38]. Chemotherapy seems to be feasible also in
patients aged 80 years or older, but a reduction in the dosage
dependent only on the chronological age can seriously affect
the efficacy of the treatment.
The Eastern Cooperative Oncology Group (ECOG) has recently analyzed data from two randomized studies employing
intensive cisplatin-based regimen for the treatment of patients
with recurrent/metastatic HN carcinoma, to evaluate the
outcome of elderly patients. Fifty-three patients aged 7080
years had comparable response rates (28% versus 33%) and
survival outcomes (1-year survival 26% versus 33%) compared with 346 younger patients. However, severe nephrotoxicity, thrombocytopenia and diarrhea were more common
in the elderly than in the younger patients, occurring in 8%
versus 2% (P = 0.04), 26% versus 12% (P = 0.009) and 17%
versus 3% (P = 0.0002), respectively [39]. Strategies to ameliorate toxicity should be pursued in the elderly.
In the era of organ preservation, chemotherapy combined
with RT has a paramount importance in the treatment of HN
tumors [34]. Elderly patients, an emerging problem for public health in the industrialized countries, cannot be excluded
a priori from programs of organ preservation. Patients aged
7079 years who are independent on the functional point of
view and do not show severe comorbidities must be treated

77

in the same exact manner as younger patients, but during the

treatment, supportive treatment must be increased. In particular the administration of bone marrow growth factors, such
as G-CSF and erythropoietin (rhEpo) must be always evaluated. Data concerning the use of rhEpo in the prevention
of chemotherapy-related anemia in early or advanced HN
cancer are not extensive [4043]. The role of recombinant
rhEpo in preventing or correcting chemotherapy-related anemia in elderly patients with HN cancer has been recently
focused by Gebbia et al. [43]. In this study, recombinant
rhEpo is able to prevent anemia, to reduce transfusion requirements and improve quality of life parameters in patients
treated with carboplatin and 5-FU as compared to untreated
controls.
The use of amifostine in the prevention of mucositis from
CT is still controversial and should be eventually considered
only when RT is administered [44]. On the other hand, topical
use of GM-CSF, administered as oral gargles, might accelerate the resolution of mucositis, even if an improvement of
the quality of life has never been clearly demonstrated.
In all patients particular attention should be paid to maintain an adequate nutritional status, since malnutrition can
affect both efficacy of chemotherapy and patients survival
[24,33,35]. In fact, nutrition is often deficient in elderly patients in general, due to several reasons, such as depression,
poor dentition, functional impairment, cognitive impairment,
lack of appetite due to chronic comorbid disease, and lack of
caregiver. Elderly patients with cancer may also face additional problems brought on by chemotherapy, such as nausea, vomiting, diarrhea, and painful oral ulcerations. Correcting malnutrition and establishing a suitable dietary plan are
simple measures that can substantially improve the patients
clinical outcome and quality of life.
The main concern with respect to emotional conditions
in these patients is depression, which is common in both
geriatric and oncology populations, and is therefore especially common in elderly patients with cancer. Depression
and cognitive disorders can be mistaken for each other and
either type of condition could adversely affect the patients
functional status and the outcome of cancer treatment.
Patients older than 80 years, patients not functionally independent and/or with severe associated comorbidities, must
be treated in the setting of new treatment protocols, in which
the choice of the regimen employed and the dose of the
drugs must be adjusted according to a comprehensive geriatric evaluation (CGA)-based score. CGA is an instrument
aimed at evaluating the overall status of the patient and its
efficacy has been documented by several randomized study
[24,33,35,45]. We recently described the preliminary results
of an ongoing trial using CGA to tailor the treatment of patients affected by aggressive non-Hodgkins lymphoma; to
date, 23 patients have been treated with reasonable efficacy
and toxicity [46]. Noteworthy is the fact that in none of the
studies concerning treatment in HN cancers that have been
published so far in the literature, a CGA has been used in the
evaluation of the clinical status of the elderly patient.

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D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

5. Combined modality treatment

To address locoregional control and systemic tumor dissemination, combined modality therapies have been evaluated. To date, induction chemotherapy has failed to improve
survival rates conclusively. However it has been used successfully with subsequent radiotherapy in studies aimed at organ
preservation. Similarly, adjuvant chemotherapy has not been
clearly demonstrated to be effective [47].
A number of important factors should be considered in
deciding the best therapy for the patient when chemoradiotherapy is used in a combined modality plan for the curative treatment of locally advanced HN cancer. It is essential
to identify appropriate patients for combination therapy. Patients with underlying comorbidities, age-related frailty, or
underlying severe psychosocial problems are not good candidates for highly intensive treatment plans. Many physicians,
however, are pressured to overestimate patient tolerance to
qualify a patient for the best treatment. These patients may
be better served by less complicated or less potentially toxic
treatment plans. The biology of the patients disease also must
be considered in selecting or planning a combined modality
approach. Patients with rapidly growing tumors or with advanced nodal presentation are less likely to be cured with
surgery or radiation therapy alone and are most likely to benefit from the addition of chemotherapy. The location and local
extension of the primary tumor is also an important factor in
selecting therapy. Small lesions in the larynx, base of tongue
and hypopharynx may benefit from an organ preservation approach, while similarly sized lesions in the anterior oral cavity
might be better treated with direct surgical and radiotherapy
approaches. The goals of chemotherapy in a treatment plan
must be considered in determining the best therapy: appropriate goals in the curative treatment of locally advanced HN
cancer include organ preservation, improved survival, optimization of quality of life and reduction in metastases [34].
A recent study by Airoldi et al. [48] assessed treatment
toxicity, patient compliance, and clinical results in 40 patients >70 years who were treated with concomitant adjuvant
chemoradiotherapy. The results of this study confirm previously established beliefs that adjuvant chemioradiotherapy
can be successfully applied in older patients who are fit to
receive such treatment. The role of the combination therapy
in the post-operative setting can only be validated by phase
III trials. A comparison of the results of the study by Airoldi
with those of the group 70 years or older treated with radiotherapy alone suggests that superior results can be obtained
with chemoradiotherapy compared with radiotherapy alone
in this age group.

6. General conclusions
In HN cancers in elderly patients, as well as in all other
tumors, therapeutical planning must be based not only on
tumor characteristics, but also on the physiological, rather

than the chronological age the patient. The main clinical

problem is, therefore, the selection of patients to be administered anticancer treatment. In patients aged 70 or older,
CGA and a multidisciplinary approach are the crucial points
for an adequate therapeutical planning. A determinant factor in the prognosis of the patient with HN tumors of any
age is the multidisciplinary management of the disease. Surgeons, radiation-therapy specialists, medical oncologists and
geriatricians must actively cooperate in a multidisciplinary
setting.

Reviewers
Dr. Ashok R. Shaha, MD, FACS, Memorial SloanKettering Cancer Center, Head and Neck Service, 1275 York
Ave, New York, NY 10021, USA.
Prof. Francois Eschwege, Departement de Radiotherapie,
Institut Gustave Roussy, 39, rue Camille Desmoulins, F94805 Villejuif, France.
Prof. Jean-Claude Horiot, Directeur, Centre de Lutte contre le Cancer G.F. Leclerc, 1, rue Marion, BP 77980, F-21079
Dijon, France.
Dr. Philippe Pasche, Privat Docent & MER, Medecin Adjoint, Service dORL et de Chirurgie Cervico-faciale, Centre
Hospitalier Universitaire Vaudois (CHUV), Av. du Bugnon,
CH-1011 Lausanne, Switzerland.

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Biographies
Daniele Bernardi M.D. was born in 1961 and graduated at the University of Padova in 1988, where he obtained the Specialty Degree in Medical Oncology in 1994.
He is a Member of the American Society of Clinical Oncology (ASCO) and the Italian Society of Medical Oncology
(AIOM); he is presently a Staff Physician at the National
Cancer Institute of Aviano, Italy. He has performed several observerships in highly esteemed institutions abroad,
including the Karolinska Institute of Stockholm, Sweden,

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D. Bernardi et al. / Critical Reviews in Oncology/Hematology 53 (2005) 7180

the Stanford University of Palo Alto, CA, USA and the H.

Lee Moffitt Cancer Center of Tampa, FL, USA. His current research interests include tumors in the elderly, genitourinary tumors and HIV-related malignancies, areas where
he has authored numerous published articles.
Luigi Barzan is the chairman of the Division of Otolaryngology, General Hospital of Pordenone and consultant at the
Centro di Rifermento Oncologico of Aviano, Italy. His activity is focused on head and neck oncologic surgery. He
has published over 130 papers in Italian and international
journals, participates in many mono- and multi-institutional
research projects and protocols of therapy and is an active
member of scientific societies.
Giovanni Franchin is a full time hospital assistant at the
Division of Radiotherapy of the Centro di Riferimento Oncologico of Aviano, Italy. His areas of interest are therapy
of solid tumors, Head & Neck cancer, Lung cancer, Thyroid
cancer, Innovative Radiotherapy Modalities (Conformal Radiation Therapy and IMRT). He is a member of the ESTRO
organization.
Roberta Cinelli is a specialist in Infectious Diseases and
works at the Division of Medical Oncology A of the Centro
di Riferimento Oncologico of Aviano, Italy. She is involved
in several mono- and multi-institutional research projects
and protocols of therapy. She is author and co-author of over
20 publications in international journals.

Luca Balestreri is full time hospital assistant at the Division of Radiology of the Centro di Riferimento Oncologico
of Aviano, Italy. His areas of interest are: Magnetic Resonance Imaging, Computerized Tomography and Interventistic Radiology, particularly regarding early diagnosis and
staging in oncologic setting.
Umberto Tirelli is the director of the Department of Medical Oncology and the head of the Division of Medical
Oncology A at the Centro di Riferimento Oncologico of
Aviano, Italy. His activity is focused on tumors, in particularly tumors in the elderly, malignant lymphomas and
new antineoplastic drugs; on infectious diseases (neoplastic complications, sexual transmission, discrimination); and
recently on CFS. He has published over 540 papers in the
most important international and national journals. He also
participates in many mono- and multi-institutional research
projects and is an active member of international scientific
societies.
Emanuela Vaccher works as a Senior Assistant at the Division of Medical Oncology A at the Centro di Riferimento
Oncologico of Aviano, Italy, She is an active member of the
Head-Neck cancer CRO Committee and the Chief of the
Terapia medica dei tumori del capocollo Unit. She coordinates the activity of the Scientific Secretariat for the Italian Cooperative Group on Tumors and AIDS (GICAT). She
authored over 250 publications and more than 280 communications.