Journal of Cranio-Maxillofacial Surgery (2008) 36, 75e88

Ó 2007 European Association for Cranio-Maxillofacial Surgery

doi:10.1016/j.jcms.2007.06.007, available online at http://www.sciencedirect.com

Preoperative chemoradiotherapy in the management

of oral cancer: A review

Clemens KLUG, MD, DMD, PhD,1 Dominik BERZACZY, MD, Martin VORACEK, DSc, PhD,2
Werner MILLESI, MD, DMD, PhD3
1
Hospital of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, AKH, Währinger Gürtel 18-20,
A-1090 Vienna, Austria (Head: Ewers Rolf, MD, DMD, PhD); 2 Department of Basic Psychological Research,
School of Psychology, University of Vienna, Liebiggasse 5, A-1010 Vienna, Austria (Head: Leder Helmut, PhD);
3
Department for Oral and Maxillofacial Surgery and Dentistry and Ludwig Boltzmann Institute for Gerostomatology,
Hospital Hietzing, Wolkersbergenstrasse 1, A-1130 Vienna, Austria (Head: Millesi Werner, MD, DMD, PhD)

SUMMARY. Introduction: Multi-modality treatment concepts involving preoperative radiotherapy (RT) or che-
moradiotherapy (CRT) and subsequent radical resection are used much less frequently than postoperative treat-
ment for oral and oropharyngeal squamous cell carcinomas. In some centres, however, the preoperative
approach has been established for several years. Material: The present review is a compilation of the existing
evidence on this subject. Methods: In a literature-based meta-analysis, the survival data of 1927 patients from
32 eligible publications were analysed. Results: The calculated survival rates of documented patients show re-
markably good results with preoperative CRT and radical surgery. However, the findings of this analysis are
based on data with a large proportion of studies using consecutive patient series. Conclusion: Hard evidence
providing sufficient data from prospective randomised studies is as yet missing for preoperative CRT. Prospec-
tive randomised studies are mandatory in this area. Ó 2007 European Association for Cranio-Maxillofacial
Surgery

Keywords: oral cancer, preoperative, chemoradiotherapy

INTRODUCTION method is advantageous regarding morbidity and quality-

Oral and oropharyngeal cancers constitute the sixth most
common cancer in the world. The global ratio of deaths
to registrations is 0.46 for oral cancer and 0.64 for pha-
ryngeal cancer (Warnakulasuriya, 2005). Patients are
treated by surgery, radiotherapy (RT), chemotherapy
(CT), and combinations of these procedures. In cases
of limited disease (T1e2, N0), monotherapy consisting
of either surgery or RT is deemed sufficient; there is una-
nimity of opinion concerning the oncological prognosis
of this approach. In cases of advanced operable cancers,
usually combinations of surgery and RT with or without
CT are used pre- or postoperatively (Lung et al., 2007) or
in maximised multi-modality treatment (Kovacs, 2006).
Inoperable advanced tumours are usually managed with
a combination of RT and CT. Currently there is no con-
sensus of opinion regarding the chronological sequence
of surgery, RT, and/or CT. In literature searches, studies
employing adjuvant strategies of RT or chemoradiother-
apy (CRT) after surgery outnumber those of preoperative
concepts. Nevertheless, for about 20 years, preoperative
therapy concepts have been established as the standard
approach in some centres, and are rated positively in an-
alytical reports. The published literature fails to provide
sufficient data as to whether there is a prognostic differ-
ence between the two approaches for the treatment of ad-
vanced operable tumours. Likewise, it is not clear which
of-life after therapy. The aim of the present review is to
summarise all available experience with concepts of pre-
operative CRT, not to provide treatment recommenda-
tions or guidelines.
METHODS
Search strategy and selection criteria
Relevant studies were identified and retrieved through 10
searches in PubMed. The search terms used and the study
exclusion criteria are given in Table 1. These searches,
performed up to July 15, 2005, yielded a total of 2941
articles, of which 2914 articles were excluded at this
stage. Studies were eligible if published later than 1985
(excluding historical treatment regimes); if tumours in
the oral cavity and the oropharynx constituted less than
45% (arrived at by selection in the primary screening
of literature) of all included tumours; or if the primary tu-
mours were not diagnosed as advanced squamous call
carcinoma (SCC). Studies referring to therapeutic con-
cepts other than preoperative CRT or preoperative RT
were also excluded. Articles which were identified as du-
plicate publications, or had sample overlap with other
articles, were not clearly related to the topic, or did not
report the required information, were also excluded.
The literature searches were restricted to European

75
76 Journal of Cranio-Maxillofacial Surgery

Table 1 e Literature search strategy by keywords

Searches 1 2 3 4 5 6 7 8 9 10
Keywords Oral cancer + keywords below Head neck cancer + keywords below
Preoperative x x x x x x x x x x
Radiochemotherapy x
CRT x
RT x x x x
CT x x
Chemoradiation x x
Total hits per search 22 13 78 283 2 83 153 647 1549 111

Excluded because of
Publication date 0 0 6 91 0 0 2 64 483 0
Localisation 0 0 5 25 0 53 135 453 766 105
Diagnosis 0 0 1 2 0 0 0 15 12 1
Therapeutic concept 0 0 14 25 0 1 3 22 29 0
Redundant data 5 3 9 11 1 8 3 14 16 2
Lack of data 12 6 30 103 0 14 6 61 211 0
Found in previous 0 1 7 11 1 5 4 12 19 3
searches
Language 0 0 1 9 0 1 0 5 7 0
Excluded per search 17 10 73 277 2 82 153 646 1543 111
Included per search 5 3 5 6 0 1 0 1 6 0

x, Buildup of search terms; numbers indicate retrieved, excluded, or included studies.

languages. Additional searches in the EMBASE data-
base, congruent with those detailed above, revealed no
further studies. Next, the reference lists of all articles re-
trieved from the PubMed searches, which were eligible
for inclusion, were searched for citation of possible fur-
ther studies of relevance. This procedure yielded four fur-
ther studies. Then, cited reference searches for all eligible
studies were performed in the ISI Web of Science. This
prospective search strategy yielded one further study.
The final sample of 32 studies included in the meta-anal-
ysis was consensually selected by two investigators (CK
and DB).
sampling error, but rather due to between-study heteroge-
neity. Overall, the significance level was set to p\ 0.05.
In order to better understand the impact of different study
characteristics, taken as predictor variables, we also per-
formed an ecologic regression analysis of reported sur-
vival rates. For this model, survival rate was taken as
the dependent variable and years of survival estimation
(1, 2, 3, 4, or 5 years), the midpoint of study enrolment
period (data estimated for three studies with lacking
data), the organ preservation protocol (yes or no), and
the preoperative protocol (RT vs. CRT) served as the pre-
dictor variables.

Data extraction RESULTS

Data extraction from the individual studies was done in-
dependently, according to a previously created data ex-
traction sheet, by three investigators (CK, DB, and
MV). When the extracted information was discordant
across investigators, consensus was achieved by joint
discussion. Survival rates for the longest available period
were taken out of the text, tables, or KaplaneMeyer
diagrams.
Statistical methods
We performed a meta-analysis of the single-group sur-
vival rates reported in 32 studies via the generic inverse
variance method implemented in the RevMan software
(The Nordic Cochrane Centre, 2003). Since the survival
rates analysed here were not extreme (i.e., neither very
low nor very high), no data transformation was applied.
Between-study heterogeneity was assessed with the Hed-
ges Q statistic and the I2 statistic (Higgins et al., 2003).
The latter ranges between 0% and 100%, measuring
the degree of between-study inconsistency in results,
and is interpreted as the approximate proportion of total
between-study variation in estimates not resulting from
Included studies
Based on the inclusion criteria, 32 publications (totalling
2978 patients) from 10 countries (see Fig. 1) were eligi-
ble for the meta-analysis. These included (a) three pro-
spective randomised studies (676 patients), (b) 15
prospective non-randomised studies (948 patients), and
(c) 14 retrospective analyses of consecutively treated
patients (1354 patients). There were 27 single-centre
studies (2125 patients) and five multi-centre or multina-
tional studies in the sample. Depending on the outcomes
investigated, subsequent analyses were based on the fol-
lowing patient sample sizes: 2978 (total), 2015 (preoper-
ative treatment concept), 1927 (stage III/IV survival
data), 1257 (histopathological response data), and 928
(data of treatment-related mortality). Studies were
weighted according to meta-analytical convention (in-
verse of the precision of the effect size).
Treatment description
All studies included at least one study arm in which a pre-
operative treatment concept was used (see Table 2 for

Fig. 1 e Centres applying a preoperative treatment protocol.
details). This included preoperative CRT (22 studies;
1339 patients), RT alone (six studies; 547 patients), or
a mixture of both (four studies; 129 patients). For further
analysis, the latter group of studies was either assigned to
the CRT or the RT group, according to the predominant
mode of preoperative treatment used. In 25 studies (1601
patients), surgery was applied in all cases. In seven stud-
ies (414 patients) treatment was adapted to the response
to induction CRT or RT, radical RT for good responders
and surgery for the other patients. In one study (Valente
et al., 1993) (28 patients), preoperative CRT and postop-
erative RT were performed. Preoperatively administered
total doses to the focal tumour ranged from 20 to 60 Gy,
with a median of 45 Gy, delivered in 25 (median) indi-
vidual fractions. Chemotherapeutic agents used were
platinum-based cytostatics, taxans, 5-FU, mitomycin or
combinations of these (in one study CT was administered
intra-arterially; Robbins et al., 2004).
Patients
Across the 32 studies, a total of 2015 patients (79.6%
men, 20.4% women) were treated with a valid therapy
concept for histologically confirmed SCC. The median
age of the patients at the time of diagnosis was 57.2 years
(range, 32e83 years). The tumours were exclusively lo-
cated in the oral cavity and the oropharynx in 22 studies
(1381 patients), whereas other locations, such as the hy-
popharynx and the larynx, were included in nine studies
Preoperative chemoradiotherapy in the management of oral cancer 77
(593 patients; proportion of oral sites: 45e79%). One
study (Chang et al., 1988) (41 patients) lacked precise
data, but the tumours were ‘‘predominantly’’ in oral sites.
Fifteen studies (732 patients) reported exclusively on
stage III/IV tumours, the remaining 17 studies (1283)
had a median percentage of 80.0% stage III/IV tumours.
In five of the latter group of studies survival data for
stage III/IV patients were available (Table 3, footnote
h). For survival analysis we used the stage III/IV data
if available. The overall percentage of stages III/IV of
the analysed patients was 91.7%. Across all studies,
the median follow-up period was 47 months (median
range, 20.4e84.6 months, data missing for five studies).
Treatment-dependent mortality was reported in 13 stud-
ies (median rate, 5%; range, 0e9.4%).
Histopathological response evaluation
Tumour response to preoperative RT or CRT was ana-
lysed by histological investigation of surgical specimens
in 22 studies (Table 3) (Knobber et al., 1987; Chang
et al., 1988; Dobrowsky et al., 1991; Slotman et al.,
1992; Valente et al., 1993; Chougule et al., 1994; Mohr
et al., 1994; Muller et al., 1994; Zamboglou et al.,
1994; Glicksman et al., 1997; Goodman et al., 1997; Wa-
nebo et al., 1997, 2001; Kirita et al., 1999, 2001; Giralt
et al., 2000; Brun et al., 2001; Hermann et al., 2001; Eck-
ardt et al., 2002; Uno et al., 2003; Robbins et al., 2004;
Klug et al., 2005b). In the studies in which all subjects
Table 2 e Summary of studies selected for meta-analysis

78 Journal of Cranio-Maxillofacial Surgery

Ref. Country Organ Study type Enrolment N tot. N tot. Age m/f % Oral % III/IV Treatment Total RT Fractions
preservation period study preop. RT dosage

Knobber et al. D n p 1973e1984 87 87 54m (36e76) 71/16 100.0 75.9 rt 49.1 20e25
(1987)
Kramer et al. US n p, ra, mu 1973e1979 277 43 na 35/8 100.0 89.3 rt 50 25
(1987)
md
Chang et al. (1988) US y* p 1984e1987 43 41 60 (36e80) 33/10 na 100.0 cis 45 25
Dobrowsky et al. A n p 1985e1988 70 70 56md (29e79) 62/8 100.0 97.0 mmc, 5-FU 50 25
(1991)
Slotman et al. US n r 1982e1988 53 41 62m (44e84) 51/2 52.8 100.0 cis 45 25
(1992)
md md
Hansen et al. DK n r 1969e1985 62 62 63.6 (27e87) 31/31 100.0 59.7 rt 45 23md
(1993)
Valente et al. I n p nae1990 28 28 58.5md (24e79) 26/2 100.0 100.0 cis, 5-FU 20x 10
(1993)
Chougule et al. US yy p 1984e1990 68 68 na 51/17 45.0 100.0 cis 45 25
(1994)
Glicksman et al. US yy p 1983e1992 101 101 64md (29e84) 89/12 45.0 100.0 cis 45 25
(1994)
m
Mohr et al. (1994) D n p, ra, mu 1989e1992 268 127 54.6 103/24 100.0 95.2 cis 36 18
Muller et al. D n p 1986e1991 136 101 57md 109/27 100.0 80.0 cis 39.6 22
(1994)
Zamboglou et al. D n p, mu 1987e1991 103 30 57md (31e77) na 79.0 98.0 carb 50 25
(1994)
m
Olasz et al. (1996) H n r 1976e1993 50 50 56 42/8 100.0 76.0 rt 51.1 25e30
Glicksman et al. US (CH) yy p, mu, mn 1992e1996 74 74 61md (42e80) 59/15 48.6 100.0 cis 46.8 26
(1997)
Goodman et al. US n r 1990e1996 40 40 62.8m 27/13 56.8 100.0 cis 45 25
(1997)
Wanebo et al. US n p na 35 35 (40e71) 29/6 45.7 100.0 pac, carb 45 25
(1997)
md
Kirita et al. (1999) J n r 1988e1994 48 48 58.5 (43e84) 30/18 100.0 85.4 cis/carb, pep/5-FU 40 20
Szabo et al. (1999) H (A, D) n p, ra, mu, mn 1986e1991 131 48 52.6m (35e69) 83/12 100.0 100.0 rt 46 23
Giralt et al. (2000) E y* p 1993e1996 62 62 57md (39e74) 56/6 100.0 100.0 cis, 5-FU 60 33
Kurita et al. (2000) J n p na 20 20 na na 100.0 100.0 cis (50%) 30e40 15e20
Brun et al. (2001) SE n r 1990e1994 39 39 61md (22e79) 26/13 100.0 61.5 cis, 5-FU (10%) 50 25
Chao et al. (2001) US n r 1970e1999 430 109 58md (33e83) 80/29 100.0 71.0 rt 30md na
(28e72)
Hermann et al. D n r 1995e1996 43 43 55md (41e96) 41/2 100.0 100.0 ifo/cis 30 20
(2001)
md
Kirita et al. (2001) J n r 1988e1999 43 43 59.8 (26e85) 32/11 100.0 69.8 cis/carb, pep/5-FU 40 20
Wanebo et al. US yy p 1995e2000 43 43 (37e81) 33/10 67.4 100.0 pac, carb 45 25
(2001)
Eckardt et al. D n r 1998e2000 53 53 57md (33e76) 44/9 100.0 100.0 pac, carb 40 20
(2002)
Kunkel et al. D n r 1995e1999 35 35 59m (34e80) 27/8 100.0 100.0 cis (77.1%) 36k 18
(2003)
Shikama et al. J n r 1987e1999 161 161 64m(27e83) na 51.0 82.0 cis, 5-FU 38md na
(2003) (20e66)
 Preoperative chemoradiotherapy in the management of oral cancer 79

na, Not available; m, mean; md, median; min, minimum. Organ preservation after CRT in selected patients: n, no; y, yes. Study type: r, retrospective; p, prospective; ra, randomised; mu, multicentric; mn, multi-
underwent surgery, the specimens obtained from radical
20 surgery were investigated in all patients (Knobber
25

25
et al., 1987; Dobrowsky et al., 1991; Slotman et al.,
na

1992; Valente et al., 1993; Mohr et al., 1994; Muller

(40e70)

et al., 1994; Zamboglou et al., 1994; Goodman et al.,

1997; Wanebo et al., 1997; Kirita et al., 1999, 2001;
60md

Brun et al., 2001; Hermann et al., 2001; Eckardt et al.,

50
50

50

2002; Uno et al., 2003; Klug et al., 2005b). In studies

with organ preservation protocols, the samples were ob-
tained by multiple biopsies (Chang et al., 1988; Chou-
cis, 5-FU/pep

mmc, 5-FU

gule et al., 1994; Glicksman et al., 1997; Giralt et al.,

cis, 5-FU

2000; Wanebo et al., 2001) or nidusectomy (Robbins

et al., 2004). Histopathological response was classified
cis

according to different criteria and in different gradients.

However, complete histopathological response (pCR;
national. Treatment: rt, radiotherapy only; cis, cisplatin; carb, carboplatin; 5-FU, 5-fluorouracil; mmc, mitomycin; pac, paclitaxel; pep, peplomycin; ifo, ifosfamide.

median proportion, 48.2%; range, 26.7e74.6%) was

80.0

84.6
92.0

78.9

unanimously defined by all authors as the complete ab-

sence of vital tumour cells. A statistically significant as-
sociation between favourable histopathological response
100.0

100.0
100.0

100.0

and increased survival (or disease control) was found

in 10 out of 10 studies providing these data (Valente
et al., 1993; Mohr et al., 1994; Glicksman et al., 1997;
181/41
67/8

48/5
18/7

Goodman et al., 1997; Kirita et al., 1999, 2001; Brun

et al., 2001; Hermann et al., 2001; Uno et al., 2003;
Klug et al., 2005b). See Table 3 for histopathological re-
54.2m (34e78)
61md (33e85)

60md (18e71)

55md (32e83)

sponse and survival data.

Meta-analysis of survival data

The results of the meta-analysis are detailed in Fig. 2.

Due to differences in the reporting of survival rates
222
40

26
25

Fig. 2 contains five blocks of studies with survival rates

for the same time interval (e.g., 1-, 2-, 3-, 4-, and 5-year
survival rates). If more than one time interval was given
222
75

53
25

for the survival estimation the longest available was cho-

sen for the meta-analysis. Mean survival rates weighted
1986e2000

1999e2000
1995e2000

1990e2000

according to N survival are given in the bottom line of

each block of studies in Fig. 2.
Concerning the ecological regression model, for obvi-
ous reasons, years of survival estimation were entered
into the model first. As expected, the model was signifi-
cant, F(1,31) ¼ 7.38, p ¼ 0.011, adjusted R2 ¼ 0.17. The
regression equation was as follows: survival rate
(%) ¼ 81.98  5.65  years of survival estimation. In
p
p
r

other words, the regression model results indicated

Additionally 24 Gy postop when extranodal spread.

a 5.65% change (decrease) in the survival rate per

unit increase in the predictor (years of survival estima-
tion). Following this, statistical control for varying sur-
vival estimations (1e5 years) across studies, the further
three predictors (midpoint of study enrolment period, or-
Additionally 40 Gy postoperative.
yz

gan preservation protocol, and preoperative protocol)

n

Based on nidusectomy findings.

were entered into the model. The regression model re-

* Based on clinical findings.

mained significant after this second-block variables had

Based on biopsy findings.

been entered, F(4,31) ¼ 9.33, p \ 0.001, adjusted

US
D

R2 ¼ 0.52. The change in variance explained by the sec-

J

ond-block variables was significant, DR2 ¼ 0.38,

Kessler et al., 2004
Uno et al. (2003)

DF(3,26) ¼ 8.21, p\ 0.001. Thus, the three further pre-

Robbins et al.

dictor variables explained significantly more variation

Klug et al.
(2005a,b)

in the survival rates over and above the variation ex-

(2004)

plained (and thereby statistically controlled) by varying

k
y
z
x

survival estimations.
 80 Journal of Cranio-Maxillofacial Surgery
Table 3 e Outcomes of studies selected for meta-analysis

Ref. Follow-up months Years* Survival rate % (95% CI) Survivors N survival Mortality rate % Deathsy N mortality pCR rate % pCR abs. N response

Knobber et al. (1987) na 3 41 (29.1e52.9) 27 66z na na na 33.3 29 87

Kramer et al. (1987) 60 4 30.2 (16.5e43.9) 10 43x 8.1 11 136 na na na
Chang et al. (1988) 20md (9e38) 3 45 (29.8e60.2) 18 41 na na na 52.6 10 19
Dobrowsky et al. (1991) (18e54) 3 61 (49.6e72.4) 43 70x na na na 48.6 34 70
Slotman et al. (1992) 40md (20e96) 3 58.5 (43.4e73.6) 24 41 9.4 5 53 65.9 27 41
Hansen et al. (1993) 146.4md 5 53.2 (40.8e65.6) 33 62x na na na na na na
Valente et al. (1993) (30e55) 3 82 (67.8e96.2) 23 28 3.6 1 28 53.6 15 28
Chougule et al. (1994) na 5 32 (20.9e43.1) 22 68 na na na 51.9 14 27
Glicksman et al. (1994) 41md (10e108) 5 49 (39.3e58.8) 49 101 5.0 5 101 na na na
Mohr et al. (1994) (30e60) 3 81.4 (74.6e88.2) 103 127x na na na 37.0 47 127
Muller et al. (1994) 38md 3 79 (71.1e86.9) 80 101x na na na 36.6 37 101
Zamboglou et al. (1994) 10md (7e20) 2 69 (52.5e85.6) 21 30x na na na 26.7 8 30
Olasz et al. (1996) 36 3 57 (43.3e70.7) 29 50x na na na na na na
Glicksman et al. (1997) 26md (12e48) 3 54 (42.6e65.4) 40 74 1.4 1 74 74.6 44 59
Goodman et al. (1997) 36.5md 5 60 (44.8e75.2) 24 40 na na na 52.5 21 40
Wanebo et al. (1997) 12md 1 83 (70.6e95.4) 29 35 2.9 1 35 67.6 23 34
Kirita et al. (1999) 86md (61e144) 5 80.5 (68.4e92.6) 33 41z 0 0 48 50.0 24 48
Szabo et al. (1999) 60 5 31.3 (18.1e44.4) 15 48 2.1 1 48 na na na
Giralt et al. (2000) 39md (33e69) 3 76 (65.4e86.6) 47 62 0 0 62 58.0 29 50
Kurita et al. (2000) na 2 60 (38.5e81.5) 12 20 na na na na na na
Brun et al. (2001) 48min 5 46 (30.4e61.6) 18 39x na na na 48.7 19 39
Chao et al. (2001) 54md (18e276) 2 67 (58.2e75.8) 73 109x na na na na na na
Hermann et al. (2001) 25md 2 56 (41.2e70.84) 24 43 na na na 39.5 17 43
Kirita et al. (2001) 60.5md (8e152) 5 83.3 (69.95e96.7) 25 30z na na na 58.1 25 43
Wanebo et al. (2001) 50md (45e60) 4 68 (54.1e81.9) 29 43 2.3 1 43 50.0 19 38
Eckardt et al. (2002) 21md (1e40) 3 84 (74.1e93.9) 44 53 0 0 53 57.7 30 52
Kunkel et al. (2003) na 3 68.6 (53.2e84.0) 24 35 na na na na na na
Shikama et al. (2003) 47md 5 58 (50.4e65.6) 93 161x na na na na na na
Uno et al. (2003) 74md 5 56 (40.6e71.4) 22 40x na na na 35.0 14 40
Kessler et al. (2004) na 3 78 (62.1e93.9) 20 26x na na na na na na
Robbins et al. (2004) 56md (28e84) 5 54 (34.5e73.5) 14 25x 4.0 1 25 73.7 14 19
Klug et al. (2005a,b) 72.3md (24e152) 5 56 (48.7e63.4) 98 175z 5.4 12 222 48.2 107 222

na, Not available; md, median. Survival rate corresponds to the ratio of survivors and N survival pCR rate corresponds to the ratio of pathohistological complete responders (pCR abs.) and N response. Treatment-
related mortality rate corresponds to the ratio of treatment-related deaths and N mortality. N survival includes only these patients.
* Years of survival estimation.
y
Treatment-related deaths.
z
A survival rate was published for the stage III/IV subgroups.
x
No survival rate was published for stage III/IV.

Fig. 2 e Results of the meta-analysis. Included are five groups of studies with varying time periods for overall survival data. Statistics shown are
between-study heterogeneity, study weight, and median survival.
The final regression equation was as follows: survival
rate (%) ¼ 1224.20 to 5.91  years of survival estima-
tion + 0.65  mid-enrolment year  13.30  organ pres-
ervation (0 ¼ no; 1 ¼ yes) + 14.33  preoperative
protocol (0 ¼ RT; 1 ¼ CRT). According to this model,
a study’s survival rate would be influenced as follows:
decreased by 5.91% per one unit (i.e., 1 year) increase
in survival estimation; increased by 0.65% by one year
time of enrolment more recently than in the past; de-
creased by 13.30% for studies involving an organ pres-
ervation protocol relative to studies with radical
resection; and increased by 14.33% for CRT studies rel-
ative to RT studies. Standardised regression coefficients
(b), significance test statistics (t), and p-values for the
four predictors in the final regression models were as fol-
lows: years of survival estimation b ¼ 0.47 (t ¼ 3.69,
p \0.001); midpoint of study enrolment period b ¼ 0.25
Preoperative chemoradiotherapy in the management of oral cancer 81
(t ¼ 1.64, p ¼ 0.11); organ preservation protocol
b ¼ 0.37 (t ¼ 2.79, p ¼ 0.01); and preoperative proto-
col b ¼ 0.42 (t ¼ 2.66, p ¼ 0.01). Therefore, apart from
years of survival estimation being the most important
predictor for survival rates, the second-most important
predictor was the type of preoperative protocol, followed
by the type of organ preservation protocol, and enrolment
period, with only the last predictor not being statistically
significant.
Following the heuristic insights obtained from the eco-
logic regression model described in Methods section, our
subsequent analyses focused on the two subgroups of
studies reporting 3- and 5-year survival rates which con-
stituted the majority of the studies (25 of 32) included in
the meta-analysis. In order to reduce, better understand,
and explain between-study heterogeneity, we conducted
sensitivity analyses for the meta-analysis findings, and
82 Journal of Cranio-Maxillofacial Surgery
these were guided by the findings from the ecologic re-
gression model.
In a first step, we excluded those studies in the sub-
groups with survival rates for 3 and 5 years that used
a preoperative RT protocol (Knobber et al., 1987; Slot-
man et al., 1992; Olasz et al., 1996; Szabo et al., 1999;
Brun et al., 2001). Excluding these studies, the mean sur-
vival rate was 73.4% (70.2e76.7%) for the 3-year
group, still preserving much of the heterogeneity in out-
comes between the remainder of studies (c2 ¼ 46.90,
df ¼ 10, p\ 0.00001, I2 ¼ 78.7%). Within the 5-year
group, the mean survival rate was 57.3% (53.7e
60.8%), there being much between-study heterogeneity
in survival rates (c2 ¼ 51.81, df ¼ 8, p \ 0.00001,
I2 ¼ 84.6%).
In a second step, we excluded studies with an organ
preservation protocol (i.e., involving a study arm without
surgery) in the 3-year group (Chang et al., 1988; Glicks-
man et al., 1997; Giralt et al., 2000) and in the 5-year
group (Chougule et al., 1994; Glicksman et al., 1994;
Robbins et al., 2004). For the 3-year survival-rate group,
heterogeneity was further reduced, but still significant
(c2 ¼ 18.73, df ¼ 7, p ¼ 0.009, I2 ¼ 62.6%). The mean
survival rate across the remaining eight studies in this
group was 76.9% (73.2e80.6%). Similarly, for the
5-year survival-rate group, heterogeneity was reduced,
but still substantial (c2 ¼ 22.92, df ¼ 5, p ¼ 0.00004,
I2 ¼ 78.2%). The mean survival rate across the six stud-
ies in this group was 62.6% (58.4e66.8%).
Among the group of remaining studies with preopera-
tive CRT and radical resection in all cases, the Deutsch-
Österreichisch-Schweizerischer Arbeitskreis für Tumoren
im Kiefer-Gesichtsbereich (DÖSAK) study (Mohr et al.,
1994) is the only prospective randomised trial. Patients
with resectable SCC of the oral cavity or oropharynx
(stages III and IV in 95%) were randomised into an
arm of the preoperative CRT plus surgery arm and a sur-
gery alone-arm. Both groups were similar in their patient
and tumour characteristics as demonstrated with the
DÖSAK’s computer-aided individual prognosis (CIP)
survival estimation provided for both groups as well as
during follow-up. An improvement in survival of 20% af-
ter 3 years was found for the combined treatment arm
compared with the surgery alone-arm. The survival data
of the combined treatment arm of this study are reported
in Table 3.
DISCUSSION
This review includes a literature-based meta-analysis of
studies using preoperative CRT or RT for advanced
SCC of the oral cavity and the oropharynx. Thus far, it
is the most comprehensive analysis performed of the ex-
isting results of the above-mentioned therapy concepts.
The limitations are as follows: it is a literature-based
meta-analysis, which is less powerful than meta-analyses
of individual patient data (Pignon and Hill, 2001); sec-
ondly, the heterogeneity of the studies included in the re-
view. Prospective as well as retrospective studies with
randomisation or stratification, with or without control
groups, were included in the analysis. This was done be-
cause of the small number of documented patients who
were given preoperative therapy. The goal of this review
was to summarize available results of preoperative ther-
apy as well as to throw light on important accompanying
factors such as morbidity, post-therapeutic quality-of-
life, and factors related to surgery.
Overall survival was used as the main parameter since
it is undisputed as an endpoint and clear across studies.
Published control rates were not used because the defini-
tions were inhomogeneous. Data of disease-specific
survival, progression-free survival, local control, locore-
gional control, and disease control were collected. How-
ever, the consistency of these data across publications
was not sufficient for a meta-analytical evaluation. The
publications were ‘‘homogenised’’ by eliminating studies
based on previously determined criteria. In an ecologic
regression analysis, the variables of preoperative treat-
ment concept (CRT vs. RT) and organ preservation
(organ preservation in selected patients vs. radical resec-
tion in all patients) were determined as useful criteria.
Sensitivity analysis leads to a reduction of inter-study
heterogeneity after exclusion and showed an improve-
ment of survival for the remaining studies with similar
characteristics. For comparison of our data with results
of other established treatment concepts we have included
Table 4 summarising the data of recent meta-analyses.
Comparison with their data is intended for hypothesis
generation rather than for rating the superiority of one
or the other strategy.
Comparing data of CRT plus surgery protocols with
meta-analytical data of predominantly non-surgically
treated patients, one can assume that the factor of resect-
ability accounts for a survival difference ranging from
14% (CRT-arm in the Pignon meta-analysis 1, Pignon
et al., 2000, vs. CRT-arm in the RTOG, Cooper et al.,
2004, study) to 35% (CRT-arm in the Pignon meta-anal-
ysis 2, Pignon et al., 2000, vs. our meta-analysis). Thus,
the classification of operability seems highly significant.
However, surgeons are inclined to assess operability very
differently. For instance, del Campo et al. (1997) men-
tioned the following criteria for nonresectability: when
the tumour was fixed to a bone structure in the region,
or to lymph nodes, or had other invasive features making
surgical removal impossible. In contrast, for our cohort,
we defined unresectability as follows: infiltration of pre-
vertebral fascia, the internal carotid artery, and the skull
base (Klug et al., 2005a). Similarly, clear definitions of
the surgical procedure were included in the DÖSAK
study (Mohr et al., 1994). Differences in the assessment
depend on various factors: the surgeon’s skills and expe-
rience as well as his opinion on extensiveness of surgery;
but they also result from infrastructural differences of in-
stitutions. It has to be mentioned that many studies do not
provide exact data about their criteria for nonresectabil-
ity; the relatively soft statement ‘‘nonresectability has
been defined by the head and neck surgeon’’ is found
in many instances. As surgical procedures are, in fact,
more difficult to standardize than the administration of
CT or RT, more reliable evidence such as that given in
the meta-analyses included in Table 4 will probably not
become available for surgically treated patients in the
near future.
 Preoperative chemoradiotherapy in the management of oral cancer 83

Table 4 e Data for comparison

Meta-analyses with pooled survival data
Ref. N patients* Enrolment Characteristics Results
Pignon et al. (2000) 10,741 1965e1993 MA1 (63 trials): LRT (RT or surgery) with 5-YSR: 36% CT+, 32% CT
CT (CT+) vs. LRT without CT (CT) in
advanced HNSCC
Pignon et al. (2000) 861 1965e1993 MA 2 (six trials): neoadjuvant with or 5-YSR: 27% CT+, 24% CT
without adjuvant CT plus RT vs. concomitant
or alternating CRT in patients with advanced
HNSCC rated inoperable
El-Sayed and Nelson (1996) 3708 na MA (25 trials): local definitive treatment 5-YSR: 30% CT+, 23% CT
(RT, surgery or both) vs. LRT with
adjuvant or adjunctive CT
Randomised trials of postoperative CRT
Ref. N patients* Enrolment Patient description Protocol description Results
Cooper et al. (2004) 416 1995e2000 High risk characteristics Postoperative 5-YSR: 45% CT+, 40% CT
evident in surgical specimen RT vs. CRT
(positive margins, $2 involved
nodes or extracapsular spread);
oral and oropharyngeal sites:
67/72%
Bernier et al. (2004) 334 1994e2000 pT3,4 at any nodal stage, pT1,2 Postoperative 5-YSR: 53% CT+, 40% CT
pN0,1 with unfavourable RT vs. CRT
pathological findings;
oral and oropharyngeal
sites: 56/57%

MA, meta-analysis; LRT, locoregional treatment; CT, chemotherapy; RT, radiotherapy; HNSCC, head neck squamous cell carcinoma; 5-YSR, 5-year
overall survival rate; CRT, chemoradiotherapy; na, not available.
* N patients correspond to patients with survival data.

Wennerberg’s (1995) review compared pre- and post-
operative RT with the dominant tumour sites of larynx
and hypopharynx. In the discussion, various theoretical
arguments were cited in favour of, or against, one or
other approach. Catchphrases used for arguments in fa-
vour of preoperative RT were hypoxic cell, avascular
scar, and delay due to postoperative complications, while
arguments in favour of postoperative RT included
phrases such as less morbidity, loss of information and
cell kinetic effects of surgery. These arguments are valid
to the present day. Wennerberg conducted a literature
overview of 11 studies comprising 1358 patients (326
in prospective studies) with pre- and postoperative RT.
He concluded in his review that the bulk of evidence
clearly suggests that postoperative locoregional control
is superior to preoperative RT. However, in terms of
overall survival there were no significant differences.
An important study included was the prospective rando-
mised trial of the Radiation Therapy Oncology Group
(RTOG), which was published by Tupchong et al.
(1991). The study included a comparison of pre- and
postoperative RT for tumours mainly located in the hy-
popharynx (32% oral locations, therefore it is not in-
cluded in our meta-analysis) and the larynx and
showed no significant differences in survival, but did
show a difference in locoregional control in favour of
postoperative RT. Wennerberg’s summary is largely
based on these results. Our literature search revealed no
significant prospective randomised study comparing pre-
operative and postoperative multi-modality concepts
with concomitant CT for tumours located in the oral cav-
ity and the oropharynx. Among the studies selected with
regard to the specific tumour location, only Kessler et al.,
2004 (CRT) and Chao et al., 2001 (RT without concom-
itant CT) conducted a group comparison between the
preoperative and postoperative approaches. In Kessler’s
non-randomised prospective trial, the preoperative group
achieved significantly better 3-year overall survival than
the postoperative group. However, this study was biased
by the fact that the postoperative group included more
severely ill patients. Chao et al. (2001) found a control
benefit for postoperative therapy but no significant differ-
ences in survival (similar to Tupchong et al., 1991).
Taken together, the available data do not allow an assess-
ment of the oncological superiority of either approach.
Two prospective randomised studies of postoperative
concomitant CRT were conducted by the RTOG (Cooper
et al., 2004) and the EORTC (Bernier et al., 2004) and
published in the New England Journal of Medicine in
2004. Characteristics and results of these studies are
shown in Table 4. The most relevant prospective rando-
mised study of the preoperative concept is the study of
the DÖSAK (Mohr et al., 1994). It showed a significantly
better 3-year overall survival in the preoperative multi-
modal treatment arm with 20% fewer deaths after 3 years
than for the control arm with surgery alone. Similar good
results for the preoperative arm of this study are found in
our meta-analysis for those studies with strict protocols
of radical resection in all cases after preoperative CRT.
Comparability of the quoted studies is certainly limited
since the inclusion criteria are not equal (e.g., EORTC in-
cluded stage I/II tumours with unfavourable pathological
findings as well as stage III/IV tumours and including
sites other than oral). Nevertheless, for hypothesis gener-
ation, some comparative interpretations can be made.
Our interpretation is that the oncological outcome after
preoperative CRT and radical resection in all cases is
not poorer but could, in fact, be even better than for
84 Journal of Cranio-Maxillofacial Surgery
postoperative CRT. This, however, does not correspond
to the results of Tupchong et al. (1991) and Wennerberg
(1995). Whether this inconsistency can be explained by
different distribution of tumour locations (Tupchong
et al.: predominantly the hypopharynx and the larynx,
only 32% in the oral cavity or the oropharynx) is uncer-
tain. In this respect, the results of a phase-III trial of the
preoperative multimodal concept currently in progress in
several German centres (Hannover, Heidelberg) are ea-
gerly anticipated (Sinikovic et al., 2005).
Influence of radiation dose
The analysis of the influence of the administered focal ra-
diation dose showed no significant association between
this parameter and survival; an association of this type
was also not anticipated because of the relatively homo-
geneous distribution of the radiation dose. Interestingly,
in the preoperative approach, a median radiation dose
of 45 Gy is administered. Most protocols for postopera-
tive radiation (see the above-mentioned studies of the
RTOG, Cooper et al., 2004; and the EORTC, Bernier
et al., 2004) use higher doses. It may therefore be spec-
ulated that the preoperative approach with a lower radia-
tion dose leads to an overall survival rate that is not
poorer than that achieved with postoperative treatment.
This might result in a quality-of-life advantage for the pa-
tient, because the patient experiences reduced long-term
sequelae from radiation. A dose reduction would appear
to be advantageous in view of the critical complication of
infected osteoradionecrosis (Chang et al., 2001).
Influence of concomitant chemotherapy
Preoperative therapy, based on CRT or just RT, was the
predictor variable in the ecologic regression analysis that
demonstrated the most statistically significant association
with survival (better survival in studies with CRT). This
finding was confirmed in our meta-analysis, as evidenced
by an improvement of the 3- and 5-year survival by 3%
after elimination of studies employing RT alone. This
trend did not achieve statistical significance, but it may
be assumed that sensitizing CT is of positive prognostic
value when RT is administered preoperatively. The large
diversity of chemotherapeutic agents and their dosages
used in the studies do not allow any conclusions concern-
ing an association between these parameters and overall
survival.
Histopathological response evaluation
The preoperative treatment concept allows histological
evaluation of the tumours’ response to CRT. In 22 stud-
ies, an analysis of this nature was performed. However,
histopathological response was graded very diversely in
these studies. Definitions were comparable only with re-
spect to histopathological complete response (pCR),
which was defined as the absence of vital tumour cells
in the resected specimen. The prognostic relevance of
pCR was confirmed in all studies. It was found that the
grading of pCR was superior to classical prognostic fac-
tors such as tumour stage, T and N classifications, etc.
This realisation has led to a variety of clinical ap-
proaches. On the one hand, the radical surgery approach
was discarded, and response was determined through
multiple biopsies or nidusectomy. The result was then
used as a criterion for a further organ-preserving proce-
dure or radical surgery. On the other hand, non-invasive
diagnostic procedures (Kunkel et al., 2003, FDG-PET;
Klug et al., 2004, CT) were evaluated, which might allow
the assessment of histopathological response prior to sur-
gery. Organ preservation was determined as a significant
prognostic factor in our ecologic regression analysis in
the same manner as the variable of preoperative therapy
(CRT or RT). This finding is supported by our meta-anal-
ysis, which revealed a somewhat better survival for stud-
ies employing radical surgery in all cases after exclusion
of studies using organ preservation strategies in selected
patients. However, this trend did not achieve statistical
significance; it needs to be further investigated in con-
trolled randomised trials. Authors who found no reliable
criterion for deviating from the radical-surgery approach
interpreted the grade of histopathological response as
a major factor for the intensification of post-treatment
care or further preventive tumour therapy (Hermann
et al., 2001; Klug et al., 2005b). The option of
downstaging is also discussed as an alternative to radical
surgery (according to pretherapeutic tumour extensions)
and organ preservation. Histopathological response be-
haviour is used to establish the patient’s individual
safety margin for resection. The goal is to reduce the
degree of surgical intervention. However, recent studies
(Kirita et al., 2001; Klug et al., 2004) show that the tu-
mour does not always shrink concentrically under CRT
and that vital tumour cell nests may still be present in
the periphery. Comparison with non-invasive diagnostic
procedures and the histopathological response is ex-
pected to provide information that will help the clinician
to assess size reduction preoperatively. However, our
own investigation with volumetric CT (Klug et al.,
2004) showed a relatively high rate of false predictions;
the procedure was therefore rated unsuitable. FDG-PET
promises to be very informative with respect to response
(Kunkel et al., 2003) and should be the subject of further
investigations.
Factors influencing histopathological response
Several studies have focused on factors that influence re-
sponse. These factors include the oxygen saturation of tu-
mour tissue, depending on the haemoglobin content of
peripheral blood (Glaser et al., 2001) and the microves-
sel density of the tumour (Brun et al., 2001). In both
studies, significant associations were observed between
the analysed factor, histopathological response and sur-
vival. In any case, it was found that the preoperative set-
ting of CRT is suitable to obtain important data about
cellular and subcellular changes in tumour tissue,
because both pretherapeutic tissue samples as well as
post-CRT tumour specimens are routinely available.
Long-term observation of different genetic tumour
markers in this setting might provide important
 Preoperative chemoradiotherapy in the management of oral cancer 85

information about tumour biology and the mode of action multi-modality therapy with preoperative CRT, the re-
of the preoperative therapy used. sults were in a similar range to those achieved with other
treatment concepts (Klug et al., 2002). However, it
should be pointed out that in the above-mentioned
Morbidity and mortality
QOL investigations, coping mechanisms were not as-
sessed, and may have levelled any differences. Further-
According to the conclusions drawn in the studies in-
more, it should be noted that patients with recurrent
cluded in this analysis, the toxicity grades of the pre-
disease have significantly poorer QOL than tumour-free
treatment did not cause any of the authors to deviate
patients. Therefore, in tumour treatment, the achievable
from the preoperative approach or alter the protocol. Vi-
post-therapeutic QOL after the application of a therapy
olations of the protocol, discontinuation of therapy, and
concept cannot be viewed separately from the success
death during preoperative therapy were reported in iso-
rate of the treatment. In a therapy concept with a lower
lated cases and also did not cause any deviation from
survival rate, it may be assumed that a larger number
the therapy concept. The highest mortality rates were re-
of patients die because of recurrent disease, and conse-
ported (Kramer et al., 1987; Slotman et al., 1992) as
quently with poor QOL. This group of patients is
8.1% and 9.4%; in these studies the enrolment period
under-represented in most studies investigating QOL in
ended before or during the year 1988. In studies that
cancer patients.
were more recent in terms of their enrolment period, no
mortality rates higher than 5.5% have been reported.
However, with respect to morbidity and mortality, it
Surgical aspects
should be remembered that when a rigid concept of pre-
operative RT/CRT and radical surgery is applied in all
In his review Wennerberg (1995) summarised the mode
cases, some patients might well be over-treated. If one
of thought pursued by doctors involved in multi-modality
presumes a histologically complete remission rate of
treatment concepts: ‘‘radiotherapists do not like to irradi-
48% (the median value of our meta-analysis), it may
ate a scar and surgeons prefer to cut in fresh tissue.’’
be surmised that an over-invasive approach is used in
From a surgical point of view, many different aspects
one half of all patients, and that morbidity and mortality
must be considered when deciding whether one should
will be increased by this approach. Therefore, the quest
perform pre- or postoperative CRT. The published liter-
for a single criterion that allows a decision for organ
ature contains contradictory data concerning the diffi-
preservation without impairing survival is a major goal.
culty of surgery after preoperative CRT. Subjectively,
However, meta-analysis showed that studies in which
many surgeons confirm that this is the case (Bengtson
the decision for organ preservation was based on biopsy
et al., 1993). However, it was not objectively confirmed
yielded somewhat poorer survival rates (statistically sig-
in studies that registered and compared the duration of
nificant in the ecologic regression analysis, but not statis-
surgery (Kiener et al., 1991). There is also no consensus
tically significant, in the meta-analysis) than those in
of opinion about the potentially higher rate of postoper-
which a rigid concept was employed. In all studies, sur-
ative morbidity and more frequent occurrence of local
vival was significantly better in patients with pCR after
complications such as wound dehiscence or prolonged
preoperative therapy than in the other groups; neverthe-
duration of hospitalisation. Our own investigation in
less, we also see locoregional failure in some of these pa-
303 patients (Klug et al., 2005c) showed an elevated
tients. Research plays a major role in this context. It may
morbidity rate among preoperatively irradiated patients,
be hoped that molecular markers before and after preop-
but this was not in agreement with the evidence of Bengt-
erative CRT will allow the assessment of the prognosis
son et al. (1993) and Kiener et al. (1991), both of whom
with greater certainty than has been achieved thus far
did not register a higher morbidity or complication rate in
with clinical procedures. The use of a suitable criterion
reconstructive surgery after RT. In view of long-term
to guide the decision for or against organ preservation
outcome of surgery, a further aspect has to be considered;
will allow morbidity and mortality to be reduced most ef-
surgery performed in a large number of advanced tu-
fectively in the entire population.
mours of the oral region involves more complex recon-
structive measures, specifically the use of the free flap
Post-therapeutic quality-of-life technique. In this regard, the currently predominant opin-
ion may be summarised as follows: our own investiga-
Post-therapeutic quality-of-life (QOL) is being given in- tion (Klug et al., 2005c) yielded a success rate of 93%
creasing importance since the mid-1990s. Several ques- for free flaps after preoperative radiation with 50 Gy,
tionnaires have been developed; these include specific which is well within the success range for unradiated tis-
questions for patients with head and neck tumours. Kess- sue and is in agreement with the data reported by Bengt-
ler et al. (2004) performed a longitudinal QOL analysis, son et al. (1993), Guelinckx et al. (1984), Jones et al.
including a comparison between the preoperative and the (1996), and Kiener et al. (1991), all of whom found no
postoperative arm. It was found that, after initial disad- significant difference when compared with untreated tis-
vantages in the preoperative group, self-assessed QOL sue. In cases of secondary reconstruction in the presence
after 1 year was comparable in both groups. These dy- of infected osteoradionecrosis, however, one may expect
namics appear to be plausible in the preoperative group poorer results (Sinikovic et al., 2005). This is because
after a longer postoperative period of convalescence. In greater tissue damage occurs after definitive RT with
our own QOL analysis for long-term survivors after higher radiation doses (64 to more than 70 Gy), and
86 Journal of Cranio-Maxillofacial Surgery
also because the tissue usually suffers additional damage
secondary to infection or the formation of fistulae. In the
published literature on free flap surgery, it is generally
agreed that the goal of reconstruction is more easily
achieved with a non-irradiated free flap such as that em-
ployed when the preoperative RT has been given. Partic-
ularly for the reconstruction of bone after segmental
mandibulectomy, this aspect is relevant with regard to
prosthetic rehabilitation with osseointegrated dental im-
plants (Schmelzeisen et al., 1996), because a postopera-
tively irradiated microvascular bone transplant is
inferior to an implant base undamaged by radiation. In
summary, the results of reconstructive surgery seem to
favour the concept of preoperative RT.
CONCLUSION AND PERSPECTIVES
Advantages of the preoperative approach lie in the lower
focal radiation dose administered, in fact that grafts
remain undamaged, and in the possibility of adapting
further therapy to the strongest prognostic factor (histo-
pathological response to CRT). Potential disadvantages
include difficulties with the surgical procedure after
RT, specifically, in postoperative management.
When compared with the 5-year survival rates reported
in the prospective randomised RTOG (Cooper et al.,
2004) and EORTC (Bernier et al., 2004) studies with
postoperative CRT (50% and 53%, respectively), the
survival rate of 62.6% for preoperative CRT and radical
surgery, as determined by the present meta-analysis, ap-
pears to be remarkably good. Since the findings of our lit-
erature-based analysis are based on data with a large
proportion of studies with consecutive patient series
they do not justify any treatment recommendations. Com-
pared with the postoperative RT protocol, hard evidence
such as sufficient data from prospective randomised stud-
ies is yet missing. Therefore we conclude that prospective
randomised studies are essential in this area.
ACKNOWLEDGEMENT
This work was supported by the Anniversary Research
Funds of the Austrian National Bank, grant no. 10701,
to C. Klug.
References
Bengtson BP, Schusterman MA, Baldwin BJ, Miller MJ, Reece GP,
Kroll SS, Robb GL, Goepfert H: Influence of prior radiotherapy on
the development of postoperative complications and success of free
tissue transfers in head and neck cancer reconstruction. Am J Surg
166: 326e330, 1993
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefebvre JL,
Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F,
Bourhis J, Kirkpatrick A, van Glabbeke M, European
Organization for Research and Treatment of Cancer Trial 22931:
Postoperative irradiation with or without concomitant
chemotherapy for locally advanced head and neck cancer. N Engl J
Med 350: 1945e1952, 2004
Brun E, Zatterstrom U, Kjellen E, Wahlberg P, Willen R, Brun A,
Perfekt R, Tennvall J: Prognostic value of histopathological
response to radiotherapy and microvessel density in oral squamous
cell carcinomas. Acta Oncol 40: 491e496, 2001
Chang DW, Oh HK, Robb GL, Miller MJ: Management of advanced
mandibular osteoradionecrosis with free flap reconstruction. Head
Neck 23: 830e835, 2001
Chang H, Leone LA, Tefft M, Nigri PT: Advanced head and neck
cancer: response to and toxicity of multimodality therapy.
Radiology 168: 863e867, 1988
Chao KS, Majhail N, Huang CJ, Simpson JR, Perez CA, Haughey B,
Spector G: Intensity-modulated radiation therapy reduces late
salivary toxicity without compromising tumour control in patients
with oropharyngeal carcinoma: a comparison with conventional
techniques. Radiother Oncol 61: 275e280, 2001
Chougule PB, Suk S, Chu QD, Leone L, Nigri PT, McRae R, Lekas M,
Barone A, Bhat D, Bellino J: Cisplatin as a radiation sensitizer in
the treatment of advanced head and neck cancers. Results of
a phase II study. Cancer 74: 1927e1932, 1994
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH,
Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M,
Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK,
Radiation Therapy Oncology Group 9501/Intergroup:
Postoperative concurrent radiotherapy and chemotherapy for high-
risk squamous-cell carcinoma of the head and neck. N Engl J Med
350: 1937e1944, 2004
del Campo JM, Felip E, Giralt J, Raspall G, Bescos S, Casado S,
Maldonado X: Preoperative simultaneous chemoradiotherapy in
locally advanced cancer of the oral cavity and oropharynx. Am J
Clin Oncol 20: 97e100, 1997
Dobrowsky W, Dobrowsky E, Strassl H, Braun O, Gritzmann N,
Scheiber V: Combined modality treatment of advanced cancers of
the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 20:
239e242, 1991
Eckardt A, Rades D, Rudat V, Hofele C, Dammer R, Dietl B,
Wildfang I, Karstens JH: Prospective phase II study of neoadjuvant
radiochemotherapy in advanced operable carcinoma of the mouth
cavity. 3-Year outcome. Mund Kiefer Gesichtschir 6: 117e121,
2002
El-Sayed S, Nelson N: Adjuvant and adjunctive chemotherapy in the
management of squamous cell carcinoma of the head and neck
region: a meta-analysis of prospective and randomised trials. J Clin
Oncol 14: 838e847, 1996
Giralt JL, Gonzalez J, del Campo JM, Maldonado J, Sanz X, Pamias J,
Eraso A, Bescos S, Raspall G: Preoperative induction
chemotherapy followed by concurrent chemoradiotherapy in
advanced carcinoma of the oral cavity and oropharynx. Cancer 89:
939e945, 2000
Glaser CM, Millesi W, Kornek GV, et al: Impact of hemoglobin level
and use of recombinant erythropoietin on efficacy of preoperative
chemoradiation therapy for squamous cell carcinoma of the oral
cavity and oropharynx. Int J Radiat Oncol Biol Phys 50: 705e715,
2001
Glicksman AS, Slotman G, Doolittle 3rd C, Clark J, Koness J,
Coachman N, Posner M, DeRosa E, Wanebo H: Concurrent cis-
platinum and radiation with or without surgery for advanced head
and neck cancer. Int J Radiat Oncol Biol Phys 30: 1043e1050,
1994
Glicksman AS, Wanebo HJ, Slotman G, Liu L, Landmann C, Clark J,
Zhu TC, Lohri A, Probst R: Concurrent platinum-based
chemotherapy and hyperfractionated radiotherapy with late
intensification in advanced head and neck cancer. Int J Radiat
Oncol Biol Phys 39: 721e729, 1997
Goodman MD, Tarnoff M, Kain M, Slotman GJ: Interactions between
outcomes and tumour response to preoperative cisplatin-sensitized
radiotherapy in advanced head and neck cancer. Southern New
Jersey Head and Neck Cancer Treatment Group. Am J Surg 174:
527e531, 1997
Guelinckx PJ, Boeckx WD, Fossion E, Gruwez JA: Scanning electron
microscopy of irradiated recipient blood vessels in head and neck
free flaps. Plast Reconstr Surg 74: 217e226, 1984
Hansen O, Sorensen JA, Siemssen SJ, Poulsen H: Importance of the
time interval between radiotherapy and surgery in oral cancer. Eur
J Cancer B Oral Oncol 29B: 35e38, 1993
Hermann RM, Krech R, Hartlapp J, Esser E, Christoph B, Muller MK,
Wagner W: The value of qualitative regression grading as
a prognostic factor for survival after preoperative
radiochemotherapy in patients with advanced head and neck
cancer. Strahlenther Onkol 177: 277e282, 2001

Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring
inconsistency in meta-analyses. BMJ 327: 557e560, 2003
Jones NF, Johnson JT, Shestak KC, Myers EN, Swartz WM:
Microsurgical reconstruction of the head and neck:
interdisciplinary collaboration between head and neck surgeons
and plastic surgeons in 305 cases. Ann Plast Surg 36: 37e43, 1996
Kessler P, Grabenbauer G, Leher A, Schultze-Mosgau S, Rupprecht S,
Neukam FW: Patients with oral squamous cell carcinoma. Long-
term survival and evaluation of quality of life-initial results
obtained with two treatment protocols in a prospective study.
Mund Kiefer Gesichtschir 8: 302e310, 2004
Kiener JL, Hoffman WY, Mathes SJ: Influence of radiotherapy on
microvascular reconstruction in the head and neck region. Am J
Surg 162: 404e407, 1991
Kirita T, Ohgi K, Shimooka H, Yamanaka Y, Tatebayashi S,
Yamamoto K, Mishima K, Sugimura M: Preoperative concurrent
chemoradiotherapy plus radical surgery for advanced squamous
cell carcinoma of the oral cavity: an analysis of long-term results.
Oral Oncol 35: 597e606, 1999
Kirita T, Shimooka H, Yamanaka Y, Tatebayashi S, Yamamoto K,
Nishimine M, Sugimura M: Prognostic value of response to
preoperative chemoradiotherapy and residual tumour grades in
tongue carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 91: 293e300, 2001
Klug C, Keszthelyi D, Ploder O, Sulzbacher I, Voracek M, Wagner A,
Millesi W, Kornek G, Kainberger F, Kermer C, Selzer E:
Neoadjuvant radiochemotherapy of oral cavity and oropharyngeal
cancer: evaluation of tumour response by CT differs from
histopathologic response assessment in a significant fraction of
patients. Head Neck 26: 224e231, 2004
Klug C, Neuburg J, Glaser C, Schwarz B, Kermer C, Millesi W:
Quality of life 2e10 years after combined treatment for advanced
oral and oropharyngeal cancer. Int J Oral Maxillofac Surg 31:
664e669, 2002
Klug C, Wutzl A, Kermer C, Voracek M, Kornek G, Selzer E,
Glaser C, Poeschl PW, Millesi W, Ewers R: Preoperative
radiochemotherapy and radical resection for stages IIeIV oral and
oropharyngeal cancer: outcome of 222 patients. Int J Oral
Maxillofac Surg 34: 143e148, 2005a
Klug C, Wutzl A, Kermer C, Ploder O, Sulzbacher I, Selzer E,
Voracek M, Oeckher M, Ewers R, Millesi W: Preoperative
radiochemotherapy and radical resection for stages II to IV oral and
oropharyngeal cancer: grade of regression as crucial prognostic
factor. Int J Oral Maxillofac Surg 34: 262e267, 2005b
Klug C, Berzaczy D, Voracek M, Enislidis G, Rath T, Millesi W,
Ewers R: Experience with microvascular free flaps in
preoperatively irradiated tissue of the oral cavity and oropharynx in
303 patients. Oral Oncol 41: 738e746, 2005c
Knobber D, Sack H, Stutzer H, Rose KG: Pre-irradiation and surgery
of patients with squamous cell carcinoma of the oral cavity and
oropharynx: the results of a 1973e1984 study. Strahlenther Onkol
163: 706e713, 1987
Kovacs AF: Maximized combined modality treatment of an unselected
population of oral and oropharyngeal cancer patients. Final results
of a pilot study compared with a treatment-dependent prognosis
index. J Craniomaxillofac Surg 34(2): 74e84, 2006
Kramer S, Gelber RD, Snow JB, et al: Combined radiation therapy and
surgery in the management of advanced head and neck cancer:
final report of study 73-03 of the Radiation Therapy Oncology
Group. Head Neck Surg 10: 19e30, 1987
Kunkel M, Forster GJ, Reichert TE, Kutzner J, Benz P, Bartenstein P,
Wagner W: Radiation response non-invasively imaged by [18F]FDG-
PET predicts local tumour control and survival in advanced oral
squamous cell carcinoma. Oral Oncol 39: 170e177, 2003
Kurita H, Ohtsuka A, Kobayashi H, Kurashina K, Shikama N,
Oguchi M: Non-randomised study on the effects of preoperative
radiotherapy and daily administration of low-dose cisplatin against
those of radiotherapy alone for oral cancer e effects on local
control, control of metastases, and overall survival. Gan To
Kagaku Ryoho 27: 59e64, 2000
Lung T, Tascau OC, Almasan HA, Muresan O: Head and neck cancer,
treatment, evolution and post therapeutic survival e part 2: a decade’s
results 1993e2002. J Craniomaxillofac Surg 35(2): 126e131, 2007
Mohr C, Bohndorf W, Carstens J, Harle F, Hausamen JE, Hirche H,
Kimmig H, Kutzner J, Muhling J, Reuther J: Preoperative
Preoperative chemoradiotherapy in the management of oral cancer 87
radiochemotherapy and radical surgery in comparison with radical
surgery alone: a prospective, multicentric, randomised DOSAK
study of advanced squamous cell carcinoma of the oral cavity and
the oropharynx (a 3-year follow-up). Int J Oral Maxillofac Surg 23:
140e148, 1994
Muller RP, Staar S, Samek M, Pape HD: Simultaneous preoperative
radiochemotherapy with cisplatin in advanced oral cavity
carcinomas: acute response and follow-up. Recent Results Cancer
Res 134: 165e172, 1994
Olasz L, Kwashie F, Herczegh P, Bruncsics Z, Horvath A,
Kiralyfalvi L: A comparative study of preoperative B-V-M-M
chemotherapy and irradiation in advanced squamous cell cancer of
the oral cavity. Neoplasma 43: 51e56, 1996
Pignon JP, Bourhis J, Domenge C, Designe L: Chemotherapy added to
locoregional treatment for head and neck squamous-cell
carcinoma: three meta-analyses of updated individual data.
MACH-NC Collaborative Group. Meta-analysis of chemotherapy
on head and neck cancer. Lancet 355: 949e955, 2000
Pignon JP, Hill C: Meta-analyses of randomised clinical trials in
oncology. Lancet Oncol 2: 475e482, 2001
Robbins KT, Samant S, Vieira F, Kumar P: Presurgical cytoreduction
of oral cancer using intra-arterial cisplatin and limited concomitant
radiation therapy (Neo-RADPLAT). Arch Otolaryngol Head Neck
Surg 130: 28e32, 2004
Schmelzeisen R, Neukam FW, Shirota T, Specht B, Wichmann M:
Postoperative function after implant insertion in vascularized bone
grafts in maxilla and mandible. Plast Reconstr Surg 97: 719e725,
1996
Shikama N, Sasaki S, Nishikawa A, Koiwai K, Yoshino F, Hirase Y,
Kawakami R, Kadoya M, Oguchi M: Risk factors for locale
regional recurrence following preoperative radiation therapy and
surgery for head and neck cancer (stage IIeIVB). Radiology 228:
789e794, 2003
Sinikovic B, Hofele C, Karstens JH, Eckardt A: Preoperative
radiochemotherapy in stage III and IV squamous cell carcinoma of
the oral cavity: completed phase II study with a 6 year follow-up.
Int J Oral Maxillofac Surg 34(Suppl): 27, 2005
Slotman GJ, Doolittle CH, Glicksman AS: Preoperative combined
chemotherapy and radiation therapy plus radical surgery in
advanced head and neck cancer: five-year results with impressive
complete response rates and high survival. Cancer 69: 2736e2743,
1992
Szabo G, Kreidler J, Hollmann K, Kovacs A, Nemeth G, Nemeth Z,
Toth-Bagi Z, Barabas J: Intra-arterial preoperative cytostatic
treatment versus preoperative irradiation: a prospective,
randomised study of lingual and sublingual carcinomas. Cancer 86:
1381e1386, 1999
The Nordic Cochrane Centre: Review manager (RevMan) [computer
program]. Version 4.2 for Windows. Copenhagen: The Nordic
Cochrane Centre, 2003
Tupchong L, Scott CB, Blitzer PH, Marcial VA, Lowry LD,
Jacobs JR, Stetz J, Davis LW, Snow JB, Chandler R:
Randomised study of preoperative versus postoperative radiation
therapy in advanced head and neck carcinoma: long-term
follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys
20: 21e28, 1991
Uno T, Yasuda S, Nakano K, Aruga T, Isobe K, Kawakami H,
Ueno N, Kawata T, Numata T, Nagata H, Okamoto Y, Ito H:
Preoperative radiation therapy for carcinoma of the oropharynx:
prognostic factors for locoregional control and survival. In Vivo
17: 239e244, 2003
Valente G, Vercellino V, Corradi L, Tardy A, Bertetto O, Pomatto E,
Palestro G: Histopathological findings after preoperative chemo-
radiotherapy in oral and oropharyngeal carcinoma. A study of 28
resected specimens. Eur J Cancer B Oral Oncol 29B: 113e117,
1993
Wanebo H, Chougule P, Ready N, Safran H, Ackerley W, Koness RJ,
McRae R, Nigri P, Leone L, Radie-Keane K, Reiss P, Kennedy T:
Surgical resection is necessary to maximize tumour control in
function-preserving, aggressive chemoradiation protocols for
advanced squamous cancer of the head and neck (stage III and IV).
Ann Surg Oncol 8: 644e650, 2001
Wanebo HJ, Chougule P, Akerley 3rd WL, Koness RJ, McRae R,
Nigri P, Leone L, Ready N, Safran H, Webber B, Cole B:
Preoperative chemoradiation coupled with aggressive resection as
88 Journal of Cranio-Maxillofacial Surgery

needed ensures near total control in advanced head and neck Clemens KLUG, MD, DMD, PhD
cancer. Am J Surg 174: 518e522, 1997 Hospital of Cranio-Maxillofacial and Oral Surgery
Warnakulasuriya S: Global trends in the epidemiology of oral cancer: Medical University of Vienna, AKH
the current position. Oral Oncol 1(Suppl): 27, 2005 Währinger Gürtel 18-20, A-1090 Vienna, Austria
Wennerberg J: Pre versus post-operative radiotherapy of resectable
squamous cell carcinoma of the head and neck. Acta Otolaryngol Tel. +43 1 40400 4259
115: 465e474, 1995 Fax: +43 1 40400 4253
Zamboglou N, Schnabel T, Kolotas C, Achterrath W, Strehl H, E-mail: clemens.klug@meduniwien.ac.at
Dalhauser S, Vogt HG: Carboplatin and radiotherapy in the
treatment of head and neck cancer: six years’ experience. Semin Paper received 6 February 2007
Oncol 21(Suppl 12): 45e53, 1994 Accepted 5 June 2007