Preoperative chemoradiotherapy in the management of oral cancer: A review

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, Wa¨hringer Gu¨rtel 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 chemoradiotherapy (CRT) and subsequent radical resection are used much less frequently than postoperative treatment 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 remarkably 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. Prospective randomised studies are mandatory in this area. Ó 2007 European Association for Cranio-Maxillofacial Surgery

Keywords: oral cancer, preoperative, chemoradiotherapy

method is advantageous regarding morbidity and qualityof-life after therapy. The aim of the present review is to summarise all available experience with concepts of preoperative CRT, not to provide treatment recommendations or guidelines.

INTRODUCTION 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 pharyngeal 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 unanimity 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 consensus of opinion regarding the chronological sequence of surgery, RT, and/or CT. In literature searches, studies employing adjuvant strategies of RT or chemoradiotherapy (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 analytical reports. The published literature fails to provide sufficient data as to whether there is a prognostic difference between the two approaches for the treatment of advanced operable tumours. Likewise, it is not clear which

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 tumours were not diagnosed as advanced squamous call carcinoma (SCC). Studies referring to therapeutic concepts other than preoperative CRT or preoperative RT were also excluded. Articles which were identified as duplicate 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 Keywords Preoperative Radiochemotherapy CRT RT CT Chemoradiation

1 2 3 Oral cancer + keywords below x x x x x x x

Total hits per search

22

13

78

283

2

83

0 0 0 0 5 12 0

0 0 0 0 3 6 1

6 5 1 14 9 30 7

91 25 2 25 11 103 11

0 0 0 0 1 0 1

0 17

0 10

1 73

9 277

5

3

5

6

Excluded because of Publication date Localisation Diagnosis Therapeutic concept Redundant data Lack of data Found in previous searches Language Excluded per search Included per search

4

5

x

x

6 7 8 9 Head neck cancer + keywords below x x x x

x

10 x

x x

x

153

647

1549

111

0 53 0 1 8 14 5

2 135 0 3 3 6 4

64 453 15 22 14 61 12

483 766 12 29 16 211 19

0 105 1 0 2 0 3

0 2

1 82

0 153

5 646

7 1543

0 111

0

1

0

1

6

0

x

x

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

languages. Additional searches in the EMBASE database, congruent with those detailed above, revealed no further studies. Next, the reference lists of all articles retrieved from the PubMed searches, which were eligible for inclusion, were searched for citation of possible further studies of relevance. This procedure yielded four further 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-analysis was consensually selected by two investigators (CK and DB).

sampling error, but rather due to between-study heterogeneity. 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 performed an ecologic regression analysis of reported survival 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 predictor variables.

Data extraction

RESULTS

Data extraction from the individual studies was done independently, according to a previously created data extraction 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.

Included studies

Statistical methods We performed a meta-analysis of the single-group survival 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 Hedges 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

Based on the inclusion criteria, 32 publications (totalling 2978 patients) from 10 countries (see Fig. 1) were eligible for the meta-analysis. These included (a) three prospective 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 multinational studies in the sample. Depending on the outcomes investigated, subsequent analyses were based on the following patient sample sizes: 2978 (total), 2015 (preoperative 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 (inverse of the precision of the effect size). Treatment description All studies included at least one study arm in which a preoperative treatment concept was used (see Table 2 for

Preoperative chemoradiotherapy in the management of oral cancer 77

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 studies (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 postoperative 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) individual 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 located in the oral cavity and the oropharynx in 22 studies (1381 patients), whereas other locations, such as the hypopharynx and the larynx, were included in nine studies

(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 studies (median rate, 5%; range, 0e9.4%). Histopathological response evaluation Tumour response to preoperative RT or CRT was analysed 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; Wanebo et al., 1997, 2001; Kirita et al., 1999, 2001; Giralt et al., 2000; Brun et al., 2001; Hermann et al., 2001; Eckardt et al., 2002; Uno et al., 2003; Robbins et al., 2004; Klug et al., 2005b). In the studies in which all subjects

Ref.

Country

Organ preservation

Study type

Enrolment period

N tot. study

Knobber et al. (1987) Kramer et al. (1987) Chang et al. (1988) Dobrowsky et al. (1991) Slotman et al. (1992) Hansen et al. (1993) Valente et al. (1993) Chougule et al. (1994) Glicksman et al. (1994) Mohr et al. (1994) Muller et al. (1994) Zamboglou et al. (1994) Olasz et al. (1996) Glicksman et al. (1997) Goodman et al. (1997) Wanebo et al. (1997) Kirita et al. (1999) Szabo et al. (1999) Giralt et al. (2000) Kurita et al. (2000) Brun et al. (2001) Chao et al. (2001)

D

n

p

1973e1984

87

US

n

p, ra, mu

1973e1979

277

Hermann et al. (2001) Kirita et al. (2001) Wanebo et al. (2001) Eckardt et al. (2002) Kunkel et al. (2003) Shikama et al. (2003)

Age

m/f

% Oral

87

54m (36e76)

71/16

100.0

43

na

35/8

N tot. preop. RT

md

% III/IV

Treatment

Total RT dosage

Fractions

75.9

rt

49.1

20e25

100.0

89.3

rt

50

25

US A

y* n

p p

1984e1987 1985e1988

43 70

41 70

60 (36e80) 56md (29e79)

33/10 62/8

na 100.0

100.0 97.0

cis mmc, 5-FU

45 50

25 25

US

n

r

1982e1988

53

41

62m (44e84)

51/2

52.8

100.0

cis

45

25

md

rt

45

23md

100.0

cis, 5-FU

20x

10

45.0

100.0

cis

45

25

89/12

45.0

100.0

cis

45

25

54.6 57md

103/24 109/27

100.0 100.0

95.2 80.0

cis cis

36 39.6

18 22

57md (31e77)

na

79.0

98.0

carb

50

25

DK

n

r

1969e1985

62

62

63.6

I

n

p

nae1990

28

28

US

yy

p

1984e1990

68

68

US

yy

p

1983e1992

101

101

D D

n n

p, ra, mu p

1989e1992 1986e1991

268 136

127 101

D

n

p, mu

1987e1991

103

30

(27e87)

31/31

100.0

59.7

58.5md (24e79)

26/2

100.0

na

51/17

64md (29e84) m

m

md

H US (CH)

n yy

r p, mu, mn

1976e1993 1992e1996

50 74

50 74

56 61md (42e80)

42/8 59/15

100.0 48.6

76.0 100.0

rt cis

51.1 46.8

25e30 26

US

n

r

1990e1996

40

40

62.8m

27/13

56.8

100.0

cis

45

25

US

n

p

na

35

35

(40e71)

29/6

45.7

100.0

pac, carb

45

25

58.5 (43e84) 52.6m (35e69) 57md (39e74) na 61md (22e79) 58md (33e83)

30/18 83/12 56/6 na 26/13 80/29

100.0 100.0 100.0 100.0 100.0 100.0

85.4 100.0 100.0 100.0 61.5 71.0

cis/carb, pep/5-FU rt cis, 5-FU cis (50%) cis, 5-FU (10%) rt

20 23 33 15e20 25 na

55md (41e96)

41/2

100.0

100.0

ifo/cis

40 46 60 30e40 50 30md (28e72) 30

J H (A, D) E J SE US

n n y* n n n

r p, ra, mu, mn p p r r

1988e1994 1986e1991 1993e1996 na 1990e1994 1970e1999

48 131 62 20 39 430

48 48 62 20 39 109

D

n

r

1995e1996

43

43

md

md

20

J US

n yy

r p

1988e1999 1995e2000

43 43

43 43

59.8 (26e85) (37e81)

32/11 33/10

100.0 67.4

69.8 100.0

cis/carb, pep/5-FU pac, carb

40 45

20 25

D

n

r

1998e2000

53

53

57md (33e76)

44/9

100.0

100.0

pac, carb

40

20

D

n

r

1995e1999

35

35

59m (34e80)

27/8

100.0

100.0

cis (77.1%)

36k

18

J

n

r

1987e1999

161

161

64m(27e83)

na

51.0

82.0

cis, 5-FU

38md (20e66)

na

78 Journal of Cranio-Maxillofacial Surgery

Table 2 e Summary of studies selected for meta-analysis

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, multinational. Treatment: rt, radiotherapy only; cis, cisplatin; carb, carboplatin; 5-FU, 5-fluorouracil; mmc, mitomycin; pac, paclitaxel; pep, peplomycin; ifo, ifosfamide. * Based on clinical findings. y Based on biopsy findings. z Based on nidusectomy findings. x Additionally 40 Gy postoperative. k Additionally 24 Gy postop when extranodal spread.

25 50 mmc, 5-FU 78.9 181/41 n A

r

1990e2000

222

222

55md (32e83)

100.0

20 25 cis, 5-FU cis 84.6 92.0 100.0 100.0 48/5 18/7 54.2m (34e78) 60md (18e71) n yz D US

Kessler et al., 2004 Robbins et al. (2004) Klug et al. (2005a,b)

p p

1999e2000 1995e2000

53 25

26 25

67/8 n J Uno et al. (2003)

r

1986e2000

75

40

61md (33e85)

100.0

80.0

cis, 5-FU/pep

60md (40e70) 50 50

na

Preoperative chemoradiotherapy in the management of oral cancer 79

underwent surgery, the specimens obtained from radical surgery were investigated in all patients (Knobber et al., 1987; Dobrowsky et al., 1991; Slotman et al., 1992; Valente et al., 1993; Mohr et al., 1994; Muller et al., 1994; Zamboglou et al., 1994; Goodman et al., 1997; Wanebo et al., 1997; Kirita et al., 1999, 2001; Brun et al., 2001; Hermann et al., 2001; Eckardt et al., 2002; Uno et al., 2003; Klug et al., 2005b). In studies with organ preservation protocols, the samples were obtained by multiple biopsies (Chang et al., 1988; Chougule et al., 1994; Glicksman et al., 1997; Giralt et al., 2000; Wanebo et al., 2001) or nidusectomy (Robbins et al., 2004). Histopathological response was classified according to different criteria and in different gradients. However, complete histopathological response (pCR; median proportion, 48.2%; range, 26.7e74.6%) was unanimously defined by all authors as the complete absence of vital tumour cells. A statistically significant association between favourable histopathological response 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; 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 response 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 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 for the survival estimation the longest available was chosen for the meta-analysis. Mean survival rates weighted according to N survival are given in the bottom line of each block of studies in Fig. 2. Concerning the ecological regression model, for obvious reasons, years of survival estimation were entered into the model first. As expected, the model was significant, 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 other words, the regression model results indicated a 5.65% change (decrease) in the survival rate per unit increase in the predictor (years of survival estimation). Following this, statistical control for varying survival estimations (1e5 years) across studies, the further three predictors (midpoint of study enrolment period, organ preservation protocol, and preoperative protocol) were entered into the model. The regression model remained significant after this second-block variables had been entered, F(4,31) ¼ 9.33, p \ 0.001, adjusted R2 ¼ 0.52. The change in variance explained by the second-block variables was significant, DR2 ¼ 0.38, DF(3,26) ¼ 8.21, p\ 0.001. Thus, the three further predictor variables explained significantly more variation in the survival rates over and above the variation explained (and thereby statistically controlled) by varying survival estimations.

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) Kramer et al. (1987) Chang et al. (1988) Dobrowsky et al. (1991) Slotman et al. (1992) Hansen et al. (1993) Valente et al. (1993) Chougule et al. (1994) Glicksman et al. (1994) Mohr et al. (1994) Muller et al. (1994) Zamboglou et al. (1994) Olasz et al. (1996) Glicksman et al. (1997) Goodman et al. (1997) Wanebo et al. (1997) Kirita et al. (1999) Szabo et al. (1999) Giralt et al. (2000) Kurita et al. (2000) Brun et al. (2001) Chao et al. (2001) Hermann et al. (2001) Kirita et al. (2001) Wanebo et al. (2001) Eckardt et al. (2002) Kunkel et al. (2003) Shikama et al. (2003) Uno et al. (2003) Kessler et al. (2004) Robbins et al. (2004) Klug et al. (2005a,b)

na 60 20md (9e38) (18e54) 40md (20e96) 146.4md (30e55) na 41md (10e108) (30e60) 38md 10md (7e20) 36 26md (12e48) 36.5md 12md 86md (61e144) 60 39md (33e69) na 48min 54md (18e276) 25md 60.5md (8e152) 50md (45e60) 21md (1e40) na 47md 74md na 56md (28e84) 72.3md (24e152)

3 4 3 3 3 5 3 5 5 3 3 2 3 3 5 1 5 5 3 2 5 2 2 5 4 3 3 5 5 3 5 5

41 (29.1e52.9) 30.2 (16.5e43.9) 45 (29.8e60.2) 61 (49.6e72.4) 58.5 (43.4e73.6) 53.2 (40.8e65.6) 82 (67.8e96.2) 32 (20.9e43.1) 49 (39.3e58.8) 81.4 (74.6e88.2) 79 (71.1e86.9) 69 (52.5e85.6) 57 (43.3e70.7) 54 (42.6e65.4) 60 (44.8e75.2) 83 (70.6e95.4) 80.5 (68.4e92.6) 31.3 (18.1e44.4) 76 (65.4e86.6) 60 (38.5e81.5) 46 (30.4e61.6) 67 (58.2e75.8) 56 (41.2e70.84) 83.3 (69.95e96.7) 68 (54.1e81.9) 84 (74.1e93.9) 68.6 (53.2e84.0) 58 (50.4e65.6) 56 (40.6e71.4) 78 (62.1e93.9) 54 (34.5e73.5) 56 (48.7e63.4)

27 10 18 43 24 33 23 22 49 103 80 21 29 40 24 29 33 15 47 12 18 73 24 25 29 44 24 93 22 20 14 98

66z 43x 41 70x 41 62x 28 68 101 127x 101x 30x 50x 74 40 35 41z 48 62 20 39x 109x 43 30z 43 53 35 161x 40x 26x 25x 175z

na 8.1 na na 9.4 na 3.6 na 5.0 na na na na 1.4 na 2.9 0 2.1 0 na na na na na 2.3 0 na na na na 4.0 5.4

na 11 na na 5 na 1 na 5 na na na na 1 na 1 0 1 0 na na na na na 1 0 na na na na 1 12

na 136 na na 53 na 28 na 101 na na na na 74 na 35 48 48 62 na na na na na 43 53 na na na na 25 222

33.3 na 52.6 48.6 65.9 na 53.6 51.9 na 37.0 36.6 26.7 na 74.6 52.5 67.6 50.0 na 58.0 na 48.7 na 39.5 58.1 50.0 57.7 na na 35.0 na 73.7 48.2

29 na 10 34 27 na 15 14 na 47 37 8 na 44 21 23 24 na 29 na 19 na 17 25 19 30 na na 14 na 14 107

87 na 19 70 41 na 28 27 na 127 101 30 na 59 40 34 48 na 50 na 39 na 43 43 38 52 na na 40 na 19 222

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. Treatmentrelated 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.

80 Journal of Cranio-Maxillofacial Surgery

Table 3 e Outcomes of studies selected for meta-analysis

Preoperative chemoradiotherapy in the management of oral cancer 81

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 estimation + 0.65  mid-enrolment year  13.30  organ preservation (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; decreased by 13.30% for studies involving an organ preservation protocol relative to studies with radical resection; and increased by 14.33% for CRT studies relative 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 follows: years of survival estimation b ¼ 0.47 (t ¼ 3.69, p \0.001); midpoint of study enrolment period b ¼ 0.25

(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 protocol 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 ecologic regression model described in Methods section, our subsequent analyses focused on the two subgroups of studies reporting 3- and 5-year survival rates which constituted 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 regression model. In a first step, we excluded those studies in the subgroups with survival rates for 3 and 5 years that used a preoperative RT protocol (Knobber et al., 1987; Slotman et al., 1992; Olasz et al., 1996; Szabo et al., 1999; Brun et al., 2001). Excluding these studies, the mean survival rate was 73.4% (70.2e76.7%) for the 3-year group, still preserving much of the heterogeneity in outcomes 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; Glicksman 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 studies in this group was 62.6% (58.4e66.8%). Among the group of remaining studies with preoperative CRT and radical resection in all cases, the Deutsch¨ sterreichisch-Schweizerischer Arbeitskreis fu¨r Tumoren O ¨ SAK) study (Mohr et al., im Kiefer-Gesichtsbereich (DO 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 surgery alone-arm. Both groups were similar in their patient and tumour characteristics as demonstrated with the ¨ SAK’s computer-aided individual prognosis (CIP) DO survival estimation provided for both groups as well as during follow-up. An improvement in survival of 20% after 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 existing 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); secondly, the heterogeneity of the studies included in the review. 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 therapy as well as to throw light on important accompanying factors such as morbidity, post-therapeutic quality-oflife, 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 definitions were inhomogeneous. Data of disease-specific survival, progression-free survival, local control, locoregional control, and disease control were collected. However, 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 treatment concept (CRT vs. RT) and organ preservation (organ preservation in selected patients vs. radical resection in all patients) were determined as useful criteria. Sensitivity analysis leads to a reduction of inter-study heterogeneity after exclusion and showed an improvement 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 resectability 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-analysis 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) mentioned 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 prevertebral fascia, the internal carotid artery, and the skull base (Klug et al., 2005a). Similarly, clear definitions of ¨ SAK the surgical procedure were included in the DO study (Mohr et al., 1994). Differences in the assessment depend on various factors: the surgeon’s skills and experience as well as his opinion on extensiveness of surgery; but they also result from infrastructural differences of institutions. It has to be mentioned that many studies do not provide exact data about their criteria for nonresectability; 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* Pignon et al. (2000) 10,741

Enrolment 1965e1993

Pignon et al. (2000)

1965e1993

El-Sayed and Nelson (1996)

861

3708

na

Randomised trials of postoperative CRT Ref. N patients* Enrolment Cooper et al. (2004) 416 1995e2000

Bernier et al. (2004)

334

1994e2000

Characteristics MA1 (63 trials): LRT (RT or surgery) with CT (CT+) vs. LRT without CT (CT) in advanced HNSCC MA 2 (six trials): neoadjuvant with or without adjuvant CT plus RT vs. concomitant or alternating CRT in patients with advanced HNSCC rated inoperable MA (25 trials): local definitive treatment (RT, surgery or both) vs. LRT with adjuvant or adjunctive CT

Results 5-YSR: 36% CT+, 32% CT 5-YSR: 27% CT+, 24% CT

5-YSR: 30% CT+, 23% CT

Patient description Protocol description Results 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% 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 postoperative 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 favour 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 randomised 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 hypopharynx (32% oral locations, therefore it is not included 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 preoperative and postoperative multi-modality concepts with concomitant CT for tumours located in the oral cavity 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 differences in survival (similar to Tupchong et al., 1991). Taken together, the available data do not allow an assessment 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 randomised study of the preoperative concept is the study of ¨ SAK (Mohr et al., 1994). It showed a significantly the DO better 3-year overall survival in the preoperative multimodal 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 included stage I/II tumours with unfavourable pathological findings as well as stage III/IV tumours and including sites other than oral). Nevertheless, for hypothesis generation, 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 uncertain. 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 eagerly anticipated (Sinikovic et al., 2005). Influence of radiation dose The analysis of the influence of the administered focal radiation dose showed no significant association between this parameter and survival; an association of this type was also not anticipated because of the relatively homogeneous distribution of the radiation dose. Interestingly, in the preoperative approach, a median radiation dose of 45 Gy is administered. Most protocols for postoperative 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 speculated that the preoperative approach with a lower radiation 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 patient, 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 concerning 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 studies, an analysis of this nature was performed. However, histopathological response was graded very diversely in these studies. Definitions were comparable only with respect 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 approaches. 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 procedure 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 surgery. 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-analysis, which revealed a somewhat better survival for studies 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 controlled 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 behaviour 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 tumour 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 expected 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 response. These factors include the oxygen saturation of tumour tissue, depending on the haemoglobin content of peripheral blood (Glaser et al., 2001) and the microvessel density of the tumour (Brun et al., 2001). In both studies, significant associations were observed between the analysed factor, histopathological response and survival. In any case, it was found that the preoperative setting 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 of the preoperative therapy used. Morbidity and mortality According to the conclusions drawn in the studies included in this analysis, the toxicity grades of the pretreatment did not cause any of the authors to deviate from the preoperative approach or alter the protocol. Violations of the protocol, discontinuation of therapy, and death during preoperative therapy were reported in isolated cases and also did not cause any deviation from the therapy concept. The highest mortality rates were reported (Kramer et al., 1987; Slotman et al., 1992) as 8.1% and 9.4%; in these studies the enrolment period ended before or during the year 1988. In studies that 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 should be remembered that when a rigid concept of preoperative RT/CRT and radical surgery is applied in all cases, some patients might well be over-treated. If one presumes a histologically complete remission rate of 48% (the median value of our meta-analysis), it may be surmised that an over-invasive approach is used in one half of all patients, and that morbidity and mortality will be increased by this approach. Therefore, the quest for a single criterion that allows a decision for organ preservation without impairing survival is a major goal. However, meta-analysis showed that studies in which the decision for organ preservation was based on biopsy yielded somewhat poorer survival rates (statistically significant in the ecologic regression analysis, but not statistically significant, in the meta-analysis) than those in which a rigid concept was employed. In all studies, survival was significantly better in patients with pCR after preoperative therapy than in the other groups; nevertheless, we also see locoregional failure in some of these patients. Research plays a major role in this context. It may be hoped that molecular markers before and after preoperative CRT will allow the assessment of the prognosis with greater certainty than has been achieved thus far with clinical procedures. The use of a suitable criterion to guide the decision for or against organ preservation will allow morbidity and mortality to be reduced most effectively in the entire population. Post-therapeutic quality-of-life Post-therapeutic quality-of-life (QOL) is being given increasing importance since the mid-1990s. Several questionnaires have been developed; these include specific questions for patients with head and neck tumours. Kessler et al. (2004) performed a longitudinal QOL analysis, including a comparison between the preoperative and the postoperative arm. It was found that, after initial disadvantages in the preoperative group, self-assessed QOL after 1 year was comparable in both groups. These dynamics appear to be plausible in the preoperative group after a longer postoperative period of convalescence. In our own QOL analysis for long-term survivors after

multi-modality therapy with preoperative CRT, the results 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 QOL investigations, coping mechanisms were not assessed, and may have levelled any differences. Furthermore, it should be noted that patients with recurrent disease have significantly poorer QOL than tumour-free patients. Therefore, in tumour treatment, the achievable post-therapeutic QOL after the application of a therapy concept cannot be viewed separately from the success rate of the treatment. In a therapy concept with a lower survival rate, it may be assumed that a larger number of patients die because of recurrent disease, and consequently with poor QOL. This group of patients is under-represented in most studies investigating QOL in cancer patients. Surgical aspects In his review Wennerberg (1995) summarised the mode of thought pursued by doctors involved in multi-modality treatment concepts: ‘‘radiotherapists do not like to irradiate a scar and surgeons prefer to cut in fresh tissue.’’ From a surgical point of view, many different aspects must be considered when deciding whether one should perform pre- or postoperative CRT. The published literature contains contradictory data concerning the difficulty of surgery after preoperative CRT. Subjectively, many surgeons confirm that this is the case (Bengtson et al., 1993). However, it was not objectively confirmed in studies that registered and compared the duration of surgery (Kiener et al., 1991). There is also no consensus of opinion about the potentially higher rate of postoperative morbidity and more frequent occurrence of local complications such as wound dehiscence or prolonged duration of hospitalisation. Our own investigation in 303 patients (Klug et al., 2005c) showed an elevated morbidity rate among preoperatively irradiated patients, but this was not in agreement with the evidence of Bengtson et al. (1993) and Kiener et al. (1991), both of whom did not register a higher morbidity or complication rate in reconstructive surgery after RT. In view of long-term outcome of surgery, a further aspect has to be considered; surgery performed in a large number of advanced tumours of the oral region involves more complex reconstructive measures, specifically the use of the free flap technique. In this regard, the currently predominant opinion may be summarised as follows: our own investigation (Klug et al., 2005c) yielded a success rate of 93% for free flaps after preoperative radiation with 50 Gy, which is well within the success range for unradiated tissue and is in agreement with the data reported by Bengtson et al. (1993), Guelinckx et al. (1984), Jones et al. (1996), and Kiener et al. (1991), all of whom found no significant difference when compared with untreated tissue. In cases of secondary reconstruction in the presence of infected osteoradionecrosis, however, one may expect poorer results (Sinikovic et al., 2005). This is because greater tissue damage occurs after definitive RT with 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 employed when the preoperative RT has been given. Particularly for the reconstruction of bone after segmental mandibulectomy, this aspect is relevant with regard to prosthetic rehabilitation with osseointegrated dental implants (Schmelzeisen et al., 1996), because a postoperatively 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 (histopathological 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, appears to be remarkably good. Since the findings of our literature-based analysis are based on data with a large proportion of studies with consecutive patient series they do not justify any treatment recommendations. Compared with the postoperative RT protocol, hard evidence such as sufficient data from prospective randomised studies 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 highrisk 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 cisplatinum 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

Preoperative chemoradiotherapy in the management of oral cancer 87 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. Longterm 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]FDGPET 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

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 chemoradiotherapy 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 cancer. Am J Surg 174: 518e522, 1997 Warnakulasuriya S: Global trends in the epidemiology of oral cancer: the current position. Oral Oncol 1(Suppl): 27, 2005 Wennerberg J: Pre versus post-operative radiotherapy of resectable squamous cell carcinoma of the head and neck. Acta Otolaryngol 115: 465e474, 1995 Zamboglou N, Schnabel T, Kolotas C, Achterrath W, Strehl H, Dalhauser S, Vogt HG: Carboplatin and radiotherapy in the treatment of head and neck cancer: six years’ experience. Semin Oncol 21(Suppl 12): 45e53, 1994

Clemens KLUG, MD, DMD, PhD Hospital of Cranio-Maxillofacial and Oral Surgery Medical University of Vienna, AKH Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria Tel. +43 1 40400 4259 Fax: +43 1 40400 4253 E-mail: [email protected] Paper received 6 February 2007 Accepted 5 June 2007