Journal of Cranio-Maxillofacial Surgery (2009) 37, 344e347

Ó 2009 European Association for Cranio-Maxillofacial Surgery

doi:10.1016/j.jcms.2008.11.012, available online at http://www.sciencedirect.com

Preoperative radiochemotherapy in the treatment of advanced oral cancer:

Outcome of 276 patients

Clemens KLUG, MD, DMD, PhD1,2, Dominik BERZACZY, MD1,2, Martin VORACEK, DSc, PhD1,2,
Christina NELL, MD, DMD1,2, Oliver PLODER, MD, DMD, PhD2,3, Werner MILLESI, MD, DMD, PhD2,4,
Rolf EWERS, MD, DMD, PhD1,2
1
Hospital of Cranio-Maxillofacial and Oral Surgery, Medical University of Vienna, Austria; 2 Department of Basic
Psychological Research, School of Psychology, University of Vienna, Austria; 3 Department for Oral and Maxillofacial
Surgery, Feldkirch Hospital, Feldkirch, Austria; 4 Department for Oral and Maxillofacial Surgery and Dentistry and
Ludwig Boltzmann Institute for Gerostomatology, Hietzing Hospital, Vienna, Austria

SUMMARY. Introduction: The aim of this study was to review survival and locoregional control in patients with
advanced oral and oropharyngeal squamous cell carcinoma treated by multimodal therapy with preoperative
radiochemotherapy and radical surgery. Material: Retrospective cohort study. Methods: Included in this
analysis are 276 consecutive patients with UICC disease stages III and IV (T2: 13.0%; T3: 16.7%; T4: 70.3%;
N0: 29.7%; N1: 20.3%; N2: 45.3%; N3: 4.7%; stage III: 16.3%; stage IV: 83.7%). All patients received preoperative
radiochemotherapy (50 Gy, Mitomycin and 5-Fluorouracil) and radical locoregional resection. Results: Median
surveillance period was 101.4 months (24e202 months). 5-year overall survival probability was 53.9%. 5-year local
control probability was 70.2%. Conclusion: These results underline the reliability of preoperative treatment of
patients with oral and oropharyngeal cancer. Ó 2009 European Association for Cranio-Maxillofacial Surgery

Keywords: preoperative radiochemotherapy, head and neck, advanced oral and oropharyngeal cancer

INTRODUCTION Inclusion criteria were:

1. UICC stage III and IV SCC of the oral cavity or oro-
Advanced oral and oropharyngeal cancer is regarded as
pharynx.
a growing health problem and the prognosis remains rel-
2. Absence of distant metastases.
atively poor (Warnakulasuriya, 2005). It is widely ac-
3. Resectability of primary tumour according to anatom-
cepted that patients with locoregionally advanced
ically defined criteria (infiltration of the skull base, of
tumours (UICC (international union against cancer) dis-
the internal carotid artery and of prevertebral fascia
ease stages III and IV) and resectable primary tumours
were defined as unresectable).
benefit from combined treatment modalities with surgery,
4. Operability of the patient.
radiotherapy (RT) and chemotherapy (CT) (Mohr et al.,
5. Absence of contraindication to RT and/or CT.
1994; McGurk et al., 2007; Preuss et al., 2007). Yet there
is no consensus whether RT and CT should be adminis- Diagnostic and staging workup included biopsy of the
tered before or after surgery (Seiwert et al., 2007). At our primary tumour site, a CT scan of head and neck, pan-
institution the preoperative approach has been the stan- orex, chest X-ray, sonography of the abdomen and clin-
dard treatment regime since 1990 for all patients with ical inspection and ink tattooing of the tumour extent
squamous cell carcinoma (SCC) staged T2 or worse. under general anesthesia.
We have published the treatment results of 222 consecu- Multimodal treatment included preoperative CT with
tive patients in 2005 (Klug et al., 2005a). The current re- Mitomycin C (15e20 mg/m2 given as intravenous bolus
view continues this work but focuses on patients with injection on day 1), and 5-Fluorouracil (5-day continuous
disease stages III and IV with the intention of improving infusion with 750 mg/m2/day), and RT with a total fo-
comparability with the existing literature. cusal dosage of 50 Gy (given in 25 daily fractions over
5 weeks). Surgery was performed after an interval of
MATERIALS AND METHODS 4e6 weeks. Tumours were resected according to the
pre-treatment extent with a safety margin of 1 cm. Resec-
By December, 31, 2006 a minimum follow-up of 24 tion was carried out in en bloc-technique together with
months had been reached for 276 consecutive patients planned neck dissection (ND) (N0: levels 1e3; N+:
who underwent multimodal therapy from January 1, levels 1e5). In cases of midline transgression, ND was
1990, to December 31, 2004. performed bilaterally.

344
 Preoperative radiochemotherapy in the treatment of advanced oral cancer 345

Table 1 e Patient and tumour characteristics Table 3 e Surgical characteristics

Age mean ^ SD 56.2 ^ 9.1 n %

Age range 28e78
Sex m/f 220 (79.7%)/56 (20.3%) Type of resection
Total 276 (100%) Mandibular partial 46 16.7
Mandibular continuity 198 71.7
Follow-up (mts.) Maxilla partial 14 5.1
Range 24.3e202 Soft tissue 18 6.5
Mean ^ SD 101.4 ^ 44.2
Total 276 100
n % Type of ND
Tumour site Unilateral supraomohyod modified radical ND (sND) 93 33.7
Anterior floor of mouth 140 50.7 Bilateral sND 31 11.2
Tongue 28 10.1 Unilateral modified radical ND (mrND) 83 30.1
mrND and controlateral SND 50 18.1
Retromolar trigone 48 17.4
Bilateral mrND 1 0.4
Alveolar crest 20 7.2
Unilateral radical ND (rND) 9 3.3
Tonsillar fossa 22 8.0
Maxilla 13 4.7 rND and controlateral sND 9 3.3
Cheek 3 1.1 Total 276 100
Palate 1 0.4
Mandibula 1 0.4
Total 276 100
UICC disease stage
III 45 16.3 Table 4 e Type of recurrence
IV 231 83.7
n %
Total 276 100
Event of recurrence total 73 26.4
Local recurrence 27 9.8
Regional recurrence 10 3.6
Table 2 e T vs N Pulmonary metastases 6 2.2
Other distant metastases 18 6.5
N0 N1 N2 N3 Total Local recurrence and pulmonary metastases 4 1.4
Regional recurrence and pulmonary metastases 1 0.4
T2 0 13 23 0 36 Regional recurrence and distant metastases 1 0.4
T3 21 11 12 2 46 Pulmonary and distant metastases 1 0.4
T4 61 32 90 11 194 Local recurrence, pulmonary, and distant metastases 5 1.8
No recurrence 203 73.6
Total 82 56 125 13 276
nor metastases
Total 276 100
Histopathology of resected tumours was conducted
with regard to response to radiochemotherapy (RCT)
and classified in histopathological grades of regression (49.6%) patients were alive and 134 (48.6%) deceased,
(RG). RG1 (no vital tumour cells), RG2 (minimal tumour including 18 (6.5%) early postoperative deaths. Recur-
remnants accounting to less than 5%), RG3 (5e50% vi- rence occurred in 73 (26.4%) patients (for detailed distri-
tal tumour cells), RG4 (more than 50% vital tumour). bution of type of recurrence see Table 4.). Overall 5-year
Acquisition of data was performed with a computerized survival probability was 53.9% (see Fig. 1) and overall 5-
database (Microsoft Excel, Microsoft Corp., USA). Miss- year locoregional control probability was 70.2% (see
ing data were acquired by inquiry of the national register Fig. 2). Histopathological response to RCT classified by
of residence. Patient data included age, sex, tumour grades of regression was distributed as follows: RG1:
site, T-, N- classifications, and UICC- staging (see n:119 (43.1%), RG2: n:51 (18.5%), RG3: n:20 (7.2%),
Tables 1 and 2). Surgical data included type of primary RG4: n:65 (23.6%) (missing values: n:21 (7.6%)).
tumour resection, type of ND and type of flap (see With respect to 5-year overall survival, statistical anal-
Table 3). Outcome data included date and type of recur- ysis showed a significant difference between responders
rence (see Table 4) and date of death where relevant. (regression grades 1 and 2, n:170) and non-responders
The KaplaneMeier method was used to estimate over- (regression grades 3 and 4, n:85) (log-rank test;
all survival and local control. The log-rank test was used p5YROS ¼ 0.001) (see Fig. 3).
for comparison of survival and local control curves of
different groups. Significance was set to p less than
0.05. All statistical analyses were performed using DISCUSSION
SPSS for Windows version 12.0.
The present work reports the results of a retrospective in-
RESULTS vestigation of 276 consecutive patients. Retrospective
analyses in cancer therapy are not regarded as strong ev-
By December, 31, 2006 a minimum follow-up (see Table 1.) idence these days. Nevertheless, we believe that our
of 24 months was reached for 276 consecutive patients. work is a valuable contribution to the current search
Retrievable survival data of 271 patients showed 137 for optimal treatment. Our study design and the
346 Journal of Cranio-Maxillofacial Surgery

overall survival overall survival for responders and non-responders

1,0 1,0
survival function nonresponder
0,9 0,9 responder
censored
0,8 non-responder-censored
0,8 responder-censored
cumulative survival

cumulative survival
0,7 0,7
0,6 0,6
0,5 0,5
0,4 0,4
0,3 0,3
0,2 0,2
0,1 0,1
0,0 0,0
0 12 24 36 48 60 72 84 96 108 120 132 144
0 12 24 36 48 60 72 84 96 108 120 132 144
survival (months) survival (months)
Fig. 1 e 5-year survival probability. Fig. 3 e 5-year survival for responders and non-responders.

locoregional control probability

1,0
control function surgeons with a high degree of specialization and moti-
0,9 censored vation. Whether the applied method is reliable becomes
0,8 evident only after some years. The results reported in
this paper are in the same range as our previous publica-
locoregional control

0,7
tion (Klug et al., 2005a). The actual analysis comprises
0,6
the data of a significantly larger cohort and focuses on
0,5 stage III and IV patients.
0,4 In the recent literature, it is widely agreed that multi-
0,3 modal treatment approaches are superior to any type of
0,2
monotherapy in advanced SSC (Salama et al., 2007). In
cases of resectable tumours surgery is generally com-
0,1
bined with RT either in a preoperative or in a postopera-
0,0 tive setting.
0 12 24 36 48 60 72 84 96 108 120 132 144
survival (months)
Whether one or the other sequence is to be preferred is
still controversial. Hitherto, prospective randomized tri-
Fig. 2 e 5-year locoregional control probability. als comparing pre- and postoperative RCT are missing.
However, the oncological outcomes seem to be in a com-
parable range. 5-year survival rates of locoregionally ad-
characteristics of our treatment protocol fulfill many cri- vanced SCC treated with postoperative RT reported in
teria of a prospective study; all patients received the mul- the prospective randomised RTOG (Radiation Therapy
timodal therapy regime that has been unchanged since Oncology Group, (50%)) and EORTC (European Orga-
1990. Likewise, follow-up is based on a 5-year observa- nization for Research and Treatment of Cancer (53%))
tion period and is applied to all patients. Data update was studies lie in a similar range to the 5-year survival rate
performed on a 2-year cycle by retrospective investiga- of 53.9% for preoperative RCT in our analysis published
tion of our institution’s documentation and interrogation in 2005 (Bernier et al., 2004; Cooper et al., 2004; Klug
of the national register of residence. This procedure ac- et al., 2005b).
counts for the retrospective setting. The present patient However, the discussion relates to side aspects of the
cohort is very homogeneous with a comparatively very treatment concept. Advantages of the preoperative con-
small amount of missing data. Other advantages of the cept shall be addressed first:
current contribution are the long observation period and The preoperative treatment concept allows histological
the large number of patients included. This long-term evaluation of the tumours’ response to RCT. We could
documentation enables a review of the liability and con- demonstrate that the histopathological response is
stancy of therapy modalities in the treatment of oral and a strong predictive factor (Klug et al., 2005c). Concepts
oropharyngeal cancer. with any kind of treatment adaption, like down-staging
Over a 14-year period, the surgical component of the or organ-preserving procedures, depend on response
treatment was carried out by a large number of surgeons. evaluation. In most preoperative protocols, radiation
The constancy in the treatment results as documented in doses are usually lower than for postoperative radiation
previous publications underlines the beneficial influence (RTOG, EORTC) (Bernier et al., 2004; Cooper et al.,
of a consistent therapeutic modality and minimizes the 2004)
influence of individuals (Klug et al., 2005b). Reduced focal dosage appears to be advantageous in
By comparison with studies having shorter enrolment view of the critical complication of infected osteoradio-
periods, the treatment is commonly performed by few necrosis (Goldwaser et al., 2007). Free flaps which are
 Preoperative radiochemotherapy in the treatment of advanced oral cancer 347

used for reconstruction are not compromised by radiation radiochemotherapy and radical resection for stages
if performed after RT. This is especially advantageous II-IV oral and oropharyngeal cancer: outcome of 222 patients.
Int J Oral Maxillofac Surg 34: 143e148, 2005a
with respect to the osseointegration of dental implants Klug C, Berzaczy D, Voracek M, Enislidis G, Rath T, Millesi W,
in bone transplants and therefore is beneficial in respect Ewers R: Experience with microvascular free flaps in
to long-term quality of life (Schmelzeisen et al., 1996). preoperatively irradiated tissue of the oral cavity and oropharynx in
In our experience, disadvantages of the preoperative 303 patients. Oral Oncol 41: 738e746, 2005b
Klug C, Wutzl A, Kermer C, Ploder O, Sulzbacher I, Selzer E,
approach lie in the fact that surgery is performed in Voracek M, Oeckher M, Ewers R, Millesi W: Preoperative
compromised tissue and may be associated with poor radiochemotherapy and radical resection for stages II to IV oral
wound-healing. We summarize our experience with the and oropharyngeal cancer: grade of regression as crucial
preoperative concept supported by present good oncolog- prognostic factor. Int J Oral Maxillofac Surg 34: 262e267,
ical outcome positively. Whether there is a prognostic 2005c
McGurk MG, Fan KF, MacBean AD, Putcha V: Complications
advantage in a pre- or postoperative setting is still not encountered in a prospective series of 182 patients treated
clear and needs further investigation in randomized mul- surgically for mouth cancer. Oral Oncol 43: 471e476, 2007
ticentric studies. Mohr C, Bohndorf W, Carstens J, Harle F, Hausamen JE, Hirche H,
Kimmig H, Kutzner J, Mühling J, Reuther J, Sack H, Schettler D,
Stellmach R, Wagner W, Wannenmacher MF: Preoperative
CONCLUSION radiochemotherapy and radical surgery in comparison with radical
surgery alone: a prospective, multicentric, randomised DOSAK
These results underline the long-term reliability of preop- study of advanced squamous cell carcinoma of the oral cavity and
erative radiochemotherapy and radical surgery in the the oropharynx (a 3-year follow-up). Int J Oral Maxillofac Surg 23:
140e148, 1994
treatment of advanced oral and oropharyngeal cancer. Preuss SF, Dinh V, Klussmann JP, Semrau R, Mueller RP,
Guntinas-Lichius O: Outcome of multimodal treatment for
ACKNOWLEDGEMENT oropharyngeal carcinoma: a single institution experience. Oral
Oncol 43: 402e407, 2007
Salama JK, Seiwert TY, Vokes EE: Chemoradiotherapy for locally
This work was supported by research grant No. 10701 advanced head and neck cancer. J Clin Oncol 25: 4118e4126,
from the Anniversary Research Fund of the Oesterreichi- 2007
sche National Bank (management by C. Klug). 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,
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