Journal of Cranio-Maxillofacial Surgery (1999) 27, 302307

# 1999 European Association for Cranio-Maxillofacial Surgery

Intraarterial chemotherapy as neoadjuvant treatment of oral cancer

Adorjan F. Kovacs,1 Bernd Turowski,2 Mostafa T. Ghahremani,1 Matthias Loitz1
1

Department of Maxillofacial Plastic Surgery (Head: Prof. Dr Dr K. Bitter), Johann Wolfgang

Goethe-University Medical School, Frankfurt am Main, Germany; 2Institute for Neuroradiology
(Head: Prof. Dr F. E. Zanella), Johann Wolfgang Goethe-University Medical School, Frankfurt am Main,
Germany
SUMMARY. Neoadjuvant chemotherapy in patients with primary squamous cell carcinomas of the oral cavity
should lead to high remission rates whilst having low morbidity. Ecacy can also be enhanced by treating small
tumour stages. As part of a multi-modality therapy of all stages of primary oral cavity carcinoma, 103 patients
were treated with neoadjuvant intraarterial (i.a.) chemotherapy. After regimen A with 100 mg/m2 i.a. cisplatin
followed by 5 day continuous intravenous infusion of 5-uorouracil (1 g/m2 per day) in 36 patients, an i.a. high
pressure chemo-perfusion with a dose of 150 mg/m2 cisplatin was used with simultaneous intravenous infusion of
9 g/m2 sodium thiosulfate (regimen B, 67 patients). Subsequent treatment comprised radical surgery and
simultaneous radiochemotherapy with docetaxel. Partial and complete remissions were found in 80.6% (regimen A)
and 67.2% (regimen B) of cases, tumour growth was inhibited in 11.1% and 31.3%. Very low toxicity could be
shown especially in regimen B. 66.7% and 74.6% of patients could be operated on radically. Survival rate was
61.1% (regimen A, 22.7 months of mean observation time) and 79.1% (regimen B, 8.4 months). Patients with highgrade remissions seemed to have a survival advantage. Neoadjuvant i.a. chemotherapy with cisplatin, especially in
its high dose variant, is a practical therapeutic tool for the treatment of all stages of primary oral cavity carcinoma.
# 1999 European Association for Cranio-Maxillofacial Surgery

systems successfully prevented complications of intraarterial (i.a.) chemotherapy, such as infections,

catheter misplacement, thromboses and haemorrhages. Robbins et al. (1992) started to combine these
concepts by using a high dose chemoradiotherapy
with cisplatin and a simultaneous application
of sodium thiosulfate for systemic, competitive
neutralisation of the cytostatic (Goel et al., 1989).
Generally, the indication for this treatment was
thought to be palliative. However, its eect on the
survival rate of all patients with oral squamous
cancer can only be investigated by using i.a. induction
chemotherapy for smaller tumour stages in addition,
as was done with systemic chemotherapy in a few
earlier studies (Martin et al., 1990; Volling and
Schroder, 1995).
This paper presents the neoadjuvant i.a. chemotherapy with cisplatin as part of a multi-modality
treatment concept of 103 patients with untreated
primary squamous cell carcinomas of the oral cavity.
All tumour stages were treated using this method. A
local remission was intended with reduction both of
tumour associated symptoms, and, possibly, aggressiveness of the tumour concerning cell spread. The
therapy was planned to have as low systemic toxicity
as possible for prevention of prognostically relevant
morbidity (due to accumulation of side-eects). The
rst regimen combined the i.a. application mode with
a systemic chemotherapy while the second regimen
used high dose cisplatin alone in combination with
sodium thiosulfate for simultaneous systemic neutralisation.

INTRODUCTION
The treatment of squamous cell carcimomas of the
oral cavity is not satisfactory in terms of patient
survival. This is a reason for the many dierent
treatment plans commonly used consisting of varying
combinations of surgery, radiation and chemotherapy. Systemic chemotherapy regimens with cisplatin
and 5-uorouracil appear to be very ecient locally
(Rooney et al., 1985) and in the subsumed prevention
of metastatic spread (Jaulerry et al., 1992). But the
advantage of induction chemotherapy for the patients
is still considered controversial (Stell and Rawson,
1990; Munro, 1995), being associated with severe
toxicity and morbidity potentially relevant to the
survival rate. The concept of `down staging' of a
tumour could not be conrmed and radical surgery is
still indispensible (Poulsen et al., 1996).
Another problem of primary chemotherapy was
the development of resistant cell lines which could be
overcome by higher doses (Teicher et al., 1987). The
reduction of peripheral toxicity combined with high
local ecacy was a further aim (Baker and Wheeler,
1983), especially important in oral cancer patients
who often suer from other intercurrent illnesses. For
50 years regional chemotherapy using the arterial
route in the head and neck region, tried to full these
claims and various cytostatic agents and technical
means were used. Most indications were palliative
treatment of advanced cancer stages and recurrences
(Sullivan et al., 1953; Bitter, 1976; Eckardt and
Kelber, 1994). Development of ne catheter delivery
302

Intraarterial chemotherapy as neoadjuvant treatment of oral cancer 303

PATIENTS AND METHODS

The study started in December 1996. Results of this
study date from May 1999.
Two unselected groups were created: 36 consecutive patients (77.8% male and 22.2% female, average
age 57.3 years) received i.a. chemotherapy with
100 mg m2 cisplatin without systemic neutralisation
followed by an intra-venous (i.v.) continuous infusion
of 1 g/m2 5-uorouracil for functional synergism
(regimen A). The second group of 67 consecutively
treated patients (83.6% male and 16.4% female,
average age 59.9 years) received i.a. high pressure
chemotherapy with the high dose of 150 mg/m2
cisplatin over 515 min in combination with parallel
i.v. application of 9 g/m2 sodium thiosulfate after a
delay of 10 s (regimen B). To avoid resistance
development in both groups, a maximum of 3 cycles
were scheduled, if no grade III or IV remission
occurred at the rst cycle. Remissions were dened:
0 tumour progression, I stable disease (no tumour
growth), II reduction of tumour mass 5 50% (lowgrade partial remission), III reduction of tumour mass 4 50% (high-grade partial remission), IV
complete remission (disappearance of the tumour).
The assessment was done by inspection, palpation
and CT examination after the rst cycle. Grades of
remission which might have been higher after the
second and third cycles were not considered in this
study to make results comparable. No biopsies were
taken after chemotherapy to avoid interference with
the planned operation.
Location of the primary tumours were typically in
the oor of the mouth (about 40%) and the tongue
(about 20%). Performance status of the patients
(Table 1) was good in a high percentage, although the
majority of them presented advanced stages of
disease (Table 1). Nevertheless, between 30% and
40% had T1 and T2 tumours. All tumours were
histologically conrmed squamous cell carcinomata;
three quarters were moderately dierentiated. Similarity of the two patient groups was best shown using
the therapy-dependent prognostic index TPI which
combines data on tumour size, inltration, regional
lymph nodes, distant metastases and age (Platz et al.,
1983) (Fig. 1).
After chemotherapy, the multi-modality treatment
plan provided radical surgery of the mouth and neck,
if operation was feasible depending on the general or
local condition. A so-called `down staging' of the
tumour was impossible. Surgery was followed by
fractionated simultaneous radio-chemotherapy of
the tumour area and the neck lymphatics over
5 weeks (51.3 Gy at 1.9 Gy per fraction) with systemic
application of docetaxel (25 mg/m2) once a week.
This last treatment modality was oered to all
patients, with or without surgery. Pretherapeutic
staging included the use of palpation, US, CT and
MR imaging for examination of the neck lymph
nodes and PET for diagnosis of second tumours,
neck lymph nodes and distant metastases. On the
morning of treatment, patients were given 74 mg

Table 1 Characteristics of the patient population according to

ECOG (Eastern Cooperative Oncology Group) for performance
status and UICC (Sobin and Wittekind, 1997) for tumour staging
Grade

0
1
2
3
4

Performance Tumour (T)

status (%)
(%)

Nodes (N)
(%)

Tumour
stages
(%)

61.1
22.2
11.1
0
5.6

70.1
15
13.4
1.5
0

/
11.1
25
0
63.9

/
17.9
30.8
1.5
19.8

38.9
16.6
38.9
5.6
/

47.8
22.4
26.9
2.9
/

/
11.1
11.1
8.3
69.5

/
10.5
23.9
11.9
53.7

dolasetron and 75 mg prednisolone i.v. Afterwards,

1.5 litres of a full electrolyte solution (with 20 mval
potassium chloride) were given by i.v. infusion over
2 h. Then catheterisation of the right femoral artery
was carried out using a size 4 (french) catheter
containing a coaxial micro-catheter. After superselective visualisation of the tumour-feeding vessel
using uoroscopy and a contrast medium, either
100 mg/m2 cisplatin dissolved in 500 ml 0.9% saline
solution was infused i.a. over 1 h (regimen A), or
150 mg/m2 cisplatin dissolved in the same amount of
saline solution was infused with controlled pressure
(2 ml/s) (regimen B). For analgesia, 0.1 to 0.3 mg
fentanyl was delivered i.v. (and on occasions 5 to
15 mg mepivacain) into the perfused artery. With a
delay of 10 s, an i.v. infusion of 9 g/m2 sodium
thiosulfate was given in parallel. After the treatment,
1 litre of full electrolyte solution with 20 mval
potassium chloride was infused i.v. over 5 h. The
next day, the patients were hyperhydrated with 3 L of
a two-third electrolyte solution, thrombosis prophylaxis with heparin S.C., also dolasetron i.v. if
necessary. Routine laboratory checks were made on
alternate days. Ward stay lasted between 4 and 6 days
for most patients of regimen B. In regimen A, this
time was prolonged by the 5 day continuous infusion
of 5-uorouracil (1 g/m2). Daily application of
allopurinol (300 mg) and anti-emetic drugs was
mandatory.
The side-eects of the cycles were noted. The sideeects of the second and third cycles were always less
pronounced than of the rst cycle.

RESULTS
There was a high overall response rate of 91.7% in
regimen A and of 98.5% in regimen B (Fig. 2).
Tumour progression was observed in only 8.3% and
1.5% of cases respectively. The synergy of cisplatin
and 5-uorouracil had a higher impact on partial and
complete remissions (55.6% and 25%) when compared with the high dose cisplatin therapy (64.2%
and 3%). Therefore, the rate of stable disease was
much higher in scheme B (31.3%). More than 75% of
these patients had only a single cycle. Repeated
courses were used for cases with very large tumours

304 Journal of Cranio-Maxillofacial Surgery

Fig. 1 Distribution of therapy-dependent prognosis index TPI for the examined patient population. White columns: regimen with i.a.
cisplatin and i.v. 5-uorouracil. Black columns: regimen with i.a. cisplatin and i.v. sodium thiosulfate.

Fig. 2 Grades of remission after rst cycle of i.a. chemotherapy. White columns: regimen with i.a. cisplatin and i.v. 5-uorouracil. Black
columns: regimen with i.a. cisplatin and i.v. sodium thiosulfate.

which were considered to be inoperable. There was

no case of a change of remission grade after
repetition of a cycle. Therefore, repeated i.a. chemotherapy provided local control.
The planned operation could not be carried out in
29 cases (12 in the rst and 17 in the second group).
Five patients died due to advanced malignancy
despite temporary local control. During pre-therapeutic examination, the tumours of 9 patients were
considered to be inoperable because of involvement
of the skull base and/or vertebrae, or inltration of

the whole tongue and oor of the mouth including

the common carotid artery. Eight patients had very
poor general condition with multiple systemic diseases. One patient suered from alcoholic myocardial
insuciency, one had inoperable bronchial malignancy and three had pulmonary metastatic spread.
For each patient, the possibility of a simultaneous
radio-chemotherapy was considered. If no further
therapy could be oered, the i.a. chemotherapy was
dened as palliative. Acceptance of the i.a. chemotherapy was high. This could be explained by the

Intraarterial chemotherapy as neoadjuvant treatment of oral cancer 305

After an observation period for the group with

regimen A of 17.5+8.1 months on average (maximum 30 months), 14 patients were dead (after
9.4+6.7 months) and 22 (61.1%) alive (after (22.7+
2.9 months). For regimen B, observation time was
7.8+5.2 months (maximum 20 months). Fourteen
patients were dead (after 5.4+2.8 months) and 53
(79.1%) alive (after 8.4+5.5 months). Looking at the
relationship of grades of remission and survival
(Table 3), there was a tendency for more patients with
low-grade remissions to die prematurely while more
patients with high-grade remissions were still alive.

fact that 26.9% of all patients of regimen B had

no clinically detectable acute side-eects (compared with 14.7% in regimen A). Therefore, only 2
patients refused the recommended continuation of
the therapy.
Surgical resection was undertaken within 3 weeks
of the last dose of chemotherapy. Of the patients in
regimen A, 66.7% could be operated on (resection
with histologically conrmed healthy margins). In
regimen B, the rate was 74.6%. Compared to the
stage-grouping (Table 1), this meant that many
patients with advanced tumours were operated on.
Twelve suprahyoid lymph node dissections were
carried out in the group with regimen A and 40 in
the group with regimen B, while the rate of functional
neck dissections was lower (11 times/18 times). There
were no unusual postoperative complications except
a higher rate of tracheotomies in the group with
regimen B (24 cases 48%) when compared to
regimen A (3 cases 12.5%), which may be due to
enhanced swelling of the area perfused with high-dose
cisplatin.
The side-eects of both i.a. chemotherapy regimens
are presented in Table 2. They are divided into
gastrointestinal side-eects (nausea/vomiting/diarrhoea), haematological side-eects (anaemia/leukopaenia/thrombopaenia), disturbances of electrolytes
(potassium, ferritin), renal and hepatic side-eects
(according to WHO: Miller et al., 1981). The regimen
B was clearly superior in nearly every case. Only the
serum potassium showed a more frequent decrease
and the renal side-eects were equal in spite of the
much larger dose in regimen B. Creatinine never
exceeded a serum value of 1.9 and showed normalisation of values after 5 days on average. Only in
regimen A was it necessary to interrupt therapy due
to hyperemesis and it had to be supplemented by
erythrocyte transfusions or colony stimulating factor
(CSF) (twice).
Other side-eects were partial temporary alopecia
(15% in regimen A and 19% in regimen B) and high
tone hearing loss (assessed subjectively in 10% in
regimen A and 15% in regimen B). One patient with
alcoholic cardiomyopathy developed cardiac decompensation after i.a. chemotherapy. In 212 catheter
interventions, only one side-eect was noted (apoplexy possibly due to an arteriosclerotic plaque or
thrombus which could have been dislodged by the
micro-catheter).

DISCUSSION
Chemotherapy cannot be the sole therapy for oral
cancer (despite initially high remission rates) if
curative treatment is planned. Radical surgery is
indispensable (Poulsen et al., 1996) and is not
compromised by preceding systemic chemotherapy
(Lore et al., 1989). These assertions are valid for i.a.
chemotherapy, too, which has enjoyed a renaissance
recently. Its advantage is a higher possible local dose
of the cytostatic agent compared to the systemic
route if a competitive peripheral neutralisation is
used (Robbins et al., 1992; Robbins et al., 1994a).
Animal experiments and clinical investigation show a
better eect from the i.a. route compared to the i.v.
route (Bitter, 1976; Harker and Stephens, 1992). The
results conrm the high initial local eectiveness of
i.a. cisplatin (Mortimer et al., 1988), especially when
in high dose (Robbins et al., 1994a, b). The comparison of two unselected groups regarding staging
and number of non-operable patients seemed possible
(as TPI and the percentage of patients actually
operated on showed) but the main task of the present
study was ecacy and practicability of i.a. chemotherapy. Overall, response was better in regimen
B. To date, the higher complete remission grades in
the regimen A do not seem to be decisive, because
they have to be seen in the context of a multimodality therapy and are countered by much greater
side-eects when compared with regimen B (Table 2),
although less than conventional systemic chemotherapy (Bachaud et al., 1993). It has to be stressed that,
in this study, remissions were assessed clinically and
not histologically. Nevertheless, the results of this
study demonstrate a connection between high-grade

Table 2 Side-eects of intraarterial chemotherapy. Group A: regimen with i.a. cisplatin and i.v. 5-uorouracil. Group B: regimen with i.a.
cisplatin and i.v. sodium thiosulfate. Grades according to WHO (Miller et al., 1981)
Grade Nausea
(%)

A
I
II
III
IV

Diarrhaea
(%)

Anaemia
(%)

Leukopaenia
(%)

Thrombocytopaenia
(%)

Sideroemia
(%)

Hypokalaemia
(%)

Serum
creatinine
(%)

Hepatic
enzymes
(GOT, GPT,
GGT) (%)

1.5
0
0
0

13.9
8.3
0
0

4.5 13.9
1.5 8.3
1.5 2.8
0
0

4.5
0
0
0

8.3
5.6
0
0

0
1.5
1.5
0

22.2
0
0
0

17.9
0
0
0

16.7
0
0
0

22.4
0
0
0

33.3 34.3 13.9

0
1.5 0
0
0
0
0
0
0

38.9 17.9 2.9

11.1 11.9 0
5.6 0 0
0
0 0

B
10.5
0
0
0

306 Journal of Cranio-Maxillofacial Surgery

Table 3 Relation of grades of remission and survival. Observation
times are mentioned in the text
Grade of
remission

Regimen A
Dead

Living

Dead

Living

0
1
2
3
4

3
2
7
1
1

0
2
6
7
7

1 (1.5%)
6 (8.9%)
7 (10.4%)
0
0

1
15
20
13
4

(8.3%)
(5.6%)
(19.4%)
(2.8%)
(2.8%)

Regimen B

(5.6%)
(16.7%)
(19.4%)
(19.4%)

(1.5%)
(22.4%)
(29.9%)
(19.4%)
(6%)

remissions and survival similar to those reported by

Ervin et al. (1987) who stated a correlation of
response to systemic induction chemotherapy with
failure-free survival. Dierent locations of primary
tumours, dierent mixtures of clinical stages of the
treated populations and dierent drugs and administration routes are the reasons for diculties in
comparison. The fact that remissions mainly occurred after the rst cycle could allow the early
distinction of responders from non-responders. The
assessment of remission, prognostically, could be
another future task for i.a. chemotherapy, as well as a
starting point for dierential therapy.
The actual aim of i.a. chemotherapy is not
necessarily complete remission, but to restrain the
tumour in its local and possibly metastatic aggressiveness before radical surgery without the very high
side-eects of systemic chemotherapy. Therefore,
stabilization of disease was also dened as a response.
The eradication of known micro-metastases is still a
problem. Although other side-eects show that free
cisplatin reaches the peripheral organs and it is
known that i.a. chemotherapy without a neutralising
agent can reach the same peripheral cytostatic levels
(Sileni et al., 1992), doubts exist about i.a. chemotherapy in this regard (Forastiere et al., 1987).
Therefore, subsequent treatment with this multimodality therapy consists of a simultaneous radiochemotherapy with weekly systemic application of
docetaxel. Postoperative radio-chemotherapy was
reported to show improvement of survival (Bachaud
et al., 1991). Nevertheless, locoregional recurrence
during the rst 2 years after treatment remains the
main problem in oral cancer patients (Brady and
Davis, 1988).
The present study focuses on the feasibility and
acceptance of i.a. chemotherapy. The data requirements regarding side-eects compared well with other
studies (Eckardt and Kelber, 1994; Robbins et al.,
1994a; Kerber et al., 1998) and serve to demonstrate
that i.a. chemotherapy, especially the high dose
variant, was particularly well tolerated. It is also
worthy of note that sodium thiosulfate was administered only during the chemotherapy perfusion in contrast to other investigations (Robbins et al., 1994a, b;
Kerber et al., 1998). The catheter interventions also
carried a very low risk.
Observation times were too short to state denitive
advantages regarding patient survival, and for subgroup analysis of the patient population according to
tumour stages and the actual treatment. Small

numbers only allow preliminary conclusions. Further

studies must include control groups. Nevertheless, it
shows that all T1 and T2 tumours can be treated
because of the signicantly reduced side-eects.
Earlier studies all reported on treatment of more
advanced cancer stages and hence the aim could only
be palliative in most cases. Logically, general survival
can only be assessed for improvement when smaller
tumour stages are also included in which a curative
approach is adopted. There are hints in prospective
studies that this may be the correct conclusion
(Volling and Schroder, 1995). A multi-modality
therapy which is supposed to be superior to a single
therapy can be carried out only when the individual
modalities have reduced side-eects which are not
cumulative. The reduction of morbidity may also
have prognostic importance.
At the present time there is no clear evidence from
controlled studies that chemotherapy has any benet
in long-term control of oral squamous cell carcinoma, and the high level of adverse side-eects makes
its use hard to justify. Using this technique as
described, it is possible to reduce the side-eects to
allow further studies into the role of dierent
chemotherapy regimens.
References
Bachaud JM, David JM, Boussin G, Daly N: Combined
postoperative radiotherapy and weekly cisplatin infusion for
locally advanced squamous cell carcinoma of the head and
neck: preliminary report of a randomized trial. Int J Radiat
Oncol Biol Phys 20: 243246, 1991
Bachaud JM, David JM, Shubinski RE et al.: Predictive factors of
a complete response to and adverse eects of a CDDP-5FU
combination as primary therapy for head and neck squamous
carcinomas. J Laryngol Otol 107: 924930, 1993
Baker SR, Wheeler RH: Intraarterial chemotherapy for head and
neck cancer. Part I. Theoretical considerations and drug
delivery systems. Head Neck Surg 6: 664682, 1983
Bitter K: Pharmacokinetic behaviour of bleomycin-cobalt-57 with
special regard to intraarterial perfusion of the maxillo-facial
region. J Maxillofac Surg 4: 226231, 1976
Brady LW, Davis LW: Treatment of the head and neck by
radiation therapy. Semin Oncol 15: 2938, 1988
Eckardt A, Kelber A: Palliative, intraarterial chemotherapy for
advanced head and neck cancer using an implantable port
system. J Oral Maxillofac Surg 52: 12431246, 1994
Ervin TJ, Clark JR, Weichselbaum RR et al.: An analysis of
induction and adjuvant chemotherapy in the multidisciplinary
treatment of squamous-cell carcinoma of the head and neck.
J Clin Oncol 5: 1020, 1987
Forastiere AA, Baker SR, Wheeler R, Medvec BR: Intra-arterial
cisplatin and FUDR in advanced malignancies conned to the
head and neck. J Clin Oncol 5: 16011606, 1987
Goel R, Cleary SM, Horton C et al.: Eect of sodium thiosulfate
on the pharmacokinetics and toxicity of cisplatin. J Natl
Cancer Inst 81: 15521560, 1989
Harker GJ, Stephens FO: Comparison of intra-arterial versus
intravenous 5-uorouracil administration on epidermal
squamous cell carcinoma in sheep. Eur J Cancer 28:
14371441, 1992
Jaulerry C, Rodriguez J, Brunin F et al.: Induction chemotherapy
in advanced head and neck tumors: results of two randomized
trials. Int J Radiat Oncol Biol Phys 23: 483489, 1992
Kerber CW, Wong WH, Howell SB, Hanchett K, Robbins KT: An
organ-preserving selective arterial chemotherapy strategy for
head and neck cancer. AJNR Am J Neuroradiol 19: 935941,
1998

Intraarterial chemotherapy as neoadjuvant treatment of oral cancer 307

Lore JM, Bonilla JA, Spaulding M, Lee KY, Kaufman S,
Sundquist N, Smeeding D: Preoperative adjuvant
chemotherapy for advanced head and neck cancer: a surgical
evaluation. J Surg Oncol Suppl. 1: 26, 1989
Martin M, Hazan A, Vergnes L et al.: Randomized study of 5uorouracil and cisplatin as neoadjuvant therapy in head and
neck cancer: a preliminary report. Int J Radiat Oncol Biol
Phys 19: 973975, 1990
Miller AB, Hoogstraaten B, Staquet M, Winkler A: Reporting
results of cancer treatment. Cancer 47: 207214, 1981
Mortimer JE, Taylor ME, Schulman S, Cummings C, Weymuller
E, Laramore G: Feasibility and ecacy of weekly intraarterial
cisplatin in locally advanced (stage III and IV) head and neck
cancers. J Clin Oncol 6: 969975, 1988
Munro AJ: An overview of randomized controlled trails of
adjuvant chemotherapy in head and neck cancer. Br J Cancer
71: 8391, 1995
Platz H, Fries R, Hudec H: Retrospektive DOSAK Studie uber
Karzinome der Mundhohle. Therapieabhangiger
Prognoseindex TPI. Dtsch Z Mund-Kiefer-GesichtsChir 7:
512, 1983
Poulsen M, Aldren C, Tripcony L, Walker Q: Is surgery necessary
in stage III and stage IV cancer of the head and neck that
responds to induction chemotherapy? Arch Otolaryngol Head
Neck Surg 122: 467471, 1996
Robbins KT, Storniolo AM, Kerber C, Seagren S, Berson A,
Howell SB: Rapid superselective high-dose cisplatin infusion
for advanced head and neck malignancies. Head Neck 14:
364371, 1992
Robbins KT, Storniolo AM, Kerber C et al.: Phase I study
of highly selective supradose cisplatin infusions for
advanced head and neck cancer. J Clin Oncol 12: 21132120,
1994a
Robbins KT, Vicario D, Seagren S et al.: A targeted supradose
cisplatin chemoradiation protocol for advanced head and neck
cancer. Am J Surg 168: 419422, 1994b

Rooney M, Kish J, Jacobs J et al.: Improved complete response

rate and survival in advanced head and neck cancer after threecourse induction therapy with 120-hour 5-FU infusion and
cisplatin. Cancer 55: 11231128, 1985
Sileni VC, Fosser V, Maggian P et al.: Pharmacokinetics and
tumour concentration of intraarterial and intravenous
cisplatin in patients with head and neck squamous cancer.
Cancer Chemother Pharmacol 30: 221225, 1992
Sobin LH, Wittekind C: UICC: TNM classication of malignant
tumours. New York: John Wiley & Sons Inc., 1997
Stell P, Rawson NSB: Adjuvant chemotherapy in head and neck
cancer. Br J Cancer 61: 779787, 1990
Sullivan RD, Jones R, Schnabel TG, Shorey J: The treatment of
human cancer with intraarterial nitrogen mustard utilising a
simplied catheter technique. Cancer 6: 121134, 1953
Teicher BA, Holden SA, Kelley MJ et al.: Characterization of a
human squamous carcinoma cell line resistant to cisdiamminedichloroplatinum(II). Cancer Res 47: 388393, 1987
Volling P, Schroder M: Vorlauge Ergebnisse einer prospektiv
randomisierten Studie zur primaren Chemotherapie bei
Mundhohlen -und Pharynxkarzinomen. HNO 43: 5864, 1995
Dr. med. Dr. med. dent. Adorjan Kovacs
Klinik und Poliklinik fur Kiefer-und Plastische
Gesichtschirurgie
Universitatsklinikum Haus 21
Theodor-Stern-Kai 7
D-60590 Frankfurt am Main
Germany
Tel.: 069-63016610
Fax: 069-63015644
Paper received 23 June 1999
Accepted 16 September 1999