Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers1
Introduction
Factors adversely influencing response and local tumour control after radiation therapy for head and neck cancers are considered being tumour cell repopulation during the course of treatment, tumour hypoxia and intrinsic radiation resistance [13], [16], [23].
This has lead to treatment schedules with shorter overall treatment time as well as administration of cytostatic drugs, to increase the local effect [9], [21]. Meta-analyses on combined radio-chemotherapy have shown advantages when both modalities have been used concurrently [3], [15], [18]. Accelerated fractionation as well as hyperfractionated radiotherapy have been used to shorten overall treatment time. Drugs predominantely toxic to hypoxic tumour cells, like mitomycin C (MMC), and others, like cisplatin and 5-fluorouracil, have gained increasing interest as an adjunct to radiation therapy. Haffty et al. [8] showed an increased local tumour control when MMC was used as an adjunct to radiation therapy in head and neck cancers. Brizel et al. [4] showed that the combination of cisplatin and 5-fluorouracil not only was feasible when combined with an accelerated fractionation regimen, but also lead to a significant improvement in therapy outcome.
Following initial results from a pilot study with an accelerated hyperfractionated regimen with and without MMC a prospectively randomized trial was initiated. After approval by the Ethical Committee of the Medical Faculty of the University of Vienna this trial started in October 1990 and closed in December 1997.
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Patients and methods
From October 1990 to December 1997, 239 patients (203 male, 36 female), aged 31–77 years (median 56 years) were treated. Initially 243 randomizations were undertaken, including re-randomization in four patients. Squamous cell cancer was diagnosed in all patients. Table 1 shows the patients characteristics in the three treatment groups and Table 2 shows the stage distribution. The majority of patients had advanced tumours (T3–4: 202/239=85%) and lymph node metastases (N1–3: 188/239=79%) and most
Toxicity of therapy
Local toxicity was the major side effect in patients treated by accelerated radiation therapy. All patients in these two treatment groups developed grade 2 toxicity (pathchy, non-confluent mucositis) and 90% of patients treated by V-CHART+MMC and V-CHART developed grade 3 toxicity (confluent extensive mucositis). The mucosal reaction typically developed after days 12–14 and reached its maximum in the third and fourth weeks after start of radiation. Grade 2 mucositis was seen in nearly all and
Discussion
Radiotherapy offers adequate therapy in most early stages of head and neck cancers. Advanced lesions often recur locally or regionally. Prolonged overall treatment time and/or split-course therapy is of disadvantage in therapy of head and neck cancers [23]. The Danish DAHANCA-Study estimated the ‘loss’ of cell kill in their split-course regime, being equivalent to a dose of 4 Gy per week to achieve a similar tumour control, compared with the regular fractionation arm of the randomized study [16]
Acknowledgements
Financial support has been received from ‘Medizinisch-wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien’. The authors are acknowledging the cooperation with following colleagues: in Vienna, Drs E. Dobrowsky, J. Widder, C. Grasl, W. Millesi, M. Burian, H. Swoboda, G. Schemper; in Wr. Neustadt, Dr R. Pavelka; in St. Pölten, Drs H. Porteder, K. Böheim; in Mistelbach, Dr L. Stoiber; in Krems, Dr H. Jünger.
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Presented in part at the 11th International Conference for Radiation Research, Dublin, Ireland, 18–23 July, 1999.