Elsevier

Radiotherapy and Oncology

Volume 57, Issue 2, 1 November 2000, Pages 119-124
Radiotherapy and Oncology

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers1

https://doi.org/10.1016/S0167-8140(00)00233-4Get rights and content

Abstract

Background and purpose: Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery. In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications, such as altered fractionation schedules and combination with chemotherapy.

Patients and methods: From October 1990 to December 1997, 239 patients with squamous cell cancers originating in the head and neck region were randomized to one of three treatment options. Standard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions (CF). The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days (V-CHART). The third study arm had identical fractionation and dose as the above accelerated treatment, with the additional administration of 20 mg/m2 mitomycin C (MMC) on day 5 of treatment (V-CHART+MMC).

Results: Main toxicity resulted from accelerated fractionation in confluent mucositis (Grade 3–4 in 95%) requiring nasogastral tube feeding, analgetics and antiphlogistics in the majority of cases. Haematological toxicity Grade 3–4 was seen after MMC administration in 18%. MMC administration did not influence mucosal reaction. Overall duration of mucositis was not different in the three treatment groups. Loco-regional tumour control was 31% after CF, 32% after V-CHART and 48% after V-CHART+MMC, respectively (P<0.05). Overall crude survival was 24% after CF, 31% following V-CHART and 41% after V-CHART+MMC, respectively (P<0.05). Median follow up was 48 months (assessment performed in February 1999).

Conclusion: Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical. A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment.

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.

Section snippets

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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    1

    Presented in part at the 11th International Conference for Radiation Research, Dublin, Ireland, 18–23 July, 1999.

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