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1991 Chris Terhaard

Radiotherapy for Carcinoma of the Larynx: Treatment Results and Prognostic Factors

In chapter I a general introduction concerning laryngeal cancer is presented. The incidence of laryngeal carcinoma increases gradually. Corrected survival (i.e. laryngeal cancer related survival) has improved over the years. An accurate classification is mandatory to compare the treatment results for laryngeal carcinoma. Therefore the differences between the UICC classification of 1962, 1978 and 1987 are discussed. The evolution of management from 1898 until 1990 of, particularly, radiotherapy of laryngeal carcinoma is described based on publications in the Nederlands Tijdschrift voor Geneeskunde.

In chapter II-VI prognostic factors for local and regional control and survival after radiotherapy for laryngeal carcinoma are analysed by uni- and multivariate methods. In chapter VII treatment strategy and future prospects are discussed.

In chapter II results of T1 laryngeal cancer are given. Local control was 91% for T1 glottic cancer. A total dose of 66 Gy in 33 fractions was used. After salvage surgery ultimate locoregional control was 97%. A significantly increased risk of local failure was seen for tumours, extending to the entire length of the vocal cord and in patients who continued smoking.
Local control was 84% and regional control was 81% for tumours restricted to the supraglottic region and with normal mobility of the vocal cords. Regional control was significantly worse for tumours with extension to more than one subsite (T1b), compared to tumours confined to one subsite (T1a) For this reason T1b supraglottic carcinoma was correctly incorporated by the UICC in T2 stage in 1987.
Local control was achieved in 2 of 3 T1 subglottic tumours.

In chapter III results of treatment for T2 laryngeal carcinoma are shown. Patients received 70 Gy in 7 weeks to the primary tumours. Vocal cord mobility appeared to be a significant prognostic factor for ultimate locoregional control and survival. So it is our proposal to subdivide T2 tumours into: T2a: normal mobility of the vocal cords T2b: impaired mobility of the vocal cords.

Chapter IV describes the results of a selective course of radiotherapy for advanced laryngeal carcinoma. Radiation alone for advanced laryngeal carcinoma will result in a local cure rate of 50%. Salvage surgery will be successful in 50% of the patients with a local recurrence. To identify patients with a high chance of local control with radiation alone, tumour response after 50 Gy in 5 weeks was used. In patients with T-stage reduction or tumour regression of more than 50%, radiotherapy was continued to a total dose 70 Gy in 7 weeks. Local control was 69% for T3 and 43% for T4 tumours. If no or only minor regression was seen a laryngectomy was performed. The tumour response after 50 Gy may select from T3 tumours a favourable group of patients for radiation alone, aiming at an im proved local control for this selected group.

In chapter V study design and general results are shown of a retrospective study, conducted by the Dutch Head and Neck oncology Group (NWHHT), concerning T3 laryngeal carcinoma (UICC 1978). Patients' history and tumour characteristics, obtained before treatment, are reported. Five year corrected survival was 70%. Treatment results have not improved over the years. Survival was correlated with tumour extension: tumours involving the vocal cord, with or without extension to the ventricle, showed the best survival rates. Patients with involvement of neck nodes at first presentation, and patients for which the preferred standard treatment could not be followed, showed an impaired survival. Patients treated with primary radiotherapy showed results equal to those of patients treated primarily by laryngectomy. The best treatment results were seen in patients treated by combined therapy. In a prospective study primary radiotherapy should be weighed against a planned combined therapy. The risk of multiple primary tumours was 20% for male patients and 7% for female patients; this difference was significant. Bronchial carcinoma was the most frequently observed second primary tumour. Prevention and early detection of these multiple primary tumours may play an important role in improving survival rates in the future.

In chapter VI a time-dose relationship for local control is presented for 104 patients treated with radical radiotherapy for T3 N0-3 M0 laryngeal carcinoma. Various fractionation schedules were used.
The correlation between local control and total dose, Nominal Standard Dose (NSD) and Extrapolated Response Dose (ERD), using the Linear-Quadratic model (LQ), was analysed. The calculated ERD-values were the only independent prognostic factor for local control and ultimate locoregional control. An as sumed mean potential doubling time of clonogenic cells of five days showed the most significant correlation with local control. NSD showed no dose-response relationship. Based on the potential doubling time of clonogenic cells the importance of more individualized fractionation schedules is discussed.

In chapter VII treatment strategy and future prospects are discussed. Two criteria are important when considering the choice of preferred treatment.
Firstly, survival after successful locoregional therapy. Patients, cured of their laryngeal carcinoma have an increased risk of second primary tumours and also of death from intercurrent disease. This may decrease the possible advantage in survival after surgery compared to primary radiotherapy.
The second important factor is quality of life after various treatment modalities. Quality of life is, generally, better after primary radiotherapy than after laryngectomy.
Based on own results and data from the literature, primary radiotherapy is preferred for T1 and T2 tumours. For T3 tumours there are various treatment options. A prospective randomized trial of planned combination of radiotherapy and surgery, and primary radiotherapy may be proposed. Primary radiotherapy, using different fractionation schedules dependent on radiobiological data, is a second option. A third option is a selective course of radiotherapy. Based on tumour response a decision is made either to proceed with radiotherapy or to perform a laryngectomy.
Surgery in combination with radiotherapy is the preferred treatment for T4 tumours. Primary radiotherapy, using alternative fractionation schedules, may be another option.
For N1 neck nodes primary radiotherapy is preferred; however for N2-3 neck nodes a combination of radiotherapy and neck dissection is the treatment of choice.
At present chemotherapy and radiosensitisers have no established part to play in the curative treatment of advanced laryngeal carcinoma.
The use of the radiobiological parameters, radiosensitivity alfa and potential doubling time of clonogenic cells (Tpot), is discussed to determine the optimal fractionation schedule, for each tumour individually. Different fractionation schedules are evaluated using these parameters in the LQ-model. At this moment the measurement of a is better established than measurement of a. So, analyses may be based on the values of alfa
In general an accelerated fractionation schedule is advisable for tumours with a short potential doubling time. For tumours with a longer potential doubling time a hyperfractionation schedule is preferable.
Based on the measured Tpot of clonogenic cells treatment may be randomized between conventional and alternative fractionation. For a Tpot of less than 4.5 days, conventional fractionation may be tested against accelerated fractionation; for a Tpot greater than 4.5 days, conventional fractionation may be tested against hyperfractionation. Based on the results of this trial the most optimal schedule for an individual tumour may be analysed and used in a future trial, in which primary radiotherapy is tested against com- bined therapy for advanced laryngeal carcinoma.

To contact the author:

Dr. C.H. Terhaard
University Hospital Utrecht,
dpt of Radiation Oncology, Q.00.1.18
PO Box 85500
3508 GA Utrecht
The Netherlands

Email: C.H.J.Terhaard[at]