Effect of gap length and position on results of treatment of cancer of the larynx in Scotland by radiotherapy: a linear quadratic analysis

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Abstract

Purpose: This paper reports on the analysis of the effect of the length and position of unplanned gaps in radiotherapy treatment schedules.

Materials and methods: Data from an audit of the treatment of carcinoma of the larynx are used. They represent all newly diagnosed cases of glottic node-negative carcinoma of the larynx between 1986 and 1990, inclusive, in Scotland that were referred to one of the five Scottish Oncology Centres for primary radical radiotherapy treatment. The end-points are local control of cancer of the larynx in 5 years and the length of the disease-free period. The local control rates at ≥5 years, Pc, were analyzed by log linear models and Cox proportional hazard models were used to model the disease-free period.

Results: Unplanned gaps in treatment are associated with poorer local control rates and an increased hazard of a local recurrence through their effect on extending the treatment time. A gap of 1 day is potentially damaging but the greatest effect is at treatment extensions of 3 or more days, where the hazard of a failure of local control is increased by a factor of 1.75 (95% confidence interval 1.20–2.55) compared to no gap. The time factor for the actual time was imprecisely estimated at 2.7 Gy/day with a standard error of 13.2 Gy/day. Among those cases who had exactly one gap resulting in a treatment extension of 1 day, there is no evidence that gap position influences local control (P=0.17). The treatment extension as a result of the gap is more important than the position of the gap in the schedule.

Conclusions: Gaps in the treatment schedule have a detrimental effect on the disease-free period. A gap has a slightly greater effect than an increase in the prescribed treatment time. Any gap in treatment is potentially damaging. The position of the gap in the schedule was shown to be not important.

Introduction

Radiotherapy schedules for the treatment of cancer of the larynx have evolved with a planned gap at the weekend. Some of the common schedules include, for example, 52.5 Gy in 20 fractions over 28 days, 60 Gy in 25 or 30 fractions over 35 or 42 days, 55 Gy in 16 fractions over 21 days and 50 Gy in 20 fractions over 28 days. Unplanned gaps occur in these schedules for a variety of reasons, such as public holidays, machine servicing, transport failure, machine breakdowns and patient illness. If the gap is long then the treatment may be altered to take into account the delay in treatment completion.

The outcome for various patient groups from centres in North America and Europe since 1980 have shown that unplanned interruption of treatment resulting in the prolongation of the treatment time can reduce the local control rate and hence the cure rate 1, 21, 22. The conclusion from recent overviews of these studies 2, 7, 8is that a break in treatment of about 1 week is associated with an absolute reduction in local control rates of 10–12%; hence a break of 1 day may reduce the control rate by around 1.4%.

Linear quadratic modelling analyses of data from hospital records of patients treated in different overall times for carcinoma of the larynx have estimated the time factor for tumour control, expressed as the extra dose per additional day of overall treatment time to maintain the same level of tumour control. About 0.6–0.7 Gy/day, using 2 Gy fractions, was required to maintain the same level of tumour control after a lag period of about 3–4 weeks 11, 21, 26, 27, 31, 33.

The above analyses focused on the overall length of treatment time and did not specifically consider unplanned gaps. In the pooled analysis of Robertson et al. [28], the effect of unplanned gaps were specifically estimated independently of the planned treatment time. This analysis revealed small but important reductions in the probability of local control at ≥2 years associated with an increased treatment time. From these results, one would conclude that for a specified schedule, where dose and fraction number are specified, any gap is potentially damaging.

This paper reports on an audit of the treatment of patients with glottic node-negative carcinoma of the larynx and assesses the impact of gaps on the radiotherapy treatment schedule. This differs from previous analyses as the position, length and reason for each gap in the schedule are known. Thus, we know that a gap in treatment occurred and can then see its effect on the prolongation of the total treatment time. In the previous study [28], the treatment extension was estimated on the basis of knowledge of the dose and fractions administered. Thus, the current data are more reliable for the estimation of the direct effect of a gap as we are able to restrict the analysis to patients in whom the treatment schedule was not modified to compensate for the gap.

Section snippets

Materials

A database of all newly diagnosed cases of carcinoma of the larynx between 1986 and 1990, inclusive, in Scotland that were referred to one of the five Oncology Centres for primary radical radiotherapy treatment has been assembled. These patients were identified via the Scottish Cancer Registration Scheme and Oncology Centre Registrations, thus ensuring a complete coverage of all cases. Radiotherapy was the primary treatment for all patients. Only 3% of patients had any prior surgery and in

Methods

Mathematical models are used to estimate the effect of delays on the completion of the treatment. This enables the estimation of the tumour doubling times and the biological effect of the radiotherapy treatment, as well as the effect of the gaps on the schedule. Survival analysis models are used to assess the impact of tumour and treatment characteristics on the disease-free period.

The disease-free period is the primary end-point of the study and is defined as the time from the start of

Results

There are 629 cases who were node-negative and with the primary tumour originating in the glottis. There are 321 T1 cases (51%), 216 T2 cases (34%) and 78 T3 cases (12%). As there are only 14 T4 cases, they are combined with the T3 cases in the modelling analysis. There was no statistical evidence using interaction tests that the effects of dose and time depended upon T stage (data not shown). The doses ranged from 43 to 70 Gy with 39% of cases receiving 60 Gy. Patients were treated with

Discussion

This analysis has demonstrated that long gaps in the treatment time in excess of 2 days are associated with a poorer local control. In this analysis, and also in that of Duncan et al. [6], who report similar but less extensive results, treatment gaps were identified as opposed to using excess treatment time over planned treatment time according to specified schedules. The data are unselected using all cases from a variety of centres both large and small, reflecting the practice in the real

Unlinked references

20, 25, 29

Acknowledgements

The data on the treatment of cancer of the larynx by radiotherapy were collected under the auspices of the Scottish Oncology and Radiology Audit Group as part of a study funded by the Clinical Resource and Audit Group (GRAG), Scottish Home and Health Department, whose help is gratefully acknowledged. It is a pleasure to acknowledge the contribution of the staff in the centres who helped with the collection of the data.

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