Clinical investigation: head and neck
Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas

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Abstract

Purpose: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma.

Methods and Materials: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a Dprolif of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given.

Results: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently.

Conclusions: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.

Introduction

A substantial proportion of all patients treated by radiotherapy experience an unplanned protraction of overall treatment time 1, 2, 3, even in the case of controlled randomized clinical trials (4). The reasons for treatment protraction are varied but typically include the following: national holidays; machine breaks down; severe normal tissue reactions; intercurrent disease. For head-and-neck squamous cell carcinoma (HNSCC), protraction of overall treatment time leads to a reduction in the local control probability. This probably reflects accelerated tumor repopulation occurring during the extra treatment days (5). An extra radiation dose of approximately 0.6 Gy for each additional day of treatment (when using 2 Gy daily fractions) is required to keep the level of local control constant (6). The evidence for the detrimental effect of treatment protraction on tumor control comes from the analysis of both split-course treatment (7) and conventional treatment with unplanned gaps where the actual treatment duration and the prescribed duration were known (8). Detailed analysis of data collected from Manchester, Glasgow, Edinburgh, and Toronto have also shown similar values for the time factor for the planned prolonged continuous treatment times as for gap times (9). Recently, the Danish Head and Neck Cancer Study (DAHANCA) 6 and 7 trials, where overall treatment time was reduced by a week through increasing the weekly number of fractions from 5 to 6 while keeping the total dose fixed, resulted in an increased local tumor control and disease-free survival (10).

The fractionation IMPACT study is an intergroup analysis of individual patients’ data from five randomized trials on radiotherapy fractionation in HNSCC, which were performed over the period 1980–1995. One aim of the analysis is to advise on new improved fractionation schedules for specific subgroups of patients. The IMPACT project involves a series of detailed studies to estimate various radiobiologic parameters that characterize the response of head-and-neck carcinoma to treatment. One of these parameters is the overall treatment time. In the present study, the compliance to the prescribed overall treatment time in the IMPACT database is thoroughly examined.

Section snippets

IMPACT database

The trials included in IMPACT are the European Organization for Research and Treatment of Cancer (EORTC) 22791 (11), EORTC 22811 (12), EORTC 22851 (13), the trial from Princess Margaret Hospital (PMH) in Toronto (14), as well as a continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trial from the UK (15).

EORTC 22791 compared a conventional fractionation arm (daily fractionation of 70 Gy in 35 fractions) with pure hyperfractionation of 80.5 Gy in 70 fractions over 7 weeks.

Results

Nine randomized cases failed to receive any radiotherapy but were included in the analysis, as they clearly contribute to the overall noncompliance in an intention-to-treat analysis. The time in excess of ideal was calculated for all the 2555 cases, with information on the overall treatment time. It ranged from −45 to 97 days, with an average of 3.9 days and a median of 2 days. Figure 1 shows the distribution of the time in excess of ideal. Only in 767 patients (30%) was there an agreement

Discussion

The current analysis showed that the compliance to the overall treatment time in five major randomized clinical trials of radiotherapy fractionation was less than satisfactory. More than 1 in 4 patients finished their radiotherapy in overall treatment times exceeding the ideal by more than 5 days.

Harari et al. (2) previously used the difference between ideal and actual treatment time to evaluate the compliance to the prescribed overall treatment time in both arms of the EORTC 22791. Similar

References (29)

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