Hypofractionated Radiotherapy for Advanced Non-Small-Cell Lung Cancer: Is the LINAC Half Full?

The origin of fractionated radiotherapy dates back to observations by French investigators Regaud and Coutard, among others, during the 1920s and 1930s [1]. Before this time, there was considerable controversy regarding appropriate radiotherapy delivery, and treatment was generally administered in a single dose or in a few large fractions. Regaud documented improved tumor control of uterine carcinoma when the time of application of radium was extended to 1 week, and Coutard subsequently demonstrated that external beam therapy applied in a similar manner could cure head and neck cancer without the severe sequelae associated with single large doses [2,3]. Consequently, fractionated treatment was widely adopted throughout Europe and North America. During the intervening years, varied regional standard treatment schemes have evolved, often guided by empiric observations and practical constraints rather than objective data. It should, therefore, not be surprising that there is little consensus regarding appropriate radiation regimens for all situations. Although the presumption of a dose-response relationship is a core tenet driving the clinical practice of radiation oncology, few studies have established that higher doses of conventionally fractionated radiotherapy result in improved outcomes. Whether the substitution of fewer radiotherapy fractions, or hypofractionation, can lead to equivalent or improved results has been investigated in the definitive and palliative setting. For example, the potential role of hypofractionation for lung cancer was the subject of a recent review [4]. The practical benefits of limiting the number of sessions in the palliative setting are self-evident. On the other hand, common concerns regarding the delivery of large radiation fractions include the potential for reduced biologic efficacy and the observation that late toxic effects of therapy are enhanced as the dose per fraction delivered to normal tissues increases, particularly when large volumes of normal tissue are irradiated [5,6]. Sundstrom et al [7], from The Norwegian Lung Cancer Study Group, are to be commended for successfully completing a large, well-designed trial of hypofractionated therapy for lung cancer palliation. Appropriately, the designated primary end-points were palliative, including symptom relief from dyspnea, cough, and hemoptysis, as reported by patients and physicians. Detailed quality of life data were also obtained. In the end, all treatment regimens produced similar palliation and health-related quality of life, while differences in the toxic effects of therapy were minimal, although dysphagia appeared significantly earlier with short-course therapy. Local symptom control was achieved in 40% of patients, confirming the palliative efficacy of radiotherapy, and the concordance in the reporting of symptom relief (with the exception of cough) between patients and physicians is reassuring. The present study expands the number of randomized phase III trials examining palliative radiotherapy, as recently summarized in a Cochrane analysis [8]. A dozen trials are now included, and most support the notion that hypofractionated therapy is safe and effective in the palliative setting (Table 1) [7-19]. Recent evidence suggests, however, that perhaps one dose is not enough. A study conducted by the National Cancer Institute of Canada assigned patients to receive either a single fraction of 10 Gy or 20 Gy in five fractions [9]. While there was no difference in symptom control as judged by patient-completed daily diary cards, changes in scores on the Lung Cancer Symptom Scale indicated patients treated with fractionated radiotherapy had greater improvement in symptoms related to lung cancer, ability to carry out normal activities, and better global quality of life. Similarly, Gaze et al [10] recently reported that fractionated radiotherapy, 30 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 5 MARCH 1 2004