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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 765-768 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.938
Hypofractionated Radiotherapy for Advanced Non-Small-Cell Lung Cancer: Is the LINAC Half Full?Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, NY 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]. Sundstrøm 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 Gy in 10 fractions, resulted in better symptom relief than a single dose of 10 Gy.
Are the results of the current study likely to impact clinical practice? In the United States, the answer may be a very guarded "perhaps." Woven into the fiber of most radiation oncologists trained in the United States is the belief that prolonging the course of therapy will provide more durable tumor control and symptom relief. While American radiation oncologists may be comfortable with regimens of 30 Gy in 10 fractions or even 20 Gy in five fractions, the pen starts to quiver when writing a prescription for extreme hypofractionation (eg, one or two fractions). In the arena of distant metastatic disease, this attitude may begin to shift given the results of the recent Radiation Therapy Oncology Group (RTOG) trial confirming that a single fraction of 8 Gy provides equivalent palliation to 30 Gy in ten fractions in patients with painful bone metastases from breast or prostate carcinoma [20]. However, palliative thoracic radiotherapy has been studied less frequently in recent times. The last US cooperative group trial to address this issue was initiated in 1973 by the RTOG, when 30 Gy continuous course therapy was compared to 40 Gy given in either split course or continuous fashion [11]. Similar palliative effects were observed in all arms, while slightly higher toxicity was seen with split-course therapy. Given the lack of benefit from the higher dose, 30 Gy in 10 fractions became the standard of care. Interestingly, the trial from The Norwegian Lung Cancer Study Group employed two regimens that are more protracted and resource-consuming than the standard US regimen. One issue not addressed by this study is the role of palliative radiotherapy in the era of systemic therapy. In contrast to current clinical practice, surprisingly few patients received chemotherapy. Randomized trials during the past two decades have demonstrated a small, but statistically significant, survival benefit for patients receiving cisplatin-based chemotherapy compared with best supportive care [21,22]. Recent data suggests this benefit extends to elderly patients as well as patients with borderline baseline performance status [23,24]. Even before the development of effective chemotherapy regimens, the role of immediate radiotherapy was questioned, and a recent Medical Research Council trial—which did not permit chemotherapy—demonstrated no benefit for immediate radiotherapy compared to delayed palliative radiotherapy in patients with minimal symptoms [25]. Moreover, the majority of patients in the delayed arm never received radiotherapy. Detailed information regarding the palliative effects of chemotherapy is also available, including a randomized trial comparing gemcitabine to best supportive care using quality of life as the primary outcome [26]. Patients receiving chemotherapy reported improved quality of life and symptom relief, and at the 2-month assessment, 9% of patients assigned to receive gemcitabine required palliative radiotherapy compared with 58% of patients receiving best supportive care. Overall, however, 49% of patients on the gemcitabine arm eventually received radiotherapy, indicating that defining an appropriate palliative radiotherapy regimen remains clinically relevant. Whether combining radiotherapy with systemic chemotherapy improves symptom relief or quality of life for selected patients with advanced non-small-cell lung cancer (NSCLC) has not been extensively explored, and may be reasonable ground for future investigation. Perhaps the most important lesson from trials of palliative radiotherapy is that extended survival is possible. Patient selection is critical, and despite the unfathomably slow progress in the treatment of lung cancer, a nihilistic approach is not warranted. In fact, the authors' conclusion that protracted radiotherapy "renders no improvement in ... survival" is potentially misleading. Three-year survival was 6% in each of the protracted arms, yet only 1% in the hypofractionated arm. Moreover, when the survival analysis was limited to patients with good performance status with stage III disease (roughly half of all eligible patients), 3-year survival was 9% and 6% in the two high-dose arms, compared with 1% in the 17 Gy arm (P = .06). Similar findings were recently reported from the National Cancer Institute of Canada trial comparing protracted therapy (20 Gy in five fractions) with a single fraction of 10 Gy. Again, the survival benefit appeared limited to patients with good performance status and localized disease [9]. Other earlier trials, which limited enrollment to patients with good performance status, also demonstrated the potential for prolonged survival with protracted regimens [12,15]. Given the emergence of effective strategies for favorable-risk stage III NSCLC, with an expectation of long-term survival in as many as one fifth of patients treated with simultaneous radiation and chemotherapy, patients with localized disease must be carefully screened before being relegated to receive palliative therapy [27]. While there is now an abundance of randomized trials to guide decision making for lung cancer palliation, strikingly few modern phase III studies have been designed to elicit an optimal curative radiotherapy regimen. The widely accepted standard regimen, 60 Gy in 2 Gy daily fractions, defined by an RTOG trial conducted in the 1970s, was selected based on short-term (and nonstatistically significant) differences in outcome [28]. However, no alternative radiotherapy regimen has proved superior in a North American Cooperative Group trial [29]. Although a large-scale United Kingdom trial documented improved long-term survival for patients treated with continuous hyperfractionated accelerated radiotherapy, high-dose accelerated radiotherapy is difficult to administer simultaneously with chemotherapy [30]. Moreover, treatment regimens employing multiple daily fractions have not been widely embraced, as witnessed by the inability of the recently reported Eastern Cooperative Oncology Group trial of thrice daily radiotherapy to complete patient accrual [31]. While the boundless enthusiasm for studying novel systemic agents and molecular targeted therapies is well founded, defining the appropriate radiotherapy regimen to serve as the backbone for future investigation should also be considered a research priority. In summary, evidence from the current trial confirms that short course radiotherapy is a safe and effective tool for palliating lung cancer symptoms and is appropriate for select poor-prognosis patients. Importantly, the suggestion of improved long-term survival for favorable-risk patients treated with higher radiation doses illustrates the critical need to appropriately triage patients with locally advanced NSCLC. The challenge for the next decade will be to shift this fervor toward defining an optimal radiation schedule in the curative setting. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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