International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases
Introduction
External beam radiotherapy is a well-recognized and effective modality in the palliation of symptomatic bone metastases, a frequent manifestation of malignancies in their advanced stages.
Randomized trials have attempted to determine the optimal dose fractionation in the palliation of painful bone metastases [4], [7], [10], [12], [14], [15], [16], [22], [23], [24], [25], [26], [30], [32]. It has been observed that different conclusions could be reached depending on the endpoint definitions. The response rate to radiotherapy is a function of endpoint, and it should be noted that if very stringent criteria are utilized, the responses reported might be much lower than the traditionally accepted rates.
The Radiation Therapy Oncology Group study (RTOG 7402) concluded that low-dose, short-course schedules were as effective as high-dose protracted programs in their randomized dose fractionation trial [32]. However, analysis using combined pain and analgesic scores, with or without re-treatment, suggested improved complete response with protracted fractionation schedules [3]. The shortcomings in methodology surrounding the attempts of various groups to assess the effect of dose fractionation in metastatic bone pain were further illustrated recently [2].
Similarly, in a randomized Canadian trial comparing the efficacy of a single 8 Gy to 20 Gy in five daily fractions in the treatment of bone metastases, more patients in multiple fractionations received significant pain relief, defined as reduction in the pain score at the treated site with reduced analgesics or a pain score of zero at the treated site without an increase in analgesics. In contrast, when response was defined as pain relief alone regardless of analgesic consumption, the two regimens gave the same response rates [15].
Observed treatment response is also influenced by the type of pain scale employed, inclusion of quality of life as an endpoint, and the duration of follow-up. The Danish bone pain trial reported pain relief of 62% at 4 weeks in the single fraction arm when assessed with the categorical scale (improvement of at least one category on the five point categorical scale), but response dropped to 49% when defined as 50% reduction in pain on the visual analogue scale. The complete response changed from 15% at 4 weeks to 25% at any time during the entire follow-up period of 20 weeks. If the criteria for complete response included no use of morphine, it became 12% and only 4% if the global quality of life score that recorded complete well being was also included [22].
‘Complete response’ (CR) and ‘partial response’ (PR) as reported by one study cannot be directly compared with another. Comparison of four large European studies defining complete response rate using pain score independent of analgesic use reveals CR rates ranging from 57% in the third recent UK bone pain trial [4], to 35% in the other major study from the Dutch group [30], to 33% in the second Royal Marsden Hospital bone pain trial [12] and 27% in the first Royal Marsden Hospital bone pain trial [25]. The use of a quality of life questionnaire to define complete response in the Edinburgh bone pain trial gave a complete response rate of 39% (single treatment) to 42% (five fractions) [10]. It is, however, important to note that there are differences in the recruited population across the studies. For example, the median Karnofsky score in the Dutch study was 70 [30] with an overall 1 year survival (extrapolated from published curves) of 35% whilst one-quarter of the Edinburgh patients were WHO PS 3 or 4 [4] – with 1 year survivals of 22% and 33% in the single and fractionated arms, respectively. The first two Royal Marsden trials report 1 year survival figures of around 20% [12], [25], whilst the third large UK series positively selected for survival to 1 year with 44% alive at 12 months [4].
In addition to defining response, there exists an inherent difficulty of measuring a response when radiotherapy is given as a local treatment, while cancer pain can come from multiple sites, often also palliated by other systemic agents, including a variety of analgesics, chemotherapy, hormonal therapy, and, more recently, bisphosphonates. Other perplexing issues include the role of analgesic consumption in assessing treatment response, definition of ‘partial’ response and the interpretation of re-treatments. Clearly future trials in palliative radiotherapy evaluating clinical outcomes must not only account for patient-related eligibility criteria, radiotherapy techniques and assessment tools, but will also need to address possible treatment effects from an increasingly complex multi-disciplinary management of this group of patients.
In order to promote consistency in future clinical trial design for palliating bone metastases, an International Bone Metastases Consensus Working Party on endpoint measurements was established in April 2000 in conjunction with the American Society for Therapeutic Radiology and Oncology (ASTRO), the European Society for Therapeutic Radiology and Oncology (ESTRO), and the Canadian Association of Radiation Oncology (CARO). The working party aims to reach a consensus on a set of commonly accepted endpoint measurements for future radiotherapy trials in the following areas: (1) external beam radiotherapy; (2) radionuclides; (3) wide-beam/half-body radiotherapy; (4) quality of life issues; and (5) re-treatment. This report describes the results for external beam radiotherapy.
Section snippets
Materials and methods
Medline, PreMedline, CancerLit, PubMed (National Library of Medicine) and the Cochrane Library were searched to identify randomized trials published between 1966 and October 2000 using mesh headings (radiotherapy, radiotherapy dosage, dose fractionation, bone neoplasms/sc. {Secondary}, explode Clinical Trials, clinical trial {publication type}) and text words (bone, osseous, metastasis, radiotherapy, irradiation, radiation, pain, analgesic, trial, and study) without language restrictions.
Eligibility criteria for future trials
For studies involving more than one tumor site, stratification should be made by tumor type involved. Patients should have measurable pain (27/43 – supported by 27 out of 43 responses), e.g. a minimum pain score of 2/10, at the time of entry. If studies are designed to assess pain relief for a duration of >3 months, performance status should be an eligibility criterion (21/42), since it has been shown to correlate with the duration of survival [20], [35]. Because the physician's prediction of
Discussion
The Consensus Working Party acknowledges that numerous cultural and geographical factors influence the design and conduct of bone metastases trials. Trial design also has to face an increasingly complex, if not prolonged, disease course that likely has been modified by various systemic therapies.
In spite of differences in the treatment goal for the palliation bone metastases among investigators, this consensus has attempted to determine the ‘minimum’ features of trial design and endpoint
Participants
A. Amadeo, P. Anderson, G. Arcangeli, A. Barrett, M. Barton, G. Bauman, E. Ben Josef, S. Bentzen, A. Bezjak, P. Blitzer, O. Bruland, M. Brundage, D. Bruner, E. Chow (Chair), L. Coia (ASTRO Co-chair), C. Danjoux, L. Dawson, J. Finkelstein, W. Hartsell, S. Hayashi, J. Hayman, C. Heath, P. Hoskin (ESTRO Co-chair), G. Hruby, N. Janjan, R. Kagan, P. Kirkbride, A. Konski, J. Leer, W. Levin, Y. van der Linden, A. Loblaw, M. McKenzie, O. Nielsen, M. Niewald, A. Porter, G. Okawara, D. Penson, C. Perez,
Acknowledgements
We sincerely appreciate the valuable time and comments shared by the participants in our consensus work as listed above. We would also like to thank Drs Rose, Hussey, Larson, Janjan, Mauch and Kun from ASTRO, Drs Gerard and Bartelink from ESTRO, Drs Gospadarowicz and Kane from CARO, Dr Thomas from Toronto-Sunnybrook Regional Cancer Center for supporting the consensus, Berlex Laboratories for their educational grant and Ms Danielle Nywening for her secretarial assistance.
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