Single Fractions of Radiation for Painful Bone Metastases May Be Noninferior to Multiple Fractions
Optimal dose fractionation for radiation therapy of painful bone metastases from multiple primary sites remains undefined. In a phase III noninferiority trial reported in The Lancet Oncology, Chow et al compared 8 Gy in a single fraction vs 20 Gy in multiple fractions in patients with painful bone metastases who had received prior radiation treatment. The 8-Gy regimen was noninferior to the 20-Gy regimen in pain response in intent-to-treat analysis but not in per-protocol analysis. Moreover, the lower dose was associated with a lower frequency of some acute toxicities.
Study Details
In this nonblinded international trial, 850 patients aged ≥ 18 years with radiologically confirmed, painful bone metastases scored as ≥ 2 points on the Brief Pain Inventory were randomly assigned between January 2004 and May 2012 to receive palliative radiotherapy at 8 Gy in a single fraction (n = 425) or 20 Gy in multiple fractions (n = 425). Patients had received previous radiation therapy and were taking a stable dose and schedule of any pain-relieving drugs prescribed.
The primary endpoint was overall pain response at 2 months, defined as either complete or partial pain response. Complete response was defined as a Brief Pain Inventory worst pain score of zero with no associated increase in daily oral morphine equivalent. Partial response was defined as pain that persisted after treatment either with a worst pain score reduction of 2 or more and no increase in daily oral morphine equivalent consumption or no increase in pain and a reduction in daily oral morphine equivalent consumption of at least 25%.
The 8-Gy and 20-Gy groups were balanced for age (mean, 65 years in both), sex (57% and 60% men), primary cancer site (eg, prostate in 27% in both, breast in 28% and 25%, lung in 22% and 23%), Karnofsky performance status (70–80 in 53% and 56%, 90–100 in 23% and 21%), worst pain score at baseline (7–10 in 60% and 62%, 5–6 in 24% and 23%), site of painful lesion (eg, pelvis/hip in 36% in both, lumbosacral spine in 17% and 20%), response to initial radiation (83% in both), initial fraction schedule (single in 66% in both), and dose of daily oral morphine equivalent (mean, 47.5 and 40.0 mg).
Response Rates
A total of 19 patients in the 8-Gy group and 12 in the 20-Gy group were found to be ineligible after randomization; 140 and 132 were not assessable at 2 months and were counted as missing data in the intent-to-treat analysis. In the primary intent-to-treat analysis, pain response occurred in 28% of patients in the 8-Gy group vs 32% in the 20-Gy group (P = .21); the response difference was 4.00% with an upper limit of the 95% confidence interval [CI] of 9.2%, within the prespecified noninferiority margin of 10.0%. Complete response was observed in 8% vs 7% of patients.
In the per-protocol analysis, response was observed in 45% of patients (116/258) in the 8-Gy group vs 51% (134/263) in the 20-Gy group (P = .17); the response difference was 6.00% with an upper limit of the 95% CI of 13.2, exceeding the predefined noninferiority margin. Complete response was observed in 14% vs 11% of patients.
Toxicity
The most common acute radiation-related toxicities at 14 days were lack of appetite (56% of 8-Gy group vs 66% of 20-Gy group, P= .011) and diarrhea (23% vs 31%, P = .018). Pathologic fractures occurred in 7% vs 5% (P = .15), and spinal cord or cauda equina compression occurred in 2% vs < 1%, P = .094).
The investigators concluded, “In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist.”
Edward Chow, MBBS, Sunnybrook Health Sciences Centre, Toronto, is the corresponding author for The Lancet Oncology article.
The study was supported by the Canadian Cancer Society Research Institute, U.S. National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hopitaux de Paris. The study authors reported no potential conflicts of interest.
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