The Lancet. Oncology 2014-02
Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial.
Abstract
Background
Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy.
Methods
We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912.
Findings
Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094).
Interpretation
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.
Funding
Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.
Related Questions
Would you offer a third course of palliative radiation after two courses of 8 Gy in 1 fx?
Hip pain can mean different things - is it the ilium, ischium, acetabulum, femur, or L-spine causing the pain?If it is the exact same bone as previously treated, a third fraction of 8 Gy can generally be safely given over the course of 4 years, especially if pain relief each time has lasted ~2 years...
If vertebral body pain is not controlled with a single 8 Gy fraction, what non-SBRT dose scheme would you consider for re-treatment?
My recommendation regarding a second course of radiation after a single fraction of 8 Gy depends on… a) Did the 8 Gy work at all? My usual practice has been to recommend repeat radiation therapy only if the first course helped. You could argue that maybe 8 Gy “just wasn’t enough” but many studies sh...
How would you manage an osseous lesion that received palliative SBRT with no pain relief?
This is certainly a challenging clinical scenario, without meaningful published literature to guide recommendations. If faced with this scenario, I would try to really determine the etiology of the patient’s pain in order to determine the best treatment. First of all, did the patient have pain relie...
How do you approach re-treatment if a patient still has pain from spine metastasis after 30 Gy in 10 fractions?
There is a myth in radiation oncology that 30 Gy in 10 fractions (MF) is more durable than single fraction (SF) regimens. On average, patients treated with SF or MF regimens have pain relief that lasts about 4 months. On average, 50% of patients experience recurrence of pain, regardless of the initi...
Would you utilize single fraction palliative radiation therapy for a large bone metastasis?
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How long would you wait before considering additional treatment to the same site if bone metastasis pain fails to improve after 8 Gy x 1 fraction?
There is unfortunately very little published evidence to help guide the answer to this very important question. It's potentially a big topic, so I am going to attempt an answer from a spine reirradiation perspective (Reirradiation of other sites such as weight-bearing long bones may have different c...
How do you decide on a fractionation scheme for retreatment of a progressive/painful spine metastasis?
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