A substantial proportion of cancer patients will develop metastatic disease in the skeleton. Bone metastases can cause significant morbidity, resulting from severe pain and pathological fracture. The treatment options for painful bone metastases include analgesics, bisphosphonates, surgical intervention and radiotherapeutic treatments, including external beam radiation therapy, hemibody irradiation and radiopharmaceuticals Citation[1,2]. For patients with complicated bone metastases, such as spinal cord compression associated with vertebral metastases or pathological/impending fracture, surgical intervention in the form of decompression surgery or prophylactic/therapeutic internal fixation may be needed together with radiation treatment. For uncomplicated bone metastases, nonsurgical approaches are typically used. External beam radiotherapy is arguably the most commonly used modality for the treatment of uncomplicated bone metastases. The goal of palliative radiotherapy for bone metastases is to rapidly improve the quality of life of patients. The most desirable treatment should be clinically efficacious, minimally toxic, time efficient and cost effective. Different radiotherapy regimens, including single-fraction and multiple-fraction regimens, are used Citation[2–6]. Multiple randomized trials have demonstrated the equivalence of single-fraction and multiple-fraction palliative radiotherapy for uncomplicated bone metastases Citation[3–16]. The question is: should all patients with uncomplicated bone metastases be treated with a single fraction of 8 Gy?
Pros of a single 8-Gy fraction
Most patients with metastatic disease have a limited lifespan. Protracted treatment regimens may consume a significant proportion of the patient’s remaining life; therefore, a single 8-Gy fraction can be a very timely and cost-effective treatment. Multiple randomized trials showed similar response rates, even at the 1-year time interval Citation[2,12,17]. The duration of response and progression rates were also demonstrated to be similar, implying that a single 8-Gy fraction is a noninferior treatment, even for patients with a relatively favorable prognosis Citation[17]. A single 8-Gy fraction is more convenient for patients, especially those who are in significant pain and have limited mobility. A single 8-Gy fraction also represents effective resource utilization, especially in radiotherapy departments treating a large number of patients. In terms of acute toxicities, a statistically significant lower rate was demonstrated with a single 8-Gy fraction in the Radiation Therapy and Oncology Group (RTOG) 9714 trial compared with the regimen of 30 Gy in ten fractions (10 vs 17%) Citation[14]. In this trial, the late toxicity rates were similar between the two groups Citation[14]. From the financial stand point, a single 8-Gy fraction costs much less than a multiple-fraction regimen Citation[2].
Cons of a single 8-Gy fraction
In a reanalysis of an RTOG study, Blitzer found that number of fractions related to complete combined relief in terms of absence of pain and cessation of the use of narcotics was statistically significant Citation[18]. Ben-Josef et al. suggested that there was a radiation dose–response relationship for pain relief, and that a higher prescribed total dose would provide better long-term palliation of pain compared with short-course lower total dose treatment Citation[19]. Koswig and Budach found that more remineralization occurred in patients treated with a multiple-fraction regimen of 30 Gy in ten fractions compared with those treated with a single 8-Gy fraction Citation[20]. In multiple randomized trials comparing single-fraction and multiple-fraction radiation therapy for the palliation of painful bone metastases, reirradiation was more common among patients who initially received a single-dose regimen Citation[11,12,14,16]. Another concern regarding a single-fraction regimen is the increased risk of pathological fracture. In the global analysis of the Dutch metastasis study, there was an increased risk of pathological fracture with the use of a single-fraction regimen compared with multiple-fraction treatment (4 vs 2%; p ≤ 0.05) Citation[11]. There is an increased risk of spinal cord compression following the use of a single-fraction compared with a multiple-fraction regimen Citation[5]. Also, a single 8-Gy fraction regimen may be perceived by patients as an inferior treatment Citation[21,22].
Evidence in the literature
High-quality data from multiple randomized trials demonstrated the equivalence of a single-fraction and a multiple-fraction regimen in terms of treatment of uncomplicated painful bone metastases Citation[3–17]. Current available evidence does not support the notion that a higher-dose fractionation regimen would result in a more durable response. Although the pathological fracture rate was statistically significantly higher in the single-fraction compared with the multiple-fraction arm in the Dutch study, the absolute rate was still fairly low and the absolute difference was only 2% Citation[11]. The higher rate of pathological fracture was not observed in other randomized trials comparing single-fraction and multiple-fraction regimens Citation[7–10,12,14–16].
In a previous RTOG study, a higher fracture rate was observed after larger fractions compared with a small fraction regimen in patients with a solitary metastasis Citation[23]. For neuropathic pain, the Trans-Tasman Radiation Oncology Group (TROG) 96.05 trial randomized patients with neuropathic pain to a single 8-Gy arm versus a multiple-fraction arm utilizing a regimen of 20 Gy in five fractions. There was no difference in the overall or the complete response rate. There were no statistically significant differences in the rates of retreatment, spinal cord compression or pathological fracture between the two regimens Citation[24]. Time to treatment failure was slightly worse for the single-fraction arm compared with the multiple-fraction arm (2.4 vs 3.7 months), although the overall outcomes did not show any statistical significance.
Multiple meta-analyses on the comparison of single- versus multiple-fraction radiotherapy have been performed Citation[3–6]. In the study by Sze et al., 12 trials including 3621 sites were involved. The overall pain response rates for single- versus multiple-fraction radiotherapy were 60 versus 59% (34 vs 32% for complete response) Citation[3]. The rate of pathological fracture was higher with single-fraction radiotherapy (3 vs 1.6% for multiple-fraction regimens). The rates of retreatment for single- and multiple-fraction radiotherapy were 21.5 and 7.4%, respectively. The rates of spinal cord compression were similar. In a meta-analysis, Wu et al. reported that among the 3260 randomized patients in seven studies, complete pain response rates for single- and multiple-fraction radiotherapy were 33.4 and 32.3%, respectively Citation[6]. The corresponding overall response rates were 62.1 and 58.7%. No radiation-dose response (based on biologically effective dose) for pain control was demonstrated. Reirradiation rate was significantly higher for patients receiving single-dose radiotherapy. Chow et al. included 16 randomized trials comparing single- and multiple-fraction radiotherapy in the systematic review and found that there was no difference between single- and multiple-fraction radiotherapy regimens in terms of response rates nor statistically significant difference in pathological fracture and spinal cord compression rates Citation[5]. The reirradiation rate was significantly (2.5-times) higher for the single-dose regimen.
Expert commentary
Medical practice should be guided by the results of high quality and adequately powered Phase III randomized trials. There is compelling level I evidence from international medical literature to support the use of a single 8-Gy fraction for the treatment of most uncomplicated bone metastases. In the rare situation where very limited uncomplicated bone metastases from favorable histologies, such as breast cancer, are present without associated extraosseous metastases, a multiple-fraction regimen delivering a higher total dose may be beneficial Citation[25–27]. Also, in circumstances where there is presence of a soft-tissue mass around the bone metastasis or the bone metastasis is located in a weight-bearing bone, or when there is neuropathic pain associated with the bone metastasis, multiple-fraction radiotherapy may be appropriate in patients with good performance status Citation[24,28].
For patients with high-risk femoral metastases (defined as axial cortical involvement of >3 cm) not suitable for prophylactic fixation, a multiple-fraction regimen delivering a higher dose of radiation may be appropriate to reduce the risk of pathological fracture Citation[29]. Unfortunately, this well-researched standard of care of using a single 8-Gy fraction has not been adopted worldwide, especially in the USA. A single-fraction regimen is more cost effective compared with a multiple-fraction regimen Citation[30,31]. In a recent internet-based survey on radiotherapy dose regimens used for painful bone metastases completed by members of the American Society for Therapeutic Radiology and Oncology (ASTRO), Canadian Association of Radiation Oncology (CARO) and Royal Australian and New Zealand College of Radiologists (RANZCR), only a minority of the 962 respondents, especially those from the USA, used a single-fraction regimen for five different clinical scenarios, including nonspinal scenarios Citation[2]. The use of a single fraction was dependent upon the professional affiliation, country of training, practice location and type of practice.
What is preventing radiation oncologists from using a single 8-Gy fraction regimen for uncomplicated bone metastases? The exact reasons are not entirely clear but multiple factors may be contributory. Previous surveys have suggested that radiation oncologists perceive a need for fractionated, higher total-dose radiotherapy because of factors including solitary focus of metastasis, histological type, institutional policy, fear of tumor progression and concerns about the late effects of larger fraction treatment. Common sense would also suggest that the remuneration model may possibly affect the pattern of practice, as is evidenced by the greater use of single-fraction therapy in sites where reimbursement is identical irrespective of treatment length or complexity.
In summary, a single 8-Gy fraction is efficacious and cost effective and should be the preferred treatment for most cases of uncomplicated bone metastases. The slow adoption of evidence-based practice is most probably caused by factors other than high-quality scientific evidence. For certain subgroups of patients with neuropathic pain Citation[24], soft-tissue component around the bone metastasis Citation[28], good performance status and limited or absent extraosseous metastases Citation[25–27], multiple-fraction radiotherapy may offer an advantage. In the TROG trial comparing a single 8-Gy fraction and 20 Gy in five fractions for neuropathic pain, the latter was demonstrated to be marginally better than the former dose regimen. The lack of clear advantage may be related to the fact that 20 Gy in five fractions is still regarded as a low-dose level. A future Phase III trial comparing 8 Gy in a single fraction and 30 Gy in ten fractions for bone metastases associated with neuropathic pain is warranted and, hopefully, the results of this trial can clarify the current controversy on radiotherapy fractionation for this clinical scenario.
Acknowledgements
The authors would like to thank Ms Melody Burchett from Ohio State University College of Medicine for her help in the transcription of the manuscript.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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