The results of this study show that 30 Gy in 10 fractions has been most commonly used for PORT of metastases to the long bones in current practice in Japan. Half of the RT plans irradiated at JROSG institutes were prescribed 30 Gy in 10 fractions. In addition, the majority of the respondents also recommended this regimen in hypothetical cases (67% for Case 1, 45% for Case 2, 53% for Case 3, and 66% for Case 4). Our results are similar to those reported by previous retrospective studies about PORT for metastases to the long bones [8–11]. In most of these studies fractioned RT, such as 30 Gy in 10 fractions or 20 Gy in 5 fractions, ranging from 8 Gy to 56 Gy was used. In addition, as per the American College of Radiology (ACR) Appropriateness Criteria for Non-Spine BMs [12], which is based on multidisciplinary expert opinion, while there are no definitive data to suggest the most appropriate radiotherapy dose, 30 Gy in 10 fractions seems to be a reasonable option with the goal of eradicating microscopic residual disease. In the expert opinion, 8 Gy in 1 fraction to 35 Gy in 14 fractions are also equally appropriate.
Among the hypothetical cases, case 2 that described a single oligometastasis of non-small-cell lung cancer in the long bone, was mostly recommended for higher dose regimens (fractionated intermediate dose regimens: 40% or fractionated high dose regimens: 12%) in comparison to other hypothetical cases. Recently, SAbR-COMET study [13] showed that stereotactic body radiotherapy (SBRT) for oligometastasis provided a survival benefit (standard of care alone vs. SBRT arm; 28 vs. 41 months of median overall survival). Another previous study [14] has shown that high dose prescription by SBRT yields high rates of great local control of greater than 85% for non-spine BMs. Thus, the higher dose PORT regimens might also lead to good local control as well as survival benefit in case of oligometastasis.
Case 3
in our study was identical with Case 1 except for the radio-resistant primary tumor. In current study, none of the respondents recommended high-dose-per-fraction (greater than 5 Gy) for Case 3. Although RCC is traditionally reported to be radio-resistant to RT [15], it has been previously reported that high-dose-per-fraction RT could overcome this relative radio-resistance in RCC [16]. Similar findings for melanoma, also considered as a radio-resistant primary tumor, have also been reported [17]. However, Rades et al reported escalation of the radiation dose beyond 30 Gy in 10 fractions did not significantly improve motor function and local control of metastatic spinal cord compression in case of radio-resistant tumors including renal cell carcinoma, colorectal cancer, and malignant melanoma [18]. Therefore, whether to escalate radiation dose for radio-resistant primary tumors in a palliative care setting remains unclear.
Case 4
in our study described a patient with expected long-term survival. Sixty-six percent of respondents recommended 30 Gy in 10 fractions for Case 4, which were similar to recommendations for Case 1 with comparatively limited survival (67%). Fractioned intermediate dose or high dose was recommended by 24% of the respondents, which was higher than that recommended for Case 1 with limited survival (9%). However, according to the data reported for pain relief of bone metastases for 320 patients with painful BM surviving > 52 weeks, Van der Linden et al. reported that the responses were similar in both single and multiple fraction schedules (87% after 8 Gy, and 85% after 24 Gy) [19]. Single fraction schedule is the standard palliative treatment for all patients with painful bone metastases, including patients with an expected favorable prognosis [19]. However, the research on optimal dose fractionation in the PORT setting should also be conducted in patients with an expected favorable prognosis.
Three-quarters of respondents recommended “the entire orthopedic prosthesis” for irradiation fields during PORT. Two retrospective studies about PORT for long bones mention about irradiation fields; Townsend et al. reported that 21 out of 25 fields (84%) included the entire orthopedic prosthesis [8], and Drost et al. reported that 72 out of 74 fields (97.3%) included the entire orthopedic prosthesis [10]. It is thus common in practice to include at least the entire orthopedic prosthesis.
Although the objective of the PORT for long bones is not clear, Townsend et al. and Adamietz et al. retrospectively reported the efficacy of PORT based on the functional status of the extremities [8, 11]. Other potential objective is to reduce local progression and prevent prosthesis displacement, hence reducing the need for second surgery [10]. Our study also suggests that many Japanease radiation oncologists (54%) considered that long-course RT was preferred in PORT for the long bones due to better “local control.” However, in the palliative setting, the primary object of palliative RT is not mainly local control but benefits such as improved QOL, reduction in symptoms, and overall survival. For example, Rades et al reported on 265 patients treated with RT for metastatic spinal cord compression that 1-year local control was significantly better in long-course RT compared with short-course RT, while short-course RT and long-course RT had no significant difference with respect to the effect of RT on motor function [20].
The biggest limitation of the present study was the lack of clinical follow-up data. Especially, recommendations for hypothetical cases might not truly reflect clinical management. However, understanding the patterns of practices will be important for future clinical trials. Because there is no clear evidence for the efficacy or optimal dose-fractionation of PORT for the indication of BMs of the long bones, clinical trials to examine the efficacy or optimal dose-fractionation of PORT would be necessary in the future.