Among the randomized trials comparing single versus multiple fractions for painful bone metastases, retreatment rates were consistently higher after the single-dose schedules. Percentages varied from 11 to 42 % after a single fraction to 0–24 % after multiple fractions (Table 1). It has been proposed that because of the higher necessity for retreatment, the single-fraction regimen was not as effective as more protracted regimens when looking at durability of response. On the other hand, the retreatment percentages in the trials were most likely biased, since retreatment was done at the discretion of the treating radiation oncologists and patients, neither of whom were blinded to the initial treatment. Disbelief in the effectiveness of a single fraction, or the awareness that still more radiation was possible, may contribute to these percentages. The study protocols did not prescribe a minimum time interval between initial and retreatment, or a minimum pain score requirement, and the dose for retreatment was also not defined. In addition many patients with recurrent pain or poor response to initial radiation may have been lost to follow-up or may not be referred back to their radiation oncologist for consideration of retreatment. A reanalysis of the original database of the Dutch trial was completed using the consensus criteria for response with a closer look at specific reasons to retreat (Chow et al. 2002; van der Linden et al. 2004a, b). After 8 Gy single fraction, 24 % of the patients were retreated versus only 6 % after 24 Gy in six fractions (p < 0.001). Response to initial treatment without the effect of retreatment was 71 % after SF vs. 73 % after MF (p = 0.84). Retreatment raised the response rate to 75 % for SF; MF response rates remained unaltered (p = 0.54). The response status after initial treatment did not predict for retreatment: 35 % SF vs. 8 % MF nonresponders, and 22 % SF vs. 10 % MF patients with progressive pain were retreated. After progressive pain was observed, mean time to retreatment was 7 weeks in SF patients versus 10 weeks in MF patients. The preceding mean pain score was 7.5 in SF patients and 7.8 in MF patients. In conclusion, it appeared that physicians were more reluctant to retreat initial MF patients than initial SF patients.

Until 2014, responses to retreatment have been reported only in retrospective and nonrandomized prospective studies. Price et al. reported on seven patients who, after failure to respond to the initial single 4 Gy fraction, were given a second radiotherapy within 8 weeks (Price et al. 1986). Four of them received a single 8 Gy and the other three a fractionated course with a higher total dose. No significant pain relief was achieved by the second radiotherapy treatment in any of these seven patients (Price et al. 1988). Cole reported in 42 patients that retreatment of patients after initial single- or multiple-fraction treatment was not successful in most patients, and 50 % needed supplementary stronger analgesics (Cole 1989). Hoskin et al. randomized patients in a prospective study to either 4 or 8 Gy single dose for the initial treatment of metastatic bone pain. During the 12-week study period, 28 patients randomized to 4 Gy were retreated with radiotherapy to the same site compared to 12 randomized to 8 Gy. 12/17 (71 %) evaluable patients responded to retreatment in the 4 Gy arm and 4/9 (44 %) responded in the 8 Gy arm (Hoskin et al. 1992). Uppelschoten et al. reported that after long intervals from initial single 6 Gy of radiation, retreatment with another 6 Gy was able to reduce pain in 13 out of 18 patients (72 %) (Uppelschoten et al. 1995). Mithal et al. published a retrospective analysis of 105 consecutive patients treated with palliative radiotherapy for painful bone metastases. A total of 280 individual treatment sites were identified, of which 57 were retreated once and eight were retreated twice. The overall response rate to initial treatment was 84 % for pain relief, and to retreatment the response rate was 87 %. 7/8 (88 %) patients retreated for a second time also achieved pain relief. No relation to radiation dose, primary tumor type, or site was observed (Mithal et al. 1994). Jeremic et al. investigated the effectiveness of a single fraction of 4 Gy given for retreatment of bone metastasis after initial single-fraction radiotherapy. Of 135 patients retreated, 109 patients were retreated because of pain relapsing, and 80 (74 %) patients responded (complete response (CR) = 31 %, partial response (PR) = 42 %). Among the 26 patients that initially did not respond, 46 % responded. The authors concluded that the lack of response to an initial single fraction should not deter repeat irradiation. The same group also reported the efficacy of a second single 4 Gy retreatment for painful bone metastases following two previous single fractions. The overall response rate of 25 patients (19 responders and six nonresponders) was 80 %, with both complete response and partial response being 40 % (Jeremic et al. 2002). In Radiation Therapy Oncology Group (RTOG) studies that involved wide-field or hemibody radiotherapy, patients who relapsed after wide-field irradiation were reported to tolerate local irradiation within that field with success (Quasim 1981; Salazar et al. 1986). Van der Linden et al. studied 173 patients who were retreated within the randomized Dutch Bone Metastasis Study (n = 1157) (van der Linden et al. 2004a, b). In 137 retreated SF patients, 33 % received a second SF and 67 % received MFs. In 36 retreated initial MF patients, 25 % received second MF and 75 % received a SF. To evaluate whether response to initial treatment influenced the choice for the second treatment schedule, the response status before retreatment was studied. There was no correlation between the initial response status and the retreatment schedule. In total, 63 % of retreated patients responded to retreatment: 66 % of retreated SF patients responded compared with 46 % of MF patients (p = 0.12, HR 1.6 (0.9–3.0)). After retreatment, time to response was not different for initial SF and MF patients, but the mean duration of remission was substantially longer in initial SF patients, 16 weeks vs. only 8 weeks in initial MF patients. For SF patients, response to retreatment was irrespective of the initial response: 66 %, 67 %, and 70 % of initial nonresponders, responders, and progressive patients, respectively, responded to retreatment. Although more initial SF than MF nonresponding patients responded to retreatment, due to small numbers, this difference was not significant (66 vs. 33 %, respectively, p = 0.13, HR 3.0 (0.7–12.7)). Of nonresponders to an initial SF, 88 % responded to a second SF and 53 % to MF. Of the latter, 10 % of responses were due to a decrease in analgesic intake. Overall, no major differences in mean time to response after retreatment were reported. Mean duration of remission ranged from 4 weeks in initial MF nonresponders to 25 weeks in initial SF nonresponders. Patients with prostate cancer had the lowest success rate: 20 % of initial nonresponding patients responded, and only 19 % of patients with progression responded again. Patients with breast cancer had the highest response percentages for nonresponders and progressive patients (82 % and 89 %, respectively). Mean duration of remission was longest in initial nonresponding breast cancer patients (23 weeks). Van Helvoirt et al. actively contacted 298 consecutive patients 4 weeks after initial single-fraction therapy to evaluate response and, if necessary, to offer retreatment (van Helvoirt and Bratelli 2008). Seventy-five percent of the patients were satisfied with their pain response, and 75 % of the non-satisfied patients requested retreatment. Of these, 87 % responded after a second single fraction. In 37 patients with recurrent pain, 83 % responded to a second single fraction. In 2012, Huisman et al. performed a systematic review on ten articles and a meta-analysis on seven (Huisman et al. 2012). Of the 2,694 patients initially treated for metastatic bone pain, 527 (20 %) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58 % of patients (pooled overall response rate 0.58, 95 % confidence interval = 0.49–0.67). There was a substantial between-study heterogeneity (I ² = 63.3 %, p = 0.01) because of clinical and methodological differences between studies. In 2014, the results from the international randomized trial on retreatment in painful bone metastases were published (Chow et al. 2014a, b). A total of 850 patients were randomized between a single fraction of 8 or 20 Gy in 5 fractions for retreatment. In the intention-to-treat population, 118 (28 %) patients allocated to 8 Gy and 135 (32 %) allocated to 20 Gy 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 %]). They concluded that for retreatment, 8 Gy in a single fraction seemed to be non-inferior and less toxic than 20 Gy in multiple fractions.

In patients with longer life expectancies, a second or even third retreatment may be considered if earlier radiotherapy treatments have given satisfactory pain responses. Cumulative total doses should be calculated taking into account nearness of critical radiosensitive organs, such as the spinal cord, kidney, bowel, or skin. No clear-cut answer is yet available to guide which dose schedules should be used for a first retreatment, second retreatment, or even third retreatment.