Second Single 4 Gy Reirradiation for Painful Bone Metastasis

26 Journal of Pain and Symptom Management Vol. 23 No. 1 January 2002 Original Article Second Single 4 Gy Reirradiation for Painful Bone Metastasis Branislav Jeremic, MD, PhD, Yuta Shibamoto, MD, DMSc, and Ivan Igrutinovic, BS University Hospital (B.J., I.I.), Kragujevac, Yugoslavia; and Department of Radiation Oncology (Y.S.), Kyoto University Hospital, Kyoto, Japan Abstract To investigate the efficacy of the second 4 Gy given as a single fraction radiotherapy (RT) for patients with painful bone metastasis who had already twice received single fraction RT (4, 6, or 8 Gy plus 4 Gy), a total of 25 patients were assessed before and after re-irradiation. The patients included 19 responders and 6 nonresponders to two prior single fraction RT, the latter one being 4 Gy. The overall response rate was 80%, with both complete response (CR) and partial response (PR) being 40%. No difference was found between the previous responders and previous nonresponders regarding both CR (P 0.70) and overall response rate (P 0.35). Response duration was longer in the previous responders (P 0.0041), but the time to pain relief was similar between the two treatment groups. No acute or late highgrade toxicity was observed during this study and no pathological fractures or spinal cord compressions were seen. In this small and highly selected series of patients, the third single fraction RT of 4 Gy was effective and not toxic in the treatment of painful bone metastasis. J Pain Symptom Manage 2002;23:26 30 Cancer Pain Relief Committee, 2002. Key Words Single-fraction radiotherapy, reirradiation, bone metastasis, pain Introduction Patients with painful bone metastasis are frequently treated with external beam radiation therapy (RT). Various single and multifraction regimens have been used for the relief of bone pain. 1 14 Controversies about optimal management continue to attract attention worldwide and focus around several problems in this field. 15 17 The most effective dose/fractionation schedule is unknown and it has been suggested that more emphasis on life expectancy is needed when therapeutic discussions are made. 18 Address reprint requests to: Branislav Jeremic, MD, PhD, Department of Radiation Oncology, University Hospital, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen, Germany. Accepted for publication: April 2, 2001. Although the high efficacy of RT for bone pain is well documented, a proportion of patients experience pain relapse. These patients may be re-irradiated with either single or multifraction regimens, depending on the initial RT characteristics. Only a few reports on this approach exist. None indicate a decline in analgesic efficacy or an increase in the RT-induced toxicity. 12,19,20 Based on this experience, patients who previously did not experience pain relief may be considered for re-irradiation. 12,19,20 Some of these patients may live long enough to experience another pain relapse and may be candidates for a second reirradiation (i.e., a third RT course). There is very little information on patients having three courses of RT, emphasizing the need for better insight into this problem. This may be especially important when single-fraction regimens are used. U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(01)00366-9

Vol. 23 No. 1 January 2002 Second Single 4 Gy Reirradiation 27 Methods During a previous prospective randomized trial, 6 a total of 327 patients with painful bone metastases were treated with either 4 Gy (Group I), 6 Gy (Group II) or 8 Gy (Group III) given in a single fraction. A total of 135 patients were then retreated with a single 4 Gy fraction for either pain relapse (n 109) or no response (n 26). 19 Of this group of 135 patients, a total of 25 patients were further reirradiated either because of relapse after initial response (n 19) or persistent pain after the previous two unsuccessful RT treatments (n 6). The indication for their third treatment (second retreatment) was left at the discretion of responsible radiation oncologist, who continued to administer patient questionnaires to obtain information necessary for the evaluation of response. Characteristics of these patients are given in Table 1. The approach to treatment is described in previous reports. 6,19 Briefly, all patients were treated with 6 10 MV photons from linear accelerators. Parallel-opposed fields were used to treat pelvis, hip, and long bones, while direct fields were used to treat vertebral column. Doses were specified at mid-depth for parallel-opposed fields and at 5-cm depth for spine fields. When treating lower thoracic or lumbar-sacral or pelvic/hip field, inevitably a varying volume of gastrointestinal tract was included in the treatment volume. Measures were taken to prevent acute side effects such as nausea and vomiting or radiation-induced enteritis by placing adequate blocking and administering appropriate medication (e.g., antiemetics). In all cases of second retreatment, a tumor dose of 4 Gy was used and the same RT fields were used as in the first or second treatment. The choice of this dose was based on previous findings that this is probably the lowest effective single dose (10) and the fear of excessive toxicity, especially in the groups of patients that previously received 6 4 Gy and 8 4 Gy, respectively. 19 The initial pretreatment assessment was made by the patient on the day of treatment planning or performing the reirradiation. The pain chart originally developed at the Royal Marsden Hospital, Sutton, UK 9 was used to assess response to second reirradiation. The same response criteria used during our prospective study 6 were applied. In this validated, patient-based method, a 4-point categorical pain scale (none, mild, moderate, severe) was used, with complete response (CR) defined as a complete disappearance of pain and a partial response (PR) defined as an improvement in pain score by at least one category. The use of analgesics was assessed before treatment and whenever possible thereafter. We used the classification of analgesics that was employed during an earlier study (none, non-opioid, mild opioid, and strong opioid). 9 Because there were no significant differences in the type or quantity of analgesics taken by patients in the three treatment groups during both the initial RT 6 and the first reirradiation, 19 analgesics were not used as an endpoint. Furthermore, analgesic requirement was shown not to make difference to response rates when using these pain charts in previous studies. 9 Toxicity was also scored using the RTOG/ EORTC toxicity criteria. 21 Patients were asked to complete questionnaires at weekly intervals. The differences in response rates, duration of response and the time to the first occur- Characteristic Table 1 Characteristics of Patients Undergoing Third Radiotherapy Response after 2 nd RT NR PR/CR Total Sex M 1 7 8 F 5 12 17 Age range 47 69 41 70 41 70 median 65 62 Primary tumor Breast 1 6 7 Lung 3 4 7 Prostate 3 3 Myeloma 1 1 2 Rectum 1 2 3 Kidney 1 1 Other 2 2 Metastatic site Th spine 1 4 5 L-S spine 4 8 12 Pelvis/hip 1 5 6 Femur 2 2 Group I 3 11 14 II 2 7 9 III 1 1 2 NR nonresponders; PR partial response; CR complete response.

28 Jeremic et al. Vol. 23 No. 1 January 2002 rence of any pain relief between the treatment groups were evaluated by the chi-square or t-test. All statistical analyses were carried out using a computer program HALBAU 4 (Gendaisuugakusha, Kyoto, Japan). Results All 25 patients completed pain charts chart (Table 2). Twenty patients (80%) responded to the second reirradiation. There were 16 (84%) responders among the previous responders, and 4 (67%) responded among the previous nonresponders (P 0.35). In total, there were 4 (20%) pain relapses. They were all observed in the group of previous responders, in which they constituted 25% of these patients. Duration of response to second reirradiation was longer in previous responders (P 0.0041). Time to achieve pain relief after second reirradiation was similar in the two groups, but the time from second to the third RT was shorter in the previous nonresponders (range 1 2 weeks, median 2 weeks vs. range 15 39 weeks, median 21 weeks), owing to the responses to the first reirradiation occurring in the group of responders. Finally, survival from the second reirradiation was found to be shorter for the previous nonresponders (P 0.0012). Owing to the efficacy of the second reirradiation, a high proportion of patients remained palliated until death. In previous responders, these patients constituted 12 out of 19 (63%) irradiated patients and 12 out of 16 (75%) patients who responded. For previous nonresponders, the corresponding figures were 4 out of 6 (67%) and 4 out of 4 (100%) patients (P 0.88 for all irradiated patients and 0.26 for responders). In total, 64% of all irradiated patients remained palliated until death, with this percentage rising to 80% when only responders are taken into account. In the 4 patients who relapsed after the second reirradiation, time from documented relapse to death was 1 week. Also, median survival time of 5 nonresponders to the second reirradiation was 2 weeks (range 2 9 weeks). When put together, these data confirm high palliative efficacy of the second reirradiation, because only 2 patients remained unpalliated for more than 2 weeks of their remaining life after the second reirradiation (until death). Table 2 Characteristics of Patients Re-reirradiated (Third Radiotherapy) Characteristic Response After 2 nd RT NR PR/CR Total Patients re-reirradiated (No.) 6 19 25 Outcome CR 2 8 10 PR 2 8 10 NR 2 3 5 Relapse after 3 rd RT 4 4 Response duration (weeks) range 2 4 2 28 2 28 median 2 8 5 Time to pain relief (weeks) range 1 2 1 3 1 3 median 2 2 2 Time from 2 nd to 3 rd RT (weeks) range 1 2 15 39 1 39 median 2 21 20 Survival from 3 rd RT (weeks) range 3 6 2 30 2 30 median 4 9 7 NR nonresponders; PR partial response; CR complete response. No acute or late high-grade ( 3) toxicity of second reirradiation were observed and no pathological fractures or spinal cord compressions were seen in any of these patients during the follow up. Discussion Mithal et al. 20 were the first and the only investigators who systematically addressed the issue of reirradiation in painful bone metastases. Following the first treatment, 12 of 48 responding sites relapsed in 10 patients and 8 of these were reirradiated. Seven out of 8 (87.5%) patients responded. Among these 7 responders, 4 of 5 (80%) were reirradiated with a single fraction RT, and 3 of 3 (100%) were reirradiated with fractionated regimens. Only 1 of 7 (14%) responders relapsed 37 months after second reirradiation. Unfortunately, no information was available regarding the duration of response. Results of our study show high efficacy of a single 4 Gy RT given for the second time for either pain relapse or for previous non-response. A similar proportion of non-responders (20%) were seen in the current study when compared to that of the study of Mithal et al. (12.5%). 20 Also, a similar proportion of relapses were ob-

Vol. 23 No. 1 January 2002 Second Single 4 Gy Reirradiation 29 served in our study (20%) and in the study of Mithal et al. (14%). 20 The second single 4 Gy fraction was not toxic. No acute or late high-grade toxicity was observed and no patient experienced pathological fracture or spinal cord compression. Together with the fact that a high proportion of patients was palliated until death and that only 2 of 25 (8%) patients were not palliated for more than 2 weeks of their remaining life, these outcomes suggest a positive impact on the quality of life in this patient population. Similar to our findings with first retreatment, 19 there was a tendency of treating radiation oncologists to use 4 Gy for second reirradiation more frequently for relapses after the first and second irradiation of 4 Gy than after 6 4 Gy or 8 4 Gy (65%, 39%, and 6% of patients, respectively) were given to previous responders. It is almost certain that this concern reflects a fear of excessive toxicity, which repeated single fractions may cause. For example, of 17 patients who received treatment to the spine, there were 12 patients in the initial Group I (initially received 4 Gy 4 Gy), 5 patients in the initial Group II (initially received 6 Gy 4 Gy), and none in the initial Group III (initially received 8 Gy 4 Gy) who received a third RT treatment to their spine. This concern is probably easier to understand with an initial fraction of 8 Gy, and is likely to be unfounded after initial single fractions of 4 Gy. The latter dose theoretically would have to be administered at least 5 times to resemble one of the frequently used fractioned regimens, such as 20 Gy in 5 fractions. It is unknown why only 65% of the patients in the current study received repeated 4 Gy single fractions. This is especially interesting, given that the responses we observed were accompanied with fast onset of pain relief and no troublesome toxicity. In the study of Mithal et al., 20 there was no uniform policy for re-irradiation and various single and fractionated regimens were administered after various single and fractionated regimens. This experience suggests that there is no excessive toxicity even if a fractionated regimen is followed by 8 Gy or 10 Gy given in a single fraction. A proportion of patients who initially did not respond to RT may be reirradiated, once or more than once, and then may respond. However, they are less frequently included in retreatments, probably owing to the combination of therapeutic nihilism and fear of toxicity. In the study of Mithal et al., 20 there were 8 such patients and 6 of them responded to second reirradiation (75%). In our previous study, 46% patients who did not initially respond did so after the second 4 Gy single fraction. During the current study, there were 6 patients who did not respond to two previous single fraction RT, and of them 4 (67%) responded, showing again that unsuccessful first or even second single fraction RT should not preclude its further use, especially if 4 Gy as a single fraction is used for either initial or repeated treatment. In conclusion, this study showed high efficacy and lack of toxicity of single fraction RT consisting of 4 Gy used as a second reirradiation for either previous responders or previous nonresponders. However, these patients may have been highly selected and may not consequently represent a representative sample of patients with refractory painful bone metastasis. Also, the small patient number, short remaining life of these patients, lack of studies addressing this question, and prevailing attitudes of involved radiation oncologists clearly emphasize the need for more information that should enable better insight into this approach to treatment. To do so, future prospective randomized trials, regardless of the fractionation regimen used, must include the issue of reirradiation in the treatment design. Acknowledgments This study was supported in part by the Grant-in-Aid for Scientific Research (B) from the Japanese Ministry of Education, Science and Culture (11470190, 11877152, 10557087). References 1. Archangeli G, Giovinazzo G, Saracino B, et al. Radiation therapy in the management of symptomatic bone metastases: the effect of total dose and histology on pain relief and response duration. Int J Radiat Oncol Biol Phys 1998;42:1119 1126. 2. Barak F, Werner A, Walach N, Horn Y. The palliative efficacy of a single high dose of radiation in treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys 1987;13:1233 1235. 3. Cole DJ. A randomised trial of a single treatment versus conventional fractionation in the pallia-

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