Documentation of pain is difficult because large inter- and intra-individual variations exist for the parameter ‘pain’. Chronic pain results in important alterations of the patient’s behavior concerning all fields of life. It is recommended to use standardized questionnaires for pain documentation to evaluate the success of the treatment. Pain questionnaires should not be preserved for scientific purposes. Moreover, the clinician should increasingly perform patient interrogations by standardized pain questionnaires to sustain the decisions for further treatment. For the daily routine, such a questionnaire must be short but efficient enough to comprise the fields ‘pain’, ‘activity of patient’ and ‘consumption of analgesics’. There are a variety of different pain scores and questionnaires that supply these information in an adequate way (Foley 1989). The reader’s attention may be drawn to the well evaluated and widely used visual analog scale (VAS) and the scoring of analgesics consumption referring to Foley’s score. Additionally, it is recommended to add some well chosen questions for the patient’s daily activity that have to be scored (e.g. Health Assessment Questionnaire = HAQ). However, also an internally developed system of pain assessment may serve for the evaluation of pain therapy. Pain evaluation in most of the following clinical trials on the efficacy of Re-188 HEDP for the treatment of bone metastases are based on these recommendations.

Liepe et al. 2000 published one of the first clinical studies to investigate the influence of Re-188 HEDP on pain relief, analgesic intake, and impairment of bone marrow function (Liepe 2000). They included 14 patients with prostate- and one patient with breast cancer. All patients had a positive Tc-99m HMDP bone scan showing at least three metastases, severe bone pain under analgesics and sufficient bone marrow function with a platelet count ≥ 10⁵/μl, leukocyte count ≥ 3.0 × 10³/μl, and hemoglobin ≥ 6.0 mmol/l. Chemotherapy and bisphosphonate therapy were discontinued 4 weeks before injection of Re-188 HEDP. All patients were interviewed using standardized questions before as well as 1, 2, 3, 4, 8, and 12 weeks after therapy. Blood samples were drawn on a weekly basis for 12 weeks, and a blood count was performed. The patients were treated with 1,600–3,459 MBq of Re-188 HEDP and underwent gamma camera imaging to determine the radionuclide accumulation 4, 20, and 28 h after therapy. Patients showed a statistically significant (p = 0.001) improvement of the Karnofsky performance index from 74 ± 8 % to 84 ± 11 % 12 weeks after therapy. Eighty percent of the patients described pain relief and reduction of analgesics and 20 % of the patients could discontinue their analgesics. Mean platelet count decreased from (284 ± 84)*10³/μl to (205 ± 62)*10³/μl, and mean leukocyte count from (7.5 ± 1.5)*10³/μl to (5.9 ± 2.1)*10³/μl after therapy. The maximal differences between the values of platelets and leukocytes before and after therapy were not statistically significant. PSA levels decreased from 95 ± 83 ng/ml to 41 ± 21 ng/ml, the difference was not statistically significant. The bone accumulation 4, 20, and 28 h after therapy was 1.3 ± 0.5 %, 0.6 ± 0.3 %, and 0.45 ± 0.2 % of the injected dose of a single metastasis, and 57 ± 17 %, 15.5 ± 2 % and 11 ± 3 % in the whole body, respectively. The effective half life of Re-188 HEDP could be shown to be 15.3 ± 3.0 h in the bone metastases, and 11.4 ± 2.8 h in the whole-body corresponding to a residence time of 0.22 ± 0.25 h in the bone metastases, and of 10.54 ± 2.59 h in the whole body. The authors concluded that in their small patient population suffering from osseous metastases, Re-188 HEDP therapy for bone pain palliation was effective and was associated with minimal toxicity (Liepe 2000).

One year later, Li et al. published data on the therapeutic efficacy of Re-188 HEDP in an uncontrolled initial trial of 61 patients with different types of advanced cancer (bone metastases of lung-, prostate-, breast-, renal-, rhinopharyngeal-, and bladder cancers) for the palliation of painful bone metastases (Li 2001). All included patients had pain arising from the secondary bone metastases resistant to chronic analgesic therapy and increased Tc-99m MDP uptake in multiple skeletal foci. Additionally, all had adequate hematologic function with a baseline total platelet count greater than 100 × 10⁹/l, a baseline total leukocyte count greater than 4 × 10⁹/l, and no severe renal failure. Patients were treated with 1.1–6.9 GBq Re-188 HEDP receiving one up to six treatments per patient and the interval between two treatments was approximately 1 to 1.5 months. After treatment, the patients were followed at weekly intervals for the first 2 months and monthly thereafter for as long as 1 year. Hematologic function tests were also performed before and after treatment for 6 weeks. Pain responses were scored according to a three-point pain rating scale as complete, significant, and minimal. Prompt and significant relief of bone pain was observed in 80 % of patients overall. Among the different tumor types, pain relief was achieved in 77 % of patients with lung cancer, in 80 % with prostate cancer, in 83 % with breast cancer, in 100 % with bladder cancer, in 50 % with renal cancer, in 50 % with rhinopharyngeal cancer, and in 87 % of patients with other tumor types, with no severe side effects or hematopoietic toxicity. As concluded by the authors, that clinical trial verified that Re-188 HEDP is a useful radiopharmaceutical agent to treat painful bone metastases from various tumor types (Li 2001).

In another study published by the German group of Liepe et al. in 2003, the effect of Re-188 HEDP on pain relief, analgesic intake and impairment of bone marrow function was investigated in 27 patients with bone metastases induced from prostate cancer (Liepe et al. 2003b). All patients were interviewed using a standardized set of questions before, and after therapy for 12 weeks. The patients were treated with 2,700–3,459 MBq of Re-188 HEDP. Blood samples were taken weekly for 12 weeks, and a blood count was performed. Patients described a significantly improvement on the Karnofsky performance scale from 74 ± 7 to 85 ± 9 % 12 weeks after therapy (p = 0.001). The pain score showed a maximum decrease from 44 ± 18 to 27 ± 20 % in the third to the 8 week after therapy (p = 0.009). Seventy-six percent of the patients described a pain relief without increase of analgesic intake and 20 % of the patients could discontinue their analgesics and were pain free. Mean platelet count decreased from (286 ± 75)*10³/μl to (215 ± 92)*10³/μl, and mean leukocyte count from (7.7 ± 1.5)*10³/μl to (6.0 ± 1.9)*10³/μl in the second to the fourth week after therapy. The maximal differences between the values of platelets and leucocytes before and after therapy were not statistically significant. Based on the results of their study, the authors concluded Re-188 HEDP to be an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain in prostate cancer with minimal bone marrow toxicity (Liepe et al. 2003b).

In the same year, two other clinical trials on the effectiveness of Re-188 HEDP for the palliation of painful bone metastases were published by a group from Japan and another group from Germany. Zhang et al. published a series of 30 patients suffering from lung cancer with painful osseous metastases (Zhang 2003). All patients had scintigraphically and radiologically proven metastatic bone lesions and suffered from bone pain that required the use of analgesics. Adequate platelet count (>100 × 10⁹/l), leukocyte count (>2.5 × 10⁹/l), and renal function (plasma creatinine levels, <130 μmol/l) were required for eligibility. Although no specific recommendations were given on how to alter the analgesic treatment, the patients were requested to keep their analgesic regimens constant. Fulfillment of these criteria was also required for repeated radiopharmaceutical therapy. The intravenously administered activities of Re-188 HEDP ranged between 1.15 and 4.6 GBq. The patients were clinically followed at weekly intervals for the first 2 months, and monthly thereafter up to 1 year. Hematologic testing was performed before treatment and thereafter for 6 weeks. Pain response was scored by a four-point pain-rating scale as complete, marked, mild, and no response. Prompt and significant relief of bone pain occurred in 80 % with no significant side effects or hematopoietic toxicity. Forty-six percent of the patients discontinued analgesics after treatment. In accordance to the previously published series, author concluded that Re-188 HEDP can offer significant pain palliation and is a useful radiopharmaceutical for treating painful osseous metastases from lung cancer (Zhang 2003).

In the trial published by the German group of Palmedo et al., the effect of repeated bone targeted therapy with Re-188 HEDP in patients with progressive, hormone-resistant prostate carcinoma, and bone pain was investigated (Palmedo 2003). The aim of that study was to determine the pain palliation and the anti-tumor effect of single or repeated Re-188 HEDP treatments. A total of sixty-four patients was randomly assigned to one of two groups for radionuclide therapy with Re-188 HEDP. Inclusion criteria were multifocal pain and with at least five different sites of bone metastases, as proven by Tc-99m MDP scintigraphy and X-ray. Additionally, patients had to show progression of disease despite hormonal therapy and despite subsequent anti-androgen withdrawal. Progression of disease was defined as progression of measurable lesions or increasing PSA values (three consecutive increasing PSA values). Life expectancy of patients had to be at least 3 months. Patients with leukocyte and thrombocyte counts below 4.0 × 10⁹/l and 100 × 10⁹/l, respectively, or with impaired renal function (creatinine > 1.4 mg/dL) were excluded from the study. None of the patients received hemibody irradiation before Re-188 HEDP treatment. However, local external-beam radiation and one previous treatment with chemotherapy were allowed (time interval to Re-188 HEDP treatment at least 4 weeks). Patients with pain caused by pathologic fracture, infiltration of a nerval plexus, or peripheral nerves were also excluded. Also, confirmed visceral metastases or serious illness and organ dysfunction not related to prostate cancer caused exclusion from the study. Patients of group A received a single injection, patients of group B received two injections (interval of 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria WHO grade of 2). The effectiveness of Re-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92 % and 5.66 months, respectively (p = 0.006 and p = 0.001). In group B, 11 (39 %) of 28 patients had a PSA decrease of more than 50 % for at least 8 weeks, compared with two (7 %) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range: 0–12.2 months) and 7.0 months (range: 0–24.1 months), respectively (p = 0.0013), and the median overall survival times were 7.0 months (range: 1.3–36.7 months) and 12.7 months (range: 4.1–32.2 months), respectively (p = 0.043). Palmedo et al. concluded, that compared with single-injection therapy, repeated bone-targeted therapy with Re-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression free and overall survival. Furthermore, the authors suggested future larger studies to be justified to further evaluate the use of Re-188 HEDP (Palmedo et al. 2003).

Further evaluating the concept of repeated Re-188 HEDP administrations, the results of a retrospective study in hormone-refractory prostate cancer patients with bone pain and more than five bone metastases were very recently published in 2011 by our group (Biersack 2011). We included a total of 60 patients in that study and divided them into three different groups. In group A, 19 patients with a single injection of Re-188 HEDP were included, whereas in group B (n = 19) patients had received two injections. Group C (n = 22) consisted of patients with three or more successive Re-188 HEDP treatments. Patients in all groups had similar Gleason scores and patient’s follow-up data including PSA levels were gained from the referring physician. The time span between diagnosis of prostate cancer and first therapy ranged from 5.7 years (group C) to 6 years (group B) to 7.5 years (group A), failing to show a statistically significant difference. Mean survival from the start of Re-188 HEDP treatment was 4.50 ± 0.81 months [95 % confidence interval (CI), 2.92–6.08] for group A, 9.98 ± 2.21 months (95 % CI, 5.65–14.31) for group B, and 15.66 ± 3.23 (95 % CI, 9.33–22.0) for group C (p < 0.001). Although the three groups did not differ in Gleason score, the number of lost life years was significantly lower in group C than in groups A and B. Pain palliation was achieved in 89.5 % of group A, 94.7 % of group B, and 90.9 % of group C. As already described by Palmedo et al., in general, only reversible grade 2 thrombopenia and reversible grade 1 leukopenia were observed (Palmedo 2000, 2003; Biersack 2011). Concluding these results, post-treatment overall survival could be improved from 4.50 to 15.66 months by multiple-injection bone-targeted therapy with Re-188 HEDP, when compared with a single injection. Significant pain palliation was common and independent of administration frequency (Biersack 2011).

Comparing different radiopharmaceuticals for the treatment of bone metastases, the already mentioned German group of Liepe et al. (2005a, b) published two further clinical studies in 2005. They investigated the efficacy and toxicity in pain palliation in bone metastases of Re-188 HEDP compared to Sm-153 EDTMP and, in the second trial, to Re-186 HEDP and Sr-89 (Liepe et al. 2005a, b). In the first series, the effect of treatment with Re-188 HEDP and Sm-153 EDTMP on pain symptoms, life quality, and bone marrow function was obtained in 46 patients with prostate- and breast cancer. Criteria for patient inclusion in the study were positive Tc-99m HMDP bone scan with at least three lesions, bone pain symptoms requiring the long-term use of analgesics, sufficient bone marrow function with a platelet count ≥ 100 × 10³/μl, leukocyte count ≥ 3.0 × 10³/μl, and hemoglobin > 6.0 mmol/l (9.67 g/dl) as well as normal renal function. Thirty-one patients were treated with Re-188 HEDP (3,194 ± 387 MBq) and 15 patients with Sm-153 EDTMP (2,940 ± 545 MBq). The Re-188 HEDP group included 6 and 25 patients, and the Sm-153 EDTMP group 6 and 9 patients with breast- and prostate cancer, respectively. All patients had an interview using standardized sets of questions before and after therapy for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. After treatment with Re-188 HEDP, 77 % of patients reported pain relief and 73 % after Sm-153 EDTMP. Sixteen percent of the patients treated with Re-188 HEDP and 13 % of those given Sm-153 EDTMP could discontinue their analgesics and were pain free. Patients described a significant improvement on the Karnofsky performance scale from 73 ± 7 to 85 ± 8 % 12 weeks after Re-188 HEDP (p < 0.05) and, failing to be statistically significant, from 68 ± 9 to 74 ± 9 % after Sm-153 EDTMP. Only three patients post-Re-188 HEDP and two patients post-Sm-153 EDTMP showed a thrombocytopenia below 100 × 10³/μl. The maximum nadir of platelet and leukocyte counts was observed between the second to fourth week after treatment in both and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance scale and bone marrow toxicity between the lower beta energy Sm-153 EDTMP and the higher beta energy Re-188 HEDP. Therefore, the authors concluded that both radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity (Liepe et al. 2005a). In the second series by the same group, also published in 2005, two different radiopharmaceuticals (Re-186 HEDP and Sr-89) in addition to Re-188 HEDP were investigated to determine their efficacy and toxicity in the palliation of painful bone metastases. Data on the influence of the radiopharmaceuticals on pain symptoms, quality of life, and bone-marrow function were obtained from 64 patients with breast- and prostate cancer. Thirty-one patients were treated with Re-188 HEDP (3,194 ± 387 MBq), 15 patients with Re-186 HEDP (1,358 ± 158 MBq), and 18 patients with Sr-89 (152 ± 19 MBq). The Re-188 HEDP group included six breast- and 25 prostate cancer patients, the Re-186 HEDP group included three breast cancer patients and 12 prostate cancer patients; and the Sr-89 group included three breast- and 15 prostate cancer patients. All subjects participated in an interview using standardized sets of questions before and after the 12 week term of therapy. Blood counts were taken weekly for 6 weeks and after 12 weeks. Results showed that 77 % of patients reported pain relief after treatment with Re-188 HEDP, 67 % after treatment with Re-186 HEDP, and 72 % after treatment with Sr-89, respectively. Sixteen percent of patients treated with Re-188 HEDP, 13 % treated with Re-186 HEDP, and 17 % treated with Sr-89 were able to discontinue their analgesics and were pain free. Patients described an improvement on Karnofsky performance status from 73 ± 7 to 85 ± 8 % 12 weeks after Re-188 HEDP (p < 0.05), from 72 ± 13 to 79 ± 12 % after Re-186 HEDP, and from 62 ± 14 to 69 ± 16 % after Sr-89, failing to reach statistical significance for the two latter radiopharmaceuticals. Only three patients undergoing Re-188 HEDP therapy, one undergoing Re-186 HEDP therapy, and three undergoing Sr-89 therapy had thrombocytopenia (platelet count below 100 × 10³/μl) following treatment. The maximum nadir of platelet and leukocyte counts was observed between the second and fifth week after treatment for all radionuclides and was reversible within 12 weeks. The nadir was earlier for Re-188 HEDP with a shorter physical half life compared with Sr-89. There were no significant differences in bone marrow toxicity. Results of this study indicate that all evaluated radiopharmaceuticals were effective in pain palliation without induction of severe side effects. The increase in Karnofsky performance status after Re-188 HEDP therapy in contrast to the nonsignificant improvement after treatment with Re-186 HEDP and SR-89 was the only statistically significant finding (Liepe et al. 2005b).