Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo. The PLACORHEN study: a double-blind, placebo-controlled, randomized radionuclide study with (186)Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma. Relative efficacy of 32P and 89Sr in palliation in skeletal metastases. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.
In a multicenter, randomized controlled trial involving 126 patients with endocrine-resistant advanced prostate cancer, all of whom received external beam radiotherapy, additional treatment with a single injected dose of 400 MBq strontium-89 (Metastron) significantly improved overall pain control. Adjuvant therapy with strontium-89 also significantly reduced analgesia requirements compared with placebo and delayed disease progression, as indicated by the requirement for further external beam radiotherapy. On certain measures, patients receiving strontium-89 also showed enhanced quality of life. Accompanying these changes, levels of prostate tumor markers were significantly reduced by strontium-89 treatment. The benefits resulting from adjuvant strontium therapy were associated with tolerable hematologic toxicity. The addition of strontium-89 to external beam radiation had no effect on survival. However, it has clear implications for improved palliation in advanced prostate cancer and may also impact positively on treatment costs. We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments.
                Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 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 grade of 2). The effectiveness of rhenium-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 =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen 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 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043).
                Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP. The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra.
                Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat.
                Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression).
                (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers. To explore the efficacy of adjuvant (89)Sr applied with external beam radiotherapy (EBRT) to treat bone metastases.
                Ninety-five patients were randomized to (89)Sr (Arm A) or saline (Arm B) on Day 1 of EBRT to demonstrate a reduction in 3-month physician-assessed subjective progression from 70% to 45%.
                At 3 and 6 months, no difference between treatment arms was observed in the progression rate. At 3 months, the physician-assessed response rate for all patients was 25%, with 46% of the patients progressing. The pretreatment use of opiates was independently associated with short progression-free survival. On the basis of the quality-of-life assessments, pain relief occurred in 50% of patients and 32% experienced improvement in global quality of life, without impact from (89)Sr. Differences were observed between the physician evaluation of radiotherapy efficacy and the patient assessment. In Arm A, serum alkaline phosphatase, but not serum prostate-specific antigen, decreased during the first 3 months after treatment.
                (89)Sr, adjuvant to ERBT, does not seem to reduce the number of patients with subjective progression at 3 months. Patients should be referred for palliative RT before their bone pain requires high doses of opiates. In radiotherapy trials, the evaluation of pain and pain relief remains problematic because of the confounding use of analgesics. A Phase III randomized trial was designed to assess the effectiveness of samarium-153 (153Sm)-lexidronam for palliation of bone pain in patients with hormone-refractory prostate cancer.
                A total of 152 men with hormone-refractory prostate cancer and painful bone metastases were enrolled in a prospective, randomized, double-blind trial comparing radioactive (153Sm) versus nonradioactive (152Sm) lexidronam complexes. Patients were randomized (2:1) to the radioactive (153Sm) agent. Patient diaries recording daily pain and analgesic use were completed during a planned 16-week evaluation period. Nonresponders were informed of the treatment received after 4 weeks of treatment and, if initially treated with placebo, were allowed to receive 153Sm-lexidronam in an open-label fashion. Pain was measured using validated patient-derived visual analog scales and pain descriptor scales.
                153Sm-lexidronam had positive effects on measures of pain relief compared with placebo within 1 to 2 weeks. Reductions in opioid use were recorded at weeks 3 and 4. Because nonresponders were unblinded at week 4, statistical comparisons between the arms beyond week 4 were not possible. Mild, transient bone marrow suppression was the only adverse event associated with 153Sm-lexidronam administration. The mean nadir white blood cell and platelet count (3 to 4 weeks after treatment) was 3800/microL and 127,000/microL, respectively. Counts recovered to baseline after approximately 8 weeks. No grade 4 decreases in either platelets or white bloods cells were documented.
                These findings demonstrate that 1 mCi/kg 153Sm-lexidronam is both safe and effective for the palliation of painful bone metastases in patients with hormone-refractory prostate cancer. The study evaluates the therapeutic efficacy of Strontium-89-chloride (89Sr) and 186Re-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) in the palliation of painful bone metastases from breast cancer.
                Fifty patients with painful multifocal bone metastases from breast cancer entered the study and were randomized into two groups according to the radiopharmaceutical used: 148 MBq 89Sr i.v. (Group A: 25 patients) and 1406 MBq 186Re-HEDP i.v. (Group B: 25 patients). Pain palliation was evaluated on the basis of the Wisconsin pain test improvement at two months and response was graded as complete, partial, minimal or absent. Hematological toxicity and side effects were reported according to WHO guidelines.
                The global response rate was 84% (21/25) for 89Sr and 92% (23/25) for 186Re-HEDP, respectively. The onset of pain palliation appeared significantly earlier in Group B (p < 0.0001). The duration of pain relief ranged from two months to 14 months (mean of 125 days with a median value of 120 days) in Group A and from one month to 12 months (mean of 107 days with a median value of 60 days) in Group B (p = 0.39). A moderate hematological toxicity was apparent in both groups. Platelet and white blood cell counts returned to baseline levels within 12 weeks after 89Sr administration and 6 weeks after 186Re-HEDP administration (p < 0.01).
                Both 89Sr and 186Re-HEDP are effective and safe in bone pain palliation in breast cancer with the latter showing a significantly faster onset of pain relief. One hundred and fourteen patients with painful bone metastases participated in this randomised, dose-controlled study of the efficacy and safety of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP), a systemically administered radiopharmaceutical. Fifty-five patients received single doses of 0.5 mCi/kg and 59 patients received single doses of 1.0 mCi/kg. Treatment with 153-Sm-EDTMP produced improvement from baseline in all patient-rated efficacy assessments, including degree of pain, level of daytime discomfort, quality of sleep and pain relief. During the first 4 weeks after dose administration, when the patients evaluated efficacy daily, there were statistically significant changes from baseline with the 1.0 mCi/kg dose but not with the 0.5 mCi/kg dose. The difference between doses in visual analogue pain scores was statistically significant at week 4 (P = 0.0476). Among subsets of patients examined, female patients with breast cancer receiving 1.0 mCi/kg had the most noticeable improvement. The physicians judged that approximately half of the patients in each dose group were experiencing some degree of pain relief by week 2. This value increased to 55% for the 0.5 mCi/kg group and 70% for the 1.0 mCi/kg group at week 4. More patients in the higher dose group (54%) than in the lower dose group (44%) completed the 16-week study. A predictable level of dose-related marrow suppression was the only toxicity associated with 153Sm-EDTMP treatment. Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks. Even at their lowest point, the values were generally higher than those associated with infectious or haemorrhagic complications. Myelotoxicity was no greater in female patients than in male patients. Long-term follow-up revealed longer survival among breast cancer patients who had received the higher dose than among those who had received the lower dose. The results suggest that the 1.0 mCi/kg dose of 153Sm-EDTMP is safe and effective for the treatment of painful bone metastases. Painful bone metastases are most frequent in patients with advanced prostate or breast carcinoma. The aim of this study was to compare the analgesic effect of radionuclide therapy using Sr and Sm-EDTMP in patients with painful bone metastases of these tumours.
                One hundred patients treated with radionuclide bone palliation therapy were analysed. The study population consisted of 60 male patients with advanced prostate carcinoma and 40 female patients with advanced breast carcinoma. Fifty patients (30 men and 20 women) were treated with Sr (150 MBq). The other 50 patients were treated with Sm-EDTMP (37 MBq x kg). The treatment efficacy was evaluated by a visual analogue scale (VAS), Karnofsky performance scale, and dosage of analgesic drugs used.
                Complete pain relief was found in 40% of women and 40% of men treated using Sm-EDTMP and in 25% of women and 33% of men treated with Sr. No analgesic effect occurred in 20% of patients. A better analgesic effect was found in cases of osteoblastic metastases compared to mixed metastases. Statistically significant reduction of pain intensity, use of analgesic drugs and improvement of performance in Karnofsky scale was found in cases of both radionuclides.
                The analgesic effects of Sr and Sm-EDTMP was similar in both prostate and breast carcinoma. However, the effect was dependent on the type of metastases; better response was observed in cases of osteoblastic metastases than in patients with mixed metastases. Severe adverse reactions after this therapy were rare. Rhenium-186 (tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that simultaneously localizes in multiple skeletal metastases in patients with advanced cancer. A single intravenous administration of 30-35 mCi (1110-1295 MBq) is associated with a prompt, significant relief of osseous pain in about 80% of such patients. The efficacy of this new compound was evaluated further by utilizing a double-blind crossover comparison with 99mTc-methylene diphosphonate (MDP) as a radioactive placebo. The new rhenium compound resulted in a significantly (p less than 0.05) greater decrease in pain than did treatment with the radioactive placebo. Rhenium-186(Sn)HEDP appears to be a useful new compound for the palliation of painful skeletal metastases. (186)Re-1,1-hydroxyethylidene diphosphonate (etidronate) can be used for the palliative treatment of metastatic bone pain. A randomized, placebo-controlled study using (186)Re-etidronate was conducted on end-stage prostate cancer patients with metastatic bone pain.
                Pain relief was assessed using an electronic diary containing questions reflecting the multidimensional character of chronic pain. The diary was marked twice daily for a maximum of 14 wk (2 wk before and 12 wk after the injection). Pain response was determined using a specific decision rule in which pain intensity, medication index, and daily activities were the core determinants. A positive response day was defined as a day on which pain intensity was reduced > or = 25% compared with baseline values, while medication index and daily activities were at least constant, or on which pain intensity was reduced < 25% and medication index or daily activities improved > or = 25%, without worsening of the remaining factor. The total response (%) was defined as the number of positive response days divided by the number of days of follow-up.
                Of the 111 included patients, 79 were evaluable (43 (186)Re-etidronate, 36 placebo). Thirty-two patients were excluded from the analysis because of incomplete datasets. The total response of the patients treated with (186)Re-etidronate varied from 0% to 96% (mean, 27%, or 23/84 d). In the placebo group, the total response varied from 0% to 80% (mean, 13%, or 11/84 d; Mann-Whitney U test, P < 0.05). The number of patients who requested radiotherapy was higher in the placebo group (67%) than in the (186)Re-etidronate group (44%) (relative risk, 1.51; Fisher's exact test, P = 0.069).
                This randomized controlled trial confirmed that, compared with placebo, (186)Re-etidronate resulted in a significantly longer pain response in the treatment of bone pain from metastasized prostate cancer. To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study.
                Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia.
                One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity.
                A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded. Forty-nine patients were treated with either 3 x 75 MBq 89Sr or saline as placebo. Analysis of results 1 to 3 years after therapy revealed the ineffectiveness of 89Sr to relieve pain from metastases. Unexpectedly, a higher survival rate was found after Sr application (46% vs 4% after 2 years). Covariate analysis underlines the effect of 89Sr therapy on life expectation. 32p and 89Sr have been shown to produce significant pain relief in patients with skeletal metastases from advanced cancer. Clinically significant pancytopenia has not been reported in doses up to 12 mCi (444 MBq) of either radionuclide. To date, no reports comparing the relative efficacy and toxicity of the two radionuclides in comparable patient populations have been available. Although a cure has not been reported, both treatments have achieved substantial pain relief. However, several studies have used semiquantitative measures such as "slight," "fair," "partial" and "dramatic" responses, which lend themselves to subjective bias. This report examines the responses to treatment with 32P or 89Sr by attempting a quantification of pain relief and quality of life using the patients as their own controls and compares toxicity in terms of hematological parameters.
                Thirty-one patients with skeletal metastases were treated for pain relief with either 32P (16 patients) or 89Sr (15 patients). Inclusion criteria were pain from bone scan-positive sites above a subjective score of 5 of 10 despite analgesic therapy with narcotic or non-narcotic medication, limitation of movement related to the performance of routine daily activity and a predicted life expectancy of at least 4 mo. The patients had not had chemotherapy or radiotherapy during the previous 6 wk and had normal serum creatinine, white cell and platelet counts. 32P was given orally as a 12 mCi dose, and 89Sr was given intravenously as a 4 mCi (148 MBq) dose. The patients were monitored for 4 mo.
                Complete absence of pain was seen in 7 of 16 patients who were given 32P and in 7 of 15 patients who were given 89Sr. Pain scores fell by at least 50% of the pretreatment score in 14 of 16 patients who were given 32P and 14 of 15 patients who were given 89Sr. Mean duration of pain relief was 9.6 wk with 32P and 10 wk with 89Sr. Analgesic scores fell along with the drop in pain scores. A fall in total white cell, absolute granulocyte and platelet counts occurred in all patients. Subnormal values of white cells and platelets were seen in 5 and 7 patients, respectively, with 32P, and in 0 and 4 patients, respectively, after 89Sr therapy. The decrease in platelet count (but not absolute granulocyte count) was statistically significant when 32P patients were compared with 89Sr patients. However, in no instance did the fall in blood counts require treatment. Absolute granulocyte counts did not fall below 1000 in any patient. There was no significant difference between the two treatments in terms of either efficacy or toxicity.
                No justification has been found in this study for the recommendation of 89Sr over the considerably less expensive oral 32P for the palliation of skeletal pain from metastases of advanced cancer. The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).
This update adds new evidence on efficacy of radioisotopes versus placebo, 89Sr compared with other radioisotopes, and dose-comparisons of 153Sm and 188Re. There is some evidence indicating that radioisotopes may provide complete reduction in pain over one to six months with no increase in analgesic use, but severe adverse effects (leucocytopenia and thrombocytopenia) are frequent.