[A randomized trial of single and multifraction radiation therapy for bone metastasis: a preliminary report]. Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma. Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. [A multi-institutional prospective randomized study of radiation therapy of bone metastases]. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases. Platinum compounds as radiosensitizers in strontium-89 metabolic radiotherapy. 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. A prospective randomised trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year follow-up. Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Prospective randomised trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases.
From April, 1989 through January, 1990, a randomized trial was conducted to investigate the efficacy of single fraction radiation treatment (8, 10, 12, 15Gy) compared to a multifraction dose schedule (5Gy x 4, 5Gy x 5, 5Gy x 6) as a therapy for a bone metastasis. Both subjective and objective pain scores were used to measure the therapeutic results. A total of 31 patients participated in the trial and, for analysis, 27 of these patients were follow-up for more than 8 weeks after the start of the radiation therapy. The following statistics resulted. Of the single fraction series, symptomatic pain relief was obtained in 86% of the patients (12/14 treatment areas), and of the multifraction series, 92% (12/13). Further, a complete response was achieved in 57% (8/14) of the single fraction patients and 31% (4/13) of the multifraction patients, respectively. Between the two treatment regimens, no difference was found in the incidence of pain relief, speed of onset, or acute morbidity. Finally, no severe morbidity was seen in either arm. 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. 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. Data in the literature suggest that for painful bone metastases a single dose is as effective as fractionated radiotherapy. In the present multicentre prospective trial, the effects of 8 Gy x1 and 5 Gy x4 were compared.
                A total of 241 patients were randomized to 8 Gy (122 patients) or 20 Gy (119 patients). The primary tumour was in the breast in 39% of patients, in the prostate in 34% of patients, in the lung in 13% of patients and in other locations in 14% of patients. Outcome measures were pain relief as measured by VAS and in half of the patients also by a five-point categorical pain scale, global quality of life (QoL) and analgesic consumption. Evaluation was performed before and 4, 8, 12 and 20 weeks after treatment.
                A total of 239 patients were evaluable for response. The two groups did not differ with respect to age, sex, primary tumour, metastasis localization, analgesic consumption (type and dose), performance status, prior systemic treatment, degree of pain and QoL. The treatment was completed as planned in 98% of patients. The degree of pain relief did not differ between the two treatment groups. At 4 weeks the difference in pain relief was 6% (95% CI 7, 20%) and at 8 weeks the difference was 13% (95% CI 3, 28%). Neither was there any significant difference in the duration of pain relief, the number of new painful sites and the need for reirradiation and toxicity was minor.
                The present randomized study showed that a single fraction of 8 Gy was as effective as 5 Gy x4 in relieving pain from bone metastasis. nan From 1988 to 1991, 284 patients with prostatic cancer and painful bone metastases were treated with either radiotherapy or strontium-89 (200 MBq). Patients were first stratified according to suitability for local or hemibody radiotherapy, then randomly allocated that form of treatment or strontium-89 (i.v. injection). After 4, 8 and 12 weeks pain sites were mapped, toxicity monitored, and all additional palliative treatments recorded. There was no significant difference in median survival (after > 80% had died); 33 weeks following strontium-89 and 28 weeks following radiotherapy (p = 0.1). All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the comparable strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05). Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect. Platelets and leukocytes fell by an average 30-40% after strontium-89 but sequelae were uncommon, and other symptoms rare. Strontium-89 (89Sr) is currently used for the treatment of painful bone metastases. This study reports the use of low-dose carboplatin as a radiosensitizer in 89Sr radioisotope therapy. The study design comprised two groups: 15 patients treated with 89Sr (148 MBq) followed by carboplatin (100 mg m-2 at 7 and 21 days) and 15 patients treated with 89Sr alone. Their pain response was assessed 8 weeks post-injection. Follow-up was continued for up to 1 year in the survivors. Twenty-seven patients were evaluable. A pain response was observed in 20 of 27 (74%) patients. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). No clinically significant adverse effects or myelosuppression by carboplatin were observed. Low-dose carboplatin enhances the effects of 89Sr radioisotope therapy on pain from bone metastases. 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. In a prospective randomized trial we examined whether radiotherapy of painful bone metastases can be shortened using larger single doses without impairing effectivity.
                One hundred patients with painful bone metastases having no prior surgical intervention or treatment with x-ray therapy and had a median follow-up of 12 months were analyzed. The primary tumor was located in the breast in 43%, in the lung in 24%, and in the prostate in 14%. The most frequent sites of metastases were the pelvis (31%), the vertebral column (30%), and the ribs (20%). Further percentages of sites were: lower extremity 11%, upper extremity 6%, and skull 2%. Fifty-one patients received a short course radiotherapy with a total dose of 20 Gy in 1 week (daily dose 4 Gy), and 49 patients received 30 Gy in 3 weeks (daily dose 2 Gy).
                There were no significant differences in frequency, duration of pain relief, improvement of mobility, recalcification, frequency of pathologic fractures nor survival. There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. Survival was mostly influenced by primary tumor site, Karnofsky performance status, and possibly by the response to radiotherapy (pain relief).
                Because of the very short life expectancy of patients with metastatic bone disease, we now use 20 Gy in 1 week as our standard to reduce hospital stay. Strontium-89 is currently used for the treatment of painful bone metastases. This study reports on two preliminary experiences with low-dose platinum compounds, carboplatin and cisplatin, as radiosensitizers in 89Sr therapy.
                30 patients entered the carboplatin study: 15 patients (Group A) were treated with 148 MBq 89Sr followed by carboplatin (100 mg/m2 at 7 and 21 days) and 15 patients (Group B) were treated with 89Sr alone. 12 patients entered the cisplatin study: six patients (Arm 1) received 148 Mq 89Sr plus cisplatin (50 mg/m2) in two administrations (immediately before and 10 days after 89Sr injection) and six patients (Arm 2) received 89Sr plus two placebo administrations. Pain response was assessed 8 weeks after the therapy on the Wisconsin score modifications.
                No clinically significant adverse effects or myelosuppression by platinum compounds were observed. In carboplatin study a pain response was observed in 20 of 27 (74%) evaluable patients, 13/15 in group A and 7/12 in group B. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). In cisplatin study a pain response was observed in 10 of 12 (83%) evaluable patients, 5/6 in Arm 1 and 4/6 in Arm 2.
                Low-dose platinum compounds seem to enhance the effects of 89Sr radioisotope therapy on pain from bone metastases without relevant hematological toxicity. 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). 270 patients with painful bone metastases requiring palliative radiotherapy were randomised to receive single fractions of 4 Gy or 8 Gy in a randomised trial. Pain scores and analgesic usage were recorded before treatment and at 2, 4, 8 and 12 weeks. Pain was assessed by patients on a 4 point graded scale using pain charts administered by a central trials office. Response was defined as an improved rating compared to the pretreatment value. Compliance with the pain chart was 72% at 4 weeks. At 4 weeks, the actual response rates were 69% for 8 Gy and 44% for 4 Gy (p less than 0.001), but there was no difference in complete response (no pain) rates at 4 weeks or duration of response between the two arms. It is concluded that 8 Gy gives a higher probability of pain relief than 4 Gy, but that 4 Gy can be an effective alternative in situations of reduced tolerance. The results from a prospective randomized trial comparing two different radiation schedules for treatment of painful bone metastases in women with recurrent breast cancer are presented. A total of 217 patients with painful bone metastases were randomized to either 30 Grey (Gy) in ten fractions, five fractions a week (5F/W) or 15 Gy in three fractions 2F/W. The effect of treatment was evaluated by pain assessment, the radiological response and the degree of side-effects. The patients were rated at start of treatment and after 1, 3, 6 and 12 months. No difference between the two radiation regimes was found, neither in achieved pain relief, improvement in level of activity and medication, nor was there any difference in radiological response and side-effects from treatment. Both regimes resulted in a significant improvement in both pain score and level of activity 1 month after treatment, an improvement which persisted during the follow-up period. We conclude that 15 Gy given in three fractions 2F/W is as effective as 30 Gy in ten fractions 5F/W, but more convenient to the patient and of less cost to society. The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial.
                To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases.
                In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain.
                Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters.
                It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases. A large proportion of the practice of radiotherapy in the management of metastatic adenocarcinoma of the prostate is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites and may also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic. Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bony metastases.
                The study was a Phase-III randomized placebo control trial performed in eight Canadian Cancer Centers to evaluate the effectiveness of strontium-89 as an adjunct to local field radiotherapy. Patients with endocrine refractory metastatic prostate cancer received local field radiotherapy and either strontium-89 as a single injection of 10.8 mCi or placebo.
                One hundred twenty-six patients were recruited. No significant differences in survival or in relief of pain at the index site where noted. Intake of analgesics over time demonstrated a significant reduction in the arm treated with strontium-89. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. Tumor makers including prostate specific antigen, acid phosphatase, and alkaline phosphatase were also reduced in patients receiving strontium-89. A Quality-of-Life analysis was performed as a multivariate data set and demonstrated an overall superiority of strontium-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving strontium-89.
                It is concluded that the addition of strontium-89 is an effective adjuvant therapy to local field radiotherapy reducing progression of disease as evidenced by new sites of pain and the requirement of further radiotherapy and improving quality-of-life and need for analgesic support in this group of patients. A prospective randomized clinical trial comparing small, large and twice-a-day fraction for the relief of painful bone metastases was performed from 1981 to 1986 at Tokyo Women's Medical College Hospital. Eighty patients with painful bone metastases (92 sites) were divided into three radiation methods which were conventional fraction scheme of 5 times/week at 2 Gy/day for a total of 30 Gy/15 fractions (Group I, TDF: 49), 2 times/week at 4.5 Gy/day for a total of 22.5 Gy/5 fractions (Group II, TDF: 50) and 3 times/week at 2 Gy/day twice a day at a minimum interval of 6 h for a total of 20 Gy/10 fractions (Group III). Pain was assessed using a score and response rate was 76% in Group I, 75% in Group II and 78% in Group III which were not statistically significant mutually. Group II and III regimes were found to have an earlier shorter onset of pain relief than Group I, but the dose of onset of pain relief was almost the same. Our data suggested that individualization of radiotherapy schedules based on to assess the patient's condition and the expected quality of life and to consider radiation site and size of field, was more important than the fractionation regime in the treatment of painful bone metastases. A prospective randomised trial comparing a single fraction of 8 Gy with 30 Gy in 10 daily fractions for the relief of metastatic bone pain was performed. In 28 months, 288 patients were randomised. Pain was assessed using a questionnaire completed by the patient at home on a daily basis. No difference was found in the speed of onset or duration of pain relief between the two treatment regimes, and pain relief was independent of the histology of the primary tumour.
Radiotherapy is clearly effective at reducing pain from painful bone metastases. There was no evidence of any difference in efficacy between different fractionation schedules, nor indeed of a dose-response with total dose of radiation. For treatment of generalised bone pain both hemibody irradiation and radioisotopes can reduce the number of painful new sites.