Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. A prospective randomised trial of 4 Gy or 8 Gy single doses in the treatment of metastatic bone pain. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Platinum compounds as radiosensitizers in strontium-89 metabolic radiotherapy. Relative efficacy of 32P and 89Sr in palliation in skeletal metastases. The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer.
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. 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. 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. 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. 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. 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. 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. 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. Fifty-five patients with hormone refractory prostate cancer and painful bone metastases were randomised either to placebo or to clodronate 300 mg i.v. for 3 days, followed by oral clodronate 3200 mg for four weeks. Pain intensity was assessed using Visual Analogue Scales (VAS). Mean overall pain as well as mean pain during the best and worst periods were recorded. Forty-six patients were evaluable for efficacy. No significant differences were found between the two treatments. As regards mean worst pain a substantial numerical fall was registered for the treatment group, 21 mm, but the improvement was not significant compared to that of the placebo group. This was probably due to the limited number of patients (the study was prematurely ended due to problems recruiting patients). In conclusion, no significant differences were found between the treatment arm and the controls, in contrast to results from previous studies. Possible explanations are that the doses in this study were generally lower than in previous studies, the mean baseline pain was substantially lower and that the current study was placebocontrolled. Our data indicate that if clodronate is to be used for the alleviation of bone pain in prostate cancer, patients with high baseline should be selected and high intravenous doses should be given at start of the treatment.
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.