Radiopharmaceuticals

Patients with endocrine refractory metastatic prostate cancer Pain response using RTOG criteria, analgesic use, QoL using Visual Analogue Scale At 3 months, complete pain relief 50 % (Sr-89) vs. 36 % (placebo); discontinuation of analgesics 17.1 % (Sr-89) vs. 2.4 % (placebo). Addition of Sr-89 to EBRT reduced analgesic requirements Leukopenia grade-3/4: 12 % in Sr-89 vs. 0 % in placebo; thrombocytopenia grade-3/4: 32.8 % in Sr-89 vs. 3.4 % in placebo Porter et al. (1993)

Local EBRT plus single injection of 10.8 mCi Sr-89 (68) or placebo (58)

Patients with painful skeletal metastases Progression of disease (using QLQ C-30 v2.0 questionnaire, pain score, analgesic requirement, WHO performance status) At 3 and 6 months, no differences in the disease progression between the two groups. Role of strontium-89 as adjuvant to palliative EBRT is questionable Leukopenia grade-1/2: 36.4 % in Sr-89 vs. 13.3 % in placebo; thrombocytopenia grade-1/2: 15.9 % in Sr-89 vs. 4.4 % in placebo Smeland et al. (2003)

10 fractions of 3 Gy EBRT plus single intravenous 150 MBq Sr-89 (46) or placebo (49)

Patients with metastatic HRPC Pain response and duration of response Pain response in 91 % (Sr-89/cisplatin) vs. 63 % (Sr-89/placebo), duration of pain relief 120 days (Sr-89/cisplatin) vs. 60 days (Sr-89/placebo). Addition of a low dose of cisplatin enhances the effect of a standard dose of Sr-89 Anaemia grade-3/4: 8.5 % in Sr-89 vs. 11.4 %; leukopenia Sciuto et al. (2002)

148 MBq Sr-89 plus 50 mg/m2 cisplatin (35) vs. Sr-89 plus placebo (35) Grade-1/2: 22.9 % in Sr-89 vs. 5.7 % in placebo; thrombocytopenia grade 1/2: 2.8 % in Sr-89 vs. 5.7 % in placebo

Patients with metastatic CRPC Pain response, mobility and analgesic use At 3 months, 65–70 % of patients had pain relief with Sr-89 compared to 66.7 % with local EBRT and 67.4 % with HBI. However, patients treated with Sr-89 had fewer new sites of pain than men undergoing EBRT or HBI Leukopenia grade-3: 3.1 % in Sr-89 vs. 0 % EBRT; thrombocytopenia grade-3/4: 6.9 % in Sr-89 vs. 3.4 % in EBRT Quilty et al. (1994)

200 MBq Sr-89 (76) vs. local EBRT (72).

200 MBq Sr-89 (77) vs. HBI (80)

Patients with metastatic HRPC Subjective response using pain score, analgesic use or performance status No differences in subjective pain responses, analgesic consumption, or performance status. Interestingly, overall survival rate of patients that received local EBRT was longer than those receiving Sr-89 No grade-3/4 leukopenia; one patient in Sr-89 with grade III toxicity Oosterhof et al. (2003)

150 MBq Sr-89 (101) vs. local field EBRT (102)

Patients with metastatic bone pain Pain relief Significant pain relief produced with Sr-89 Thrombocytopenia (grade 3 toxicity in 12 %, and grade 4 in 15.4 % of patients in Sr-89 treatment group Lewington et al. (1991)

Sr-89 vs. placebo (26)

Patients with metastatic prostate cancer Pain relief No significant difference in the analgesic effect between both radionuclides was found in the group of patients with prostate carcinoma Moderate pancytopenia, granulocytopenia and/or thrombocytopenia were observed in both Sr-89 and Sm-153 group, with no significant between group differences Baczyk et al. (2007)

150 MBq Sr-89 (30) vs. 37 MBq/kg Sm-153 (30)

Patients with painful bone metastases Pain relief 62–72 % of patients had pain relief with 1.0 mCi/kg during first 4 weeks and 31% had complete/marked relief by week 4 With 1.0 mCi/kg: grade-3/4 anaemia in 6 %, thrombocytopenia in 3 % and leukopenia in 14 % (compared to 35, 0 and 0 %, respectively, with placebo) Serafini et al. (1998)

Sm-153 at 0.5 (40) or 1 mCi/kg (39) vs. placebo (39)

Patients with metastatic HRPC Pain relief Sm-153 had positive effects on measures of pain relief compared with placebo within 1–2 weeks, and also reduced opioid consumption by week 3. There was no significant difference in survival Grade 3 thrombocytopenia and leucopenia were noted in 3 and 5 % of patients, respectively, in the active treatment arm Sartor et al. (2004)

1 mCi/kg Sm-153 (101) vs. placebo (51)

Patients with painful bone metastases Pain relief At week 4 after dose administration, statistically significant pain relief was produced by 1.0 mCi/kg dose of Sm-153 Values for platelets and WBCs reached nadirs at 3 or 4 weeks with both doses and recovered by 8 weeks Resche et al. (1997)

Sm-153 at 0.5 mCi/kg (55) vs. 1.0 mCi/kg (59)

Patients with prostate cancer-induced bone pain Number of positive pain response days Mean percentage of pain response days 27 % (Re-186) vs. 13 % (placebo). The number of patients who requested radiotherapy was higher in the placebo group (67 %) than in the Re-186 group (44 %). Re-186 resulted in a significantly longer pain response in the treatment of bone pain from metastasized prostate cancer Death of five patients in rhenium group due to clinical deterioration of patient’s condition Han et al. (2002)

12 weeks treatment with 35–80 mCi Re-186 (59) vs. placebo (52)

Patients with metastatic CRPC Pain response At week 8 there were 40, 63, 56 and 71 % pain responders in the 5, 25, 50 and 100 kBq/kg groups, respectively, and of responders, 6/20 (30 %), 8/19 (42 %), 8/18 (44 %) and 11/21 (52 %) reached complete (pain index 1) or marked pain response (pain index 2), respectively. Mean pain relief duration was 44 days in the 50 and 100 kBq/kg groups, and 28 and 35 days in the 5 and 25 kBq/kg groups, respectively Anaemia (11 %) and haemoglobin decrease (15 %) in all dose groups, with no significant differences between them. For 2 weeks post-injection of higher Ra-223 doses, there was a reduction in platelet, white blood cell and neutrophil counts, which later returned back to baseline Nilsson et al. (2012)

16 weeks treatment with 5 (26), 25 (25), 50 (25) or 100 (24) kBq/kg i.v. Ra-223

Patients with metastatic CRPC PSA levels, bone alkaline phosphatase levels and pain responses The study met its primary end point with a confirmed ≥50 % PSA response in 0 % patients receiving 25 kBq/kg, 6 % receiving 50 kBq/kg, and 13 % receiving 80 kBq/kg at 24 weeks. A ≥50 % decrease in bone alkaline phosphatase levels was identified in 16, 67, and 66 patients in the 25-, 50-, and 80-kBq/kg dose groups, respectively. Reduced pain responses were reported by 29–75 % of patients with baseline pain, with a trend towards greater response in the 50-kBq/kg dose group The most common treatment-related AEs (≥10 %) occurring up to week 24 across all dose groups were diarrhoea (21 %), nausea (16 %), and anaemia (14 %). No differences in the incidence of hematologic events were seen among dose groups. In total, 70 deaths were recorded to 24 months after the first Ra 223 injection: 26, 22, and 22 deaths occurred in the 25-, 50-, and 80-kBq/kg dose groups, respectively Parker et al. (2013)

Three intravenous injections of Ra-223 (25 (41), 50 (39) or 80 (42) kBq/kg) at 6-week intervals over 24 weeks

Patients with metastatic CRPC Overall survival, time to initial ERBT or opioid use Ra-223 significantly improved overall survival in patients with CRPC (14 months), c.f. placebo (11.2 months). Time to EBRT was significantly longer in the Ra-223 group vs placebo. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38 % compared to placebo. Fewer patients in the Ra-223 group (36 %) than in the placebo group (50 %) required opioid use for pain relief Safety and tolerability of Ra-223 were highly favourable and showed a low incidence of myelosuppression (grades 3/4 neutropenia in 1.8 % and 0.8 %, and thrombocytopenia in 4 % and 2 % of the Ra-223 and placebo groups, respectively) Parker et al. (2012), Nilsson et al. (2013)

Six injections of Ra-223 at 50 kBq/kg every 4 weeks (614) vs. placebo (317)

Bisphosphonates

Men with metastatic HRPC Skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety At 15 months, zoledronic acid at 4 mg significantly reduced the mean increase from baseline in pain score and skeletal-related events in patients with prostate induced bone metastases Zoledronic acid at 4 mg given as a 15-min infusion was well tolerated, but the 8 mg dose was associated with renal function deterioration Saad et al. (2002, 2004)

Intravenous zoledronic acid at 4 mg (214) or 8 mg (221) vs placebo (208) every 3–4 weeks

Patients with bone metastases Pain relief Significantly reduced mean VAS pain score from baseline. Zoledronic acid 4 mg administered as a 15-min infusion every 3–4 weeks was well tolerated, including patients who had significant prior exposure to bisphosphonate Fatigue, nausea, and arthralgia Vogel et al. (2004)

Intravenous zoledronic acid at 4 mg (638) every 3–4 weeks for six doses

Men with metastatic bone pain Pain relief There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements or analgesic use at either week 9 or 27 Overall, pamidronate disodium was well tolerated Small et al. (2003)