Introduction
Normal bone physiology
Osteoclasts and osteoblasts
Bone, a preferred site for metastases
Rodent models of PCIBP
Rodent | Gender/species | PCa cell line/concentration/route of administration | Pain/nocifensive behaviours | Additional comments | References | |||
---|---|---|---|---|---|---|---|---|
Mechanical allodynia | Mechanical hyperalgesia | Thermal hyperalgesia | Guarding/flinching | |||||
Mice | Male/athymic nude mice | 105 ACE-1 cells in 20 μl Hanks solution/IFI | – | NA | – | + (Days 10–26 post-IFI) | Temporal development of osteoblastic tumours confined to the injected femur | |
Rats | Male/copenhagen | 1 × 106 MAT-Ly-Lu cells in 0.1 ml PBS/IFI | NA | + (Days 7–13 post-IFI) | NA | NA | Osteolytic damage of the distal epiphysis of the PCa-injected femur may have facilitated escape of PCa cells | De Ciantis et al. (2010) |
1 × 105 MAT-Ly-Lu cells in 0.1 ml Hanks’s/IFI | NA | NA | NA | + | Local swelling (knee area) and signs of motor disablement observed in the injected hind limb | Liepe et al. (2005) | ||
Male/copenhagen | 3 × 105 AT-3.1 cells in 10 μl Hanks solution/ITI | + (Days 13–20 post-ITI) | + (Days 15–19 post-ITI) | NA | NA | PCa cell metastases in the adjacent tissues to the injected tibial bone resulted in temporal reduction in body weights of PCa-inject rats, c.f. sham-rats | Zhang et al. (2005) | |
Male/Wistar | 5 × 105 AT3B-1 cells in 10 μl PBS/ITI | + (Days 13–20 post-ITI) | – | + (Days 13–23 post-ITI) | NA | Kolosov et al. (2011) | ||
Female/Dunning | 1 × 105 MAT-Ly-Lu cells in 0.1 ml Hanks’s/ITI | + (Days 10–14 post-ITI) | NA | NA | NA | Significant reduction in the tibial bone mineral density between days 3 and 14 post-ITI, indicating development of osteolytic metastases | Roudier et al. (2005) |
Mechanisms of PCa metastasis to the bone
Metastatic process: tumour dissemination to establishment
Transition: orchestration by osteoclasts domination by osteoblasts
Orchestration by osteoclasts
Domination by osteoblasts
Pathophysiology of PCIBP
Nociceptive signalling and pain
Peripheral sensitization mechanisms in PCIBP
Central pain mechanisms
Knowledge gaps in the pathobiology of PCIBP
Neuropathic pain (NP) models | Breast cancer-induced bone pain | Ostelolytic fibrosarcoma-induced bone pain |
---|---|---|
Significant increase in the peripheral receptive field size in both superficial and deeper neurons of the spinal cord (Suzuki et al. 2000) | Significant increase in the peripheral receptive field size in only superficial neurons (Yanagisawa et al. 2010) | |
Increased levels of ongoing activity of both WDR and HT neurons (Sotgiu et al. 1994) | Increased levels of ongoing activity of WDR, but not HT neurons (Urch et al. 2003) | |
Increase in the proportion of WDR neurons in the NP rats (32 %), c.f. control rats (22 %) (Liu et al. 2011) | No change in the proportion WDR neurons in tumour-bearing mice (64 %), c.f. control mice (56 %) (Khasabov et al. 2007) | |
Sensitization of both WDR and HT neurons contribute to mechanical stimuli (Sotgiu et al. 1995) | ||
WDR neurons do not exhibit sensitization to heat stimuli (Laird and Bennett 1993) | ||
NA | The amplitude of sEPSCs of SG neurons are increased, but their frequencies remained unchanged (Yanagisawa et al. 2010) | |
NA | No change in Aβ fiber-mediated EPSCs of SG neurons when compared with control animals (Yanagisawa et al. 2010) | |
NA | Spinal sensitization is present throughout multiple lumbar spinal levels rather than just the segments in which the central terminals of primary afferent sensory neurons innervate (Yanagisawa et al. 2010) |
Makers | CFA | SNL | SNT | CIBP |
---|---|---|---|---|
Sub P | ⟷ | ↘ | ↘ | ⟷ |
IB4 | ⟷ | ↘ | ↘ | ⟷ |
CGRP | ⟷ | ↘ | ↘ | ⟷ |
GAL | ⟷ | ↗ | ↗ | ↗ |
NPY | ⟷ | ↗ | ↗ | ⟷ |
ATF3 | ⟷ | ↗ | ↗ | ↗ |
GFAP | ↗ | ↗ | ↗ | ↗ |
Makers in laminae I–II | CFA | SNL | SNT | CIBP |
---|---|---|---|---|
Sub P | ↗ | ↘ | ↘ | ⟷ |
IB4 | ⟷ | ↘ | ↘ | ⟷ |
CGRP | ↗ | ↘ | ↘ | ⟷ |
GAL | ⟷ | ↗ | ↗ | ⟷ |
NPY | ⟷ | ↗ | ↗ | ⟷ |
DYN | ⟷ | ⟷ | ↗ | ⟷ |
GFAP | ↗ | ↗ | ↗ | ↗ |
OX-42 | ⟷ | ↗ | ⟷ | ⟷ |
Therapeutic strategies for the management of PCIBP
Therapeutic agents with defined analgesic potential
Radiotherapy
Bisphosphonates
Non-steroidal anti-inflammatory drugs (NSAIDs)
Patient and treatment description (# patients) | Primary endpoint | Results | Adverse events | References |
---|---|---|---|---|
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) | |
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 | |
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) |
Intravenous pamidronate at 90 mg (180) or placebo (194) every 3 weeks for 27 weeks |