Radiopharmaceuticals for the palliation of painful bone metastases—a systematic review

4.1. Palliative benefits 

In randomized studies, radiopharmaceutical use (Sr-89, Sm-153, Re-186) was associated with improved pain control and decreased analgesic consumption. When phases I and II studies are also considered, substantial pain relief occurred in approximately two-thirds of patients treated, with complete responses reported in the range of 20–30%. Comparing responses across the available trials, there appears to be no substantial difference in palliative efficacy between radiopharmaceuticals; however, only one reported randomized phase II trial compared two radiopharmaceuticals directly. A more rapid onset of pain relief was reported for the use of rhenium versus strontium in this randomized phase II trial The available data does not demonstrate a consistent dose response in terms of pain relief for the agents and doses studied. Currently, both strontium and samarium are available commercially for clinical use in Canada. The available evidence would suggest both radiopharmaceuticals are useful palliative interventions for patients with pain secondary to multiple sites of bone metastases. Other radiopharmaceuticals such as rhenium and radioactive tin are not yet available commercially, and there is less published information about these radiopharmaceuticals.

4.2. Survival benefits 

In the studies reporting survival as an endpoint, there was no clear benefit favouring radiopharmaceuticals when compared to placebo or to different doses of radiopharmaceuticals. One study suggested inferior survival for patients with hormone-refractory prostate cancer treated with Sr-89 compared to external beam radiotherapy. Given the lack of survival benefit noted in the available trials, when considering the use radiopharmaceuticals, the benefit anticipated should be in terms of pain palliation rather than improvement in overall survival.

4.3. Adverse effects 

Hematologic toxicity has been the primary adverse effect associated with radiopharmaceutical administration reported in the studies that assessed this outcome. Thrombocytopenia was reported as an adverse effect in 30–50% of patients treated with radiopharmaceuticals and was, generally, mild (grade 2 or less). Neutropenia was less commonly reported as a side effect when radiopharmaceuticals were used alone but was more common in reports of radiopharmaceuticals combined with chemotherapy. In studies comparing radiopharmaceuticals to radiotherapy, the incidence of nausea and vomiting was substantially less (<10%) with radiopharmaceutical treatment than with local (27%) or hemibody (43%) radiation. However, it should be noted that the availability of newer, more effective anti-emetics such as 5-HT3 antagonists may reduce the advantages of radiopharmaceuticals over radiotherapy in this regard.

4.4. Radiopharmaceuticals versus external beam radiotherapy 

Quilty  reported a randomized comparison between radiopharmaceutical treatment (Sr-89) with either local field radiotherapy (for patients with isolated bone metastases) or hemibody radiotherapy (for patients with multiple bone metastases) in men with hormone-refractory prostate cancer. Similar pain relief between the three modalities was noted (complete or partial pain relief in two-thirds of patients, analgesic reduction in one-third), with less nausea and vomiting seen in the strontium-treated patients (10 versus 27% local radiotherapy versus 43% hemibody radiotherapy) In a non-randomized comparison, Dearnaley demonstrated similar findings. In a more recent trial, Oosterhof  noted no difference in pain relief, time-to-pain-progression, toxicity and use of salvage therapies in a randomized trial of hormone refractory prostate cancer patients treated with Sr-89 versus local field external beam radiotherapy for one to two painful bone metastases. In a systematic review of the literature, McQuay concluded that pain relief was similar between external beam radiotherapy and radiopharmaceuticals The use of pre-treatment regimens combining 5-HT3 antagonists (such as ondansetron) and steroids prior to hemibody radiotherapy can reduce the incidence of nausea and vomiting with this modality. Thus, hemibody radiotherapy may be an appropriate alternative to radiopharmaceutical administration for the palliation of multiple sites of bone pain

4.5. Radiopharmaceuticals in combination with other agents 

Radiopharmaceuticals, specifically Sr-89, have been combined with other agents (external beam radiotherapy or chemotherapy) in some randomized trials. The combination of strontium with external beam radiotherapy was examined in one randomized controlled trial in men with hormone-refractory metastatic prostate cancer The addition of Sr-89 to external beam radiotherapy was associated with lower pain scales and analgesic consumption, as well as a longer interval to the development of new sites of painful bone metastases, compared to local field radiotherapy alone in patients with hormone refractory prostate cancer It should be noted that the dose of Sr-89 used in this trial was substantially higher than in other studies. In contrast, Smeland reported no improvement in global quality of life or pain response with the addition of Sr-89 to external beam radiotherapy. The study differed from Porter et al. in that a wider variety of cancer tumour sites were included (70% prostate, 20% breast, 10% other), a lower dose of adjuvant Sr-89 was used (150 versus 400MBq), different endpoints were examined (time to development of new metastases was not reported) and differences in statistical power (the Smeland et al. trial closed without reaching full accrual). Thus, the role of Sr-89 adjuvant to external beam radiotherapy remains uncertain.

The combination of Sr-89 with cisplatin was associated with a longer duration of pain control compared to Sr-89 alone in one study. The study by Tu suggests bone-targeted therapy in addition to other systemic cytotoxic agents may be a strategy worth exploring as a survival benefit was noted with the addition of Sr-89 to doxorubicin maintenance chemotherapy in androgen-independent prostate cancer. Additional studies of bone-seeking radiopharmaceuticals combined with chemotherapeutic agents seem warranted on the basis of these results.

4.6. Economic analyses 

McEwan reported a retrospective evaluation of cost of care for patients on the trial of local field radiotherapy with or without adjuvant Sr-89 as reported by Porter. The addition of Sr-89 to local field radiotherapy was associated with cost savings over radiotherapy alone. Based on their analysis, the authors estimated the savings from avoiding additional courses of external beam radiotherapy was sufficient to offset the costs of the Sr-89 therapy and concluded that Sr-89 plus local field radiotherapy was a potentially cost-effective therapy. Oosterhof noted a higher cost for Sr-89 versus external beam radiotherapy treatments in a randomized controlled trial of men with hormone refractory prostate cancer and one to two painful bone metastases. Detailed costing was not performed however and no estimate of potential cost differences in patients with more extensive disease (multiple bone metastases) was not noted.

4.7. Patient selection, dosing and scheduling considerations 

Radiopharmaceuticals are one potential modality for the palliation of multiple sites of bone pain. Other potentially useful modalities include systemic therapies (hormonal therapy, chemotherapy, bisphosphonates) and external beam radiotherapy (local-field or hemibody/wide-field). Ideally, the treatment of patients with painful bone metastases should occur within a multidisciplinary context in order to ensure that the therapy chosen is the one best suited for the clinical condition of the patient. For instance, in the case of a newly diagnosed, hormone-naïve patients with metastatic prostate cancer, the appropriate therapeutic strategy may be the institution of androgen ablative hormonal therapy with or without local-field radiotherapy to dominant pain sites. Likewise, patients with multiple bone metastases complicated by hypercalcemia might best be treated with bisphosphonates as an adjunct to conventional analgesics. Radiopharmaceuticals may play a valuable role in situations of multi-focal bone pain where hormonal therapy or chemotherapy options are not sufficient or available and where large-field radiotherapy is not practical (i.e. painful sites on both sides of the diaphragm)

The optimal use of radiopharmaceutical for palliation of bone pain requires careful patient selection for treatment. The selection of patients for radiopharmaceutical therapy should consider the patient's marrow function, performance status, recent use of other marrow suppression agents (chemotherapy or radiotherapy) and anticipated life expectancy. In general, a post-administration nadir of platelet and neutrophils to 40–50% of baseline can be expected with a return to baseline levels by 8–12 weeks post administration. Severe marrow suppression may result if other marrow suppressive treatments (large field radiotherapy or chemotherapy or repeat radiopharmaceutical administration) are given in close proximity to radiopharmaceutical use. Limited radiation fields (<15% of bone marrow irradiated) to treat a dominant site of bone pain may be added with radiopharmaceutical use without undo marrow compromise. Some patients with wide-spread bone metastases may have neutrophil or platelet compromise due to tumour infiltration of the marrow space or cancer-related disseminated intravascular coagulation (DIC) and may not be good candidates for radiopharmaceutical use. Adequate hepatic and renal function should be present as radiopharmaceuticals are excreted by both the fecal and urinary routes.

Patients with a partial response or complete response following radiopharmaceutical therapy may be considered for repeat administration for persistent or recurrent bone pain. In order to avoid the risk of severe, cumulative myelosupression, adequate time for marrow recovery should elapse between radiopharmaceutical administrations. In addition, other contributors to refractory or recurrent bone pain should be ruled out prior to repeat administration. These factors include

For patients with multiple sites of bone pain with a dominant painful bone metastasis, focal external beam radiotherapy for persistent bone pain at the dominant site after radiopharmaceutical therapy should be considered. Adjustment of the analgesic dose and use of other systemic agents such as bisphosphonates or palliative chemotherapy are other options that may be considered. Timing of additional therapies such as wide-field radiotherapy or chemotherapy before or after radiopharmaceutical administration should be considered carefully in order to minimize the potential for cumulative myelosupression.

4.8. Future work 

While the efficacy of radiopharmaceuticals for the palliation of bone pain is well established in some disease sites (hormone refractory prostate cancer for instance), the integration of these agents with other effective palliative interventions (bisphosphonates, palliative chemotherapy, external beam radiotherapy) requires additional clinical research. In particular, the combination of radiopharmaceuticals with systemic agents such as cisplatin and doxorubicin has been associated with improved outcomes in small randomized series and requires confirmation in larger clinical trials The potential differences in survival and economic benefit between external beam radiotherapy and radiopharmaceuticals noted by Oosterhof  should also be explored in larger clinical studies. Finally, the characterization of the efficacy of radiopharmaceuticals in larger numbers of patients with cancers other than hormone refractory prostate cancer is required. Additional randomized trials powered for appropriate palliative endpoints (pain and analgesic consumption) are required to answer these questions.