• Therapeutic Radiopharmaceutical Guidelines Group. Radiopharmaceuticals for the palliation of painful bone metastases [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jun 15. 36 p. (Practice guideline report; no. 14-1). [74 references]

Bone metastases

Assessment of Therapeutic Effectiveness
Treatment

Internal Medicine
Nuclear Medicine
Oncology
Radiation Oncology

Physicians

To evaluate the role of radiopharmaceuticals in the palliation of metastatic bone pain

Adult cancer patients with uncomplicated, multifocal painful bone metastases above and below the diaphragm whose pain is not controlled with conventional analgesic regimens and where increased uptake in the painful lesions is demonstrated on bone scan

Treatment

1. Strontium-89 plus cisplatin
2. Strontium-89 alone
3. Radiotherapy
4. Strontium-88
5. Rhenium-186
6. Hemibody radiotherapy
7. Samarium-153
8. Tin-117m
9. Phosphorus-32

• Pain response
• Analgesic consumption
• Overall survival
• Adverse effects
• Quality of life

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Six randomized controlled trials, one randomized phase II trial, one randomized crossover trial and 27 single-arm phase II trials, phase I trials, or retrospective case series investigated strontium-89 (Sr-89) and met the eligibility criteria for this systematic review. Three randomized controlled trials, two randomized phase II trials, and six single-arm phase II and phase I trials were located that investigated the use of samarium-153 (Sm-153). One randomized controlled trial, two randomized phase II trials, one randomized crossover trial, and 13 single-arm phase II and phase I trials were located that investigated the use of rhenium-186 (Re-186) or rhenium-188 (Re-188). One phase I dose-escalation trial of tin-177m (Sn-117m) and one single-arm phase II trial of phosphorus-32 (P-32) were located. A summary of the primary evidence included in this practice guideline report is provided in Table 1 in the original guideline document.

In addition to the primary studies of the various radiopharmaceuticals, one evidence-based practice guideline, one systematic review, and three economic analyses were located.

Expert Consensus (Committee)

Not applicable

Systematic Review with Evidence Tables

The available randomized controlled trials investigating the use of radiopharmaceuticals for the palliation of metastatic bone pain were quite heterogeneous with respect to the radiopharmaceutical used, the dosage and the comparison arm. Therefore, pooling of the data was judged to be inappropriate.

Expert Consensus

A subcommittee of the Therapeutic Radiopharmaceutical Guidelines Group set the original search strategy and reviewed the available literature for inclusion in this guideline report. The working group decided to restrict the review of the literature to randomized phase III trials and larger, prospective phase I and II trials where pain response using an objective response scale was reported. The results of the literature search were discussed at a meeting with the entire group in November 2002. It was decided that pooling of the pain response data was not appropriate, given the heterogeneity in response scales used, disease histologies treated, radiopharmaceuticals and doses used, and comparisons made. The group agreed, however, that sufficient evidence existed on which to base recommendations around the use of radiopharmaceuticals as a palliative intervention for uncomplicated bone pain from metastatic cancer. It was acknowledged that the combination of radiopharmaceuticals with other modalities such as chemotherapy or radiotherapy may carry benefits in terms of more durable pain response or delay in the time to new symptomatic bone metastases but that there was insufficient evidence to make recommendations for radiopharmaceutical use in this setting. The group concluded that further research into the combination of radiopharmaceuticals with other agents, as well as the appropriate time to introduce radiopharmaceuticals (for symptomatic control or as an adjunct to reduce the incidence of new painful bone metastases) was required. It was also emphasized that appropriate patient selection (good performance status, adequate bone marrow reserve, reasonable short-term life expectancy) was essential to the optimal use of radiopharmaceuticals.

Not applicable

One study reported a retrospective evaluation of cost of care for patients on the trial of local field radiotherapy with or without adjuvant strontium-89 (Sr-89). The addition of Sr-89 to local field radiotherapy was associated with cost savings over radiotherapy alone. The authors estimated the savings as 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.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 216 practitioners in Ontario (45 medical oncologists, 82 nuclear medicine physicians, and 89 radiation oncologists). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. The practitioner feedback survey was mailed out on November 6, 2003. Follow-up reminders were sent at two weeks (post card), four weeks (complete package mailed again), and two months (complete package mailed again). The Therapeutic Radiopharmaceutical Guidelines Group reviewed the results of the survey.

Final approval of the guideline report was obtained from the Practice Guidelines Coordinating Committee.

• Use of radiopharmaceuticals (strontium-89 and samarium-153) may be considered as an option for the palliation of multiple sites of bone pain from metastatic prostate cancer as these patients represented the majority (80%) of patients experiencing benefit in clinical trials where histology was specified.
• Use of radiopharmaceuticals (strontium-89 and samarium-153) may also be considered for patients with lung and breast cancers. These patients represented a substantial minority (20%) in the clinical trials where histology was specified.
• 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), unsuitability for alternate palliative interventions (wide field or local field radiotherapy, hormone therapy, chemotherapy, bisphosphonates), and anticipated life expectancy.
• Ideally the decision for radiopharmaceutical use should be based on a multidisciplinary (radiation oncology, nuclear medicine, medical oncology, palliative care) patient assessment.
• Patients with a partial response or complete response following radiopharmaceutical therapy may be considered for repeat administration for persistent or recurrent bone pain if the following is ruled out: rapid systemic disease progression, mechanical component to bone pain, underlying other bone pathology, impending or established fracture, or spinal cord compression.
• The recommended dose for strontium-89 is 148 mBq (4mCi) by slow intravenous injection (1 to 2 minutes), accompanied by intravenous or oral hydration (at least 500 mL). The recommended dose for samarium-153 is 37 mBq/kg (1 mCi/kg) by slow intravenous injection (1 to 2 minutes), accompanied by intravenous or oral hydration (at least 500 mL).

None provided

The recommendations are supported by randomized controlled trials.

Familiarity with and effective use of radiopharmaceuticals in the palliation of metastatic bone pain

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 to 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 antiemetics such as 5-HT3 antagonists may reduce the advantages of radiopharmaceuticals over radiotherapy in this regard.

• Patients with painful bone metastases should have appropriate analgesic and supportive care measures instituted in addition to other palliative interventions such as radiopharmaceuticals.
• Patients with more limited painful bone involvement, or painful lesions confined to one side of the diaphragm should be considered for focal or wide field (hemibody) external beam radiotherapy. Information on histologic subtype was not available for a significant proportion (30–40%) of patients treated on trials of palliative radiopharmaceuticals.
• The cost benefit of single-agent radiopharmaceuticals relative to other systemic agents such as bisphosphonates and chemotherapy remains to be determined.
• A subset of trials has suggested an increased benefit in terms of pain palliation with the combination of a radiopharmaceutical agent with external beam radiotherapy or chemotherapy. The combination of radiopharmaceuticals with these modalities or with others such as bisphosphonates requires further investigation in clinical trials.
• The administration of radiopharmaceuticals should be restricted to those patients with adequate bone marrow reserve and performance status (Karnofsky Performance Status >60), anticipated life expectancy of greater than four months, and uncomplicated bone metastases (no pathologic fracture or impending pathologic fracture, no spinal cord compression, or no hypercalcemia).
• The use of newer radiopharmaceuticals such as rhenium and radioactive tin are under investigation for the palliation of metastatic bone pain but are not approved for use outside clinical trials in Canada.
• Samarium-153 is currently licensed in Canada, but there is no distributor at this time.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

End of Life Care
Living with Illness

Effectiveness

• Therapeutic Radiopharmaceutical Guidelines Group. Radiopharmaceuticals for the palliation of painful bone metastases [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Jun 15. 36 p. (Practice guideline report; no. 14-1). [74 references]

Not applicable: The guideline was not adapted from another source.

2004 Jun 15

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Therapeutic Radiopharmaceuticals Guidelines Group

Members of the Therapeutic Radiopharmaceutical Guidelines Group disclosed potential conflict of interest information. No conflicts were declared.

None available

This summary was completed by ECRI on September 24, 2004. The information was verified by the guideline developer on October 20, 2004.