What is the effectiveness of unsealed radioisotopes in the management of bone pain from prostate cancer?

The administration of certain radioactive chemicals (radioisotopes) through the blood stream (as a single dose of an intravenous injection) offers one method of dealing with patients presenting with such multifocal pain. Such an approach has the advantage of not only relieving pain but also having some anti-tumour effect. The two isotopes that have been used in Australia include strontium 89 and samarium 153. The former has been more easily accessible and therefore used more commonly. These isotopes are characterised by low radiation emissions localised to the bone and have affinity for bone, especially honing onto areas where the affected bone responds to the presence of tumour cells by producing reactive bony tissue. (These areas can appear as abnormal dense areas referred to as osteoblastic metastases on X-rays.)

Nine RCTs have examined the effects of strontium 89 for the treatment of bone metastases. Two compared strontium 89 with placebo.^[1]^[2] Four compared strontium 89 with active treatment arms such as local or hemi-body irradiation^[3]^[4] or chemotherapy.^[5]^[6] Two examined the addition of strontium 89 to local external beam radiotherapy^[7]^[8] and two examined the addition of strontium 89 to chemotherapy.^[5]^[9] The heterogeneity of study design renders low volumes of evidence about any specific treatment. In addition, only non-taxane chemotherapy was used in the chemotherapy trials. Therefore these trials lose their relevance in modern-day practice where taxanes are the first-line chemotherapeutic option of choice. As a result they were not considered further in this analysis. Four RCTs examined the effects of samarium 153 for the treatment of bone metastases. Two randomised trials compared samarium with placebo^[10]^[11] and three studies compared different doses of Samarium.^[10]^[12]^[13] There are no randomised trials comparing samarium with other radioisotopes, chemotherapy or external beam irradiation.

Regrettably, the majority of the remaining studies have flaws in that they have used small sample sizes, are not head-to-head comparisons, utilise different criteria to measure response to pain, and some studies are not limited to patients with metastatic prostate cancer alone.^[1]^[14]^[12]^[13] Furthermore, while the patients in these studies appear similar to prostate cancer patients seen in palliative care practice, these studies were conducted in the pre-taxane chemotherapy and bisphosphonate era. As a result, the findings may not be generalisable to current Australian medical practice where many of the men with bone metastases might have been pre-treated with chemotherapy (taxane-based) or bisphosphonates. The potential for increased bone marrow suppression in this setting must to be taken into consideration before administering the radioisotope.

Pain control

There were four studies examining strontium 89 for metastatic bone pain relief.^[1]^[2]^[3]^[7]^[8] These varied in follow up, doses, regimen and endpoint reporting. The largest study with the highest dose showed a statistically significant decrease in analgesic use when strontium was added to local radiotherapy.^[7]^[8] The RCT comparing strontium 89 with external beam radiotherapy suggested that these treatments were equivalent.^[3] The results of the two small placebo RCTs^[1]^[2] were conflicting.

The two studies comparing samarium 153 with placebo show a trend towards pain relief with samarium 153. The prostate-cancer-specific study^[11] with the largest number of participants (n=152), showed a statistically significant benefit. All three studies examining dose show a trend towards better pain relief with higher dose. However, the size of the effect could not be adequately assessed in twoof these studies^[10]^[12]and in the third study^[13] with small numbers of prostate cancer patients (n=12), the effects were not significant.

Samarium 153 has a shorter half-life and thus it has been hypothesised may have a quicker response. However, there is currently no evidence available to support this.

Five RCTs examined the effect of strontium 89 on disease progression in men with prostate cancer.

Both trials examining the addition of strontium 89 to external beam radiotherapy suggested that strontium 89 delays progression of bony disease. In the larger (n=126) and better-quality study the delay is statistically significant,^[7]^[8] whereas in the second study^[14] the delay is not statistically significant for the prostate cancer patient subgroup. In one of the trials comparing strontium 89 with external beam radiotherapy, strontium-89 resulted in a statistically significant delay in disease progression,^[3] whereas in the other, local external beam radiotherapy was associated with better progression-free survival.^[4]

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Evidence summary and recommendations

Evidence summary

Level

References

Men with hormone refractory prostate cancer and painful bone metastases

strontium 89

Limited evidence suggests that strontium 89 is effective as a treatment for pain relief. There is no randomised control trial evidence comparing the efficacy of strontium 89 with that of modern-day taxane-based chemotherapy or bisphosphonates

II

^[1], ^[2], ^[3], ^[7], ^[8]

samarium 153

A small volume of low- to moderate-quality grade II consistent evidence suggests that samarium 153 is an effective treatment for relief of bone metastases pain. There is only one randomised trial showing a benefit. There is no randomised control trial evidence comparing its efficacy with that of strontium 89, modern-day taxane-based chemotherapy or bisphosphonates.

II

^[10], ^[11], ^[12], ^[13]

Evidence-based recommendation	Grade
Unsealed radioisotopes may be considered for the management of multifocal bone pain alongside other options of treatment in patients with hormone refractory prostate cancer.	C