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

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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 recommendationQuestion mark transparent.png 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


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References

  1. 1.0 1.1 1.2 1.3 1.4 Buchali K, Correns HJ, Schuerer M, Schnorr D, Lips H, Sydow K. Results of a double blind study of 89-strontium therapy of skeletal metastases of prostatic carcinoma. Eur J Nucl Med 1988;14(7-8):349-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2460352.
  2. 2.0 2.1 2.2 2.3 Lewington VJ, McEwan AJ, Ackery DM, Bayly RJ, Keeling DH, Macleod PM, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27(8):954-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1716935.
  3. 3.0 3.1 3.2 3.3 3.4 Quilty PM, Kirk D, Bolger JJ, Dearnaley DP, Lewington VJ, Mason MD, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 1994 Apr;31(1):33-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7518932.
  4. 4.0 4.1 Oosterhof GO, Roberts JT, de Reijke TM, Engelholm SA, Horenblas S, von der Maase H, et al. Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 2003 Nov;44(5):519-26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14572748.
  5. 5.0 5.1 Sherman EJ, Pfister DG, Ruchlin HS, Rubin DM, Radzyner MH, Kelleher GH, et al. The Collection of Indirect and Nonmedical Direct Costs (COIN) form: a new tool for collecting the invisible costs of androgen independent prostate carcinoma. Cancer 2001 Feb 15;91(4):841-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11241254.
  6. Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet 2001 Feb 3;357(9253):336-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11210994.
  7. 7.0 7.1 7.2 7.3 7.4 Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Semin Oncol 1993 Jun;20(3 Suppl 2):38-43 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7684865.
  8. 8.0 8.1 8.2 8.3 8.4 Porter AT, McEwan AJ, Powe JE, Reid R, McGowan DG, Lukka H, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993 Apr 2;25(5):805-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8478230.
  9. Nilsson S, Strang P, Ginman C, Zimmermann R, Edgren M, Nordström B, et al. Palliation of bone pain in prostate cancer using chemotherapy and strontium-89. A randomized phase II study. J Pain Symptom Manage 2005 Apr;29(4):352-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15857738.
  10. 10.0 10.1 10.2 10.3 Serafini AN, Houston SJ, Resche I, Quick DP, Grund FM, Ell PJ, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol 1998 Apr;16(4):1574-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9552068.
  11. 11.0 11.1 11.2 Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 2004 May;63(5):940-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15134985.
  12. 12.0 12.1 12.2 12.3 Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, et al. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 1997 Sep;33(10):1583-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9389919.
  13. 13.0 13.1 13.2 13.3 Tian JH, Zhang JM, Hou QT, Oyang QH, Wang JM, Luan ZS, et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med 1999 Jan;26(1):2-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9933654.
  14. 14.0 14.1 Smeland S, Erikstein B, Aas M, Skovlund E, Hess SL, Fosså SD. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Int J Radiat Oncol Biol Phys 2003 Aug 1;56(5):1397-404 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12873686.

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Appendices