Bone Metastases in Advanced Prostate Cancer
Bone Metastases in Advanced Prostate Cancer
US Oncology Review 2005
Published: October 2008
Published: October 2008
Benefit of Bisphosphonates in Advanced Prostate Cancer
Etidronate and Clodronate
Early-generation bisphosphonates including etidronate and clodronate failed to demonstrate statistically significant, durable clinical benefits in men with bone metastases secondary to prostate cancer. Although single-arm studies of oral and intravenous (IV) clodronate and etidronate demonstrated transient reductions from baseline in pain levels and analgesic use, these decreases did not reach significance.10–13 Furthermore, the clinical benefits of these agents have not been demonstrated in randomized controlled trials.14–18 In a recent randomized controlled trial involving 209 men with HRPC and bone metastases, IV clodronate (1,500mg) administered every three weeks in combination with mitoxantrone/prednisone did not significantly improve palliative response (combination of pain and analgesic scores) compared with mitoxantrone/prednisone plus placebo.17 Additionally, in a randomized controlled trial involving 311 men with metastatic prostate cancer who were receiving first-line hormonal therapy, oral clodronate (2,080mg/day) did not significantly extend bone progression-free survival, defined as the time from randomization to the development of symptomatic bone metastases or death from prostate cancer, compared with placebo, after a median of 59 months’ follow-up.18 Furthermore, the patients receiving oral clodronate experienced significantly more adverse events, particularly gastrointestinal problems, compared with placebo (risk ratio=1.71; p=0.002).
Pamidronate
Similarly, randomized studies of pamidronate in men with bone metastases from prostate cancer also failed to demonstrate clinical benefit.19,20 In a randomized openlabel trial involving 58 patients, IV pamidronate (60 or 90mg every two to four weeks) for three months reduced bone pain, but did not consistently reduce biochemical markers of bone turnover.19 In a more recent combined analysis of two multicenter, randomized placebo-controlled trials involving 374 patients with HRPC and bone metastases, IV pamidronate (90mg every three weeks) did not significantly reduce brief pain inventory (BPI) pain scores (primary end-point) or analgesic use compared with placebo after 27 weeks of treatment.20 Moreover, pamidronate failed to reduce the percentage of patients experiencing a skeletal complication compared with placebo (25% in both treatment groups at 27 weeks).
Figure 1:Treatment with Zoledronic Acid Significantly Reduced the Percentage of Patients with ≥ 1 SRE Compared with Placebo Across 24 Months of Treatment in Men with HRPC Metastatic to Bone
Zoledronic acid (4mg every three weeks for 24 months) significantly reduced the percentage of patients with any SRE compared with placebo at three, six, 15, and 24 months. Data from Saad et al.l6,22 and Lipton et al.;24 adapted with permission from Saad et al.25
Zoledronic acid (4mg every three weeks for 24 months) significantly reduced the percentage of patients with any SRE compared with placebo at three, six, 15, and 24 months. Data from Saad et al.l6,22 and Lipton et al.;24 adapted with permission from Saad et al.25
Ibandronate
Recently, in a small, open-label study, IV ibandronate demonstrated reduction of bone pain in men with HRPC and bone metastases.21 In this trial, 25 patients were treated with ibandronate (6mg) every four weeks. All patients reported high levels of bone pain at baseline, with a mean pain score of 6.5 on a visual analog scale of 0–10. After ibandronate treatment, 23 (92%) patients reported significant reductions from baseline in pain, with a mean pain score of 2.0 (p<0.001), and nine (39%) patients were completely pain-free. In addition, ibandronate significantly reduced analgesic use in 92% of the patients. However, these results have not been confirmed in a larger randomized controlled study, a particularly important consideration in trials that use a subjective assessment such as pain control given the acknowledged ‘placebo effect’ that can occur in an open-label trial.
References:
1. Parkin D M, Pisani P and Ferlay J, "Global cancer statistics", C A Cancer J. Clin. (1999), 49: pp. 33-64.
2. Jemal A,Tiwari R C, Murray T, et al., "Cancer statistics, 2004", C A Cancer J. Clin. (2004), 54: pp. 8-29.
3. Ferlay J, Bray F, Pisani P and Parkin D M,"GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide", IARC CancerBase No. 5, version 2.0. Lyon, France: IARC Press, Available at: http://wwwdep. iarc.fr/globocan/GLOBOframe.htm Accessed November 16, 2004.
4. Goodin S, Rao K V and DiPaola R S,"State-of-the-art treatment of metastatic hormone-refractory prostate cancer", Oncologist (2002), 7: pp. 360-370.
5. Coleman R E,"Metastatic bone disease: clinical features, pathophysiology and treatment strategies", Cancer Treat. Rev. (2001), 27: pp. 165-176.
6. Saad F, Gleason D M, Murray R et al., "Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer", J. Natl. Cancer Inst. (2004), 96: pp. 879-882.
7. Saad F, Gleason D, Murray R et al., "Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone", [poster], Poster presented at: American Urological Association Annual Meeting;April 26 May 1, 2003; Chicago, Illinois. Abstract 1472.
8. Weinfurt K P, Li Y, Castel L D,Timbie J W, Glendenning A and Schulman K A,"The impact of skeletal-related events on healthrelated quality of life of patients with metastatic prostate cancer", [abstract] Ann. Oncol. (2002), 13 (suppl 5): p. 180. Abstract p. 662.
9. Hillner B E, Ingle J N, Chlebowski R T et al., "American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer", [published erratum appears in J. Clin. Oncol. (2004), 22: 1351], J. Clin. Oncol. (2003), 21: pp. 4,042-4,057.
10. Carey P O and Lippert M C,"Treatment of painful prostatic bone metastases with oral etidronate disodium", Urology (1988), 32: pp. 403-407.
11.Kylmälä T,Tammela T L, Lindholm T S and Seppanen J, "The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer", Ann. Chir. Gynaecol. (1994), 83: pp. 316-319.
12. Cresswell S M, English P J, Hall R R, Roberts J T and Marsh M M, "Pain relief and quality-of-life assessment following intravenous and oral clodronate in hormone-escaped metastatic prostate cancer", Br. J. Urol. (1995), 76: pp. 360-365.
13. Heidenreich A, Hofmann R and Engelmann U H, "The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer", J. Urol. (2001), 165: pp. 136-140.
14. Elomaa I, Kylmälä T,Tammela T, et al., "Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer", Int. Urol. Nephrol. (1992), 24: pp. 159-166.
15.Kylmälä T,Taube T,Tammela T L, Risteli L, Risteli J and Elomaa I, "Concomitant i.v. and oral clodronate in the relief of bone pain-a double-blind placebo-controlled study in patients with prostate cancer", Br. J. Cancer (1997), 76: pp. 939-942.
16. Strang P, Nilsson S, Brandstedt S, et al.,"The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer", Anticancer Res. (1997), 17: pp. 4,717-4,721.
17. Ernst D S, Tannock I F, Winquist E W, et al., "Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain", J. Clin. Oncol. (2003), 21: pp. 3,335-3,342.
18. Dearnaley D , Sydes M R, Mason M D, et al., "A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial)", J. Natl. Cancer Inst. (2003), 95: pp. 1,300-1,311.
19. Lipton A, Glover D, Harvey H, et al.,"Pamidronate in the treatment of bone metastases: results of 2 dose-ranging trials in patients with breast or prostate cancer", Ann. Oncol. (1994), 5 (suppl 7): pp. S31-S35.
20. Small E J, Smith M R, Seaman J J, Petrone S and Kowalski M O,"Combined analysis of two multicenter, randomized, placebocontrolled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer", J. Clin. Oncol. (2003), 21: pp. 4,277-4,284.
21. Heidenreich A, Elert A and Hofmann R,"Ibandronate in the treatment of prostate cancer associated painful osseous metastases", Prostate Cancer Prostatic Dis. (2002), 5: pp. 231-235.
22. Saad F, Gleason D M, Murray R, et al., "A randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma", For the Zoledronic Acid Prostate Cancer Study Group, J. Nat. Cancer Inst. (2002), 94: pp. 1,458-1,468.
23. Major P P and Cook R,"Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints", Am. J. Clin. Oncol. (2002), 25 (suppl 1): pp. S10-S18.
24. Lipton A, Small E, Saad F, et al.,"The new bisphosphonate, Zometa (r) (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate", Cancer Invest. (2002), 20 (suppl 2): pp. 45-54.
25. Saad F, Gleason D, Murray R, et al.,"Early and sustained clinical benefit of zoledronic acid in men with advanced prostate cancer (PC) metastatic to bone: comparison with pamidronate", [poster], Poster presented at: Canadian Urological Association 59th Annual Meeting; June 27 July 1, 2004;Whistler, British Columbia. Abstract 30.
26. Gleason D, Saad F, Goas A and Zheng M, "Continuing benefit of zoledronic acid in preventing skeletal complications after the first occurrence in patients with prostate cancer and bone metastases", [abstract], Proc.Am. Soc. Clin. Oncol. (2003), 22: p. 379, Abstract 1522.
27. Saad F, Gleason D, Murray R, et al., "Long-term reduction of bone pain with zoledronic acid in patients with advanced prostate cancer metastatic to bone", [poster], Poster presented at:American Urological Association Annual Meeting;April 26 May 1, 2003; Chicago, Illinois, Abstract 1473.
28. Major P P, Cook R J, Chen B-L and Zheng M, "Zoledronic acid reduces the need for radiation to bone in patients with breast or prostate cancer metastatic to bone: a survival-adjusted cumulative incidence analysis", [abstract], Proc.Am. Soc. Clin. Oncol. (2004), 23: p. 739, Abstract 8058.
29. Carroll P R, Altwein J, Brawley O, et al., "Management of disseminated prostate cancer", In: Denis L, Bartsch G, Khoury S, et al, (eds), Prostate Cancer: 3rd International Consultation on Prostate Cancer-Paris. Paris: Health Publications; (2003), pp. 251-284.
30. Smith M R, Eastham J, Gleason D M, Shasha D,Tchekmedyian S and Zinner N, "Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer", J. Urol. (2003), 169: pp. 2,008-2,012.
31.Padalecki S S, Carreon M, Grubbs B, Cui Y and Guise T A, "Androgen deprivation enhances bone loss and prostate cancer metastases to bone: prevention by zoledronic acid", Oncology (2003), 17 (suppl 3): p. 32.
2. Jemal A,Tiwari R C, Murray T, et al., "Cancer statistics, 2004", C A Cancer J. Clin. (2004), 54: pp. 8-29.
3. Ferlay J, Bray F, Pisani P and Parkin D M,"GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide", IARC CancerBase No. 5, version 2.0. Lyon, France: IARC Press, Available at: http://wwwdep. iarc.fr/globocan/GLOBOframe.htm Accessed November 16, 2004.
4. Goodin S, Rao K V and DiPaola R S,"State-of-the-art treatment of metastatic hormone-refractory prostate cancer", Oncologist (2002), 7: pp. 360-370.
5. Coleman R E,"Metastatic bone disease: clinical features, pathophysiology and treatment strategies", Cancer Treat. Rev. (2001), 27: pp. 165-176.
6. Saad F, Gleason D M, Murray R et al., "Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer", J. Natl. Cancer Inst. (2004), 96: pp. 879-882.
7. Saad F, Gleason D, Murray R et al., "Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone", [poster], Poster presented at: American Urological Association Annual Meeting;April 26 May 1, 2003; Chicago, Illinois. Abstract 1472.
8. Weinfurt K P, Li Y, Castel L D,Timbie J W, Glendenning A and Schulman K A,"The impact of skeletal-related events on healthrelated quality of life of patients with metastatic prostate cancer", [abstract] Ann. Oncol. (2002), 13 (suppl 5): p. 180. Abstract p. 662.
9. Hillner B E, Ingle J N, Chlebowski R T et al., "American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer", [published erratum appears in J. Clin. Oncol. (2004), 22: 1351], J. Clin. Oncol. (2003), 21: pp. 4,042-4,057.
10. Carey P O and Lippert M C,"Treatment of painful prostatic bone metastases with oral etidronate disodium", Urology (1988), 32: pp. 403-407.
11.Kylmälä T,Tammela T L, Lindholm T S and Seppanen J, "The effect of combined intravenous and oral clodronate treatment on bone pain in patients with metastatic prostate cancer", Ann. Chir. Gynaecol. (1994), 83: pp. 316-319.
12. Cresswell S M, English P J, Hall R R, Roberts J T and Marsh M M, "Pain relief and quality-of-life assessment following intravenous and oral clodronate in hormone-escaped metastatic prostate cancer", Br. J. Urol. (1995), 76: pp. 360-365.
13. Heidenreich A, Hofmann R and Engelmann U H, "The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer", J. Urol. (2001), 165: pp. 136-140.
14. Elomaa I, Kylmälä T,Tammela T, et al., "Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer", Int. Urol. Nephrol. (1992), 24: pp. 159-166.
15.Kylmälä T,Taube T,Tammela T L, Risteli L, Risteli J and Elomaa I, "Concomitant i.v. and oral clodronate in the relief of bone pain-a double-blind placebo-controlled study in patients with prostate cancer", Br. J. Cancer (1997), 76: pp. 939-942.
16. Strang P, Nilsson S, Brandstedt S, et al.,"The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer", Anticancer Res. (1997), 17: pp. 4,717-4,721.
17. Ernst D S, Tannock I F, Winquist E W, et al., "Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain", J. Clin. Oncol. (2003), 21: pp. 3,335-3,342.
18. Dearnaley D , Sydes M R, Mason M D, et al., "A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial)", J. Natl. Cancer Inst. (2003), 95: pp. 1,300-1,311.
19. Lipton A, Glover D, Harvey H, et al.,"Pamidronate in the treatment of bone metastases: results of 2 dose-ranging trials in patients with breast or prostate cancer", Ann. Oncol. (1994), 5 (suppl 7): pp. S31-S35.
20. Small E J, Smith M R, Seaman J J, Petrone S and Kowalski M O,"Combined analysis of two multicenter, randomized, placebocontrolled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer", J. Clin. Oncol. (2003), 21: pp. 4,277-4,284.
21. Heidenreich A, Elert A and Hofmann R,"Ibandronate in the treatment of prostate cancer associated painful osseous metastases", Prostate Cancer Prostatic Dis. (2002), 5: pp. 231-235.
22. Saad F, Gleason D M, Murray R, et al., "A randomized, placebo-controlled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma", For the Zoledronic Acid Prostate Cancer Study Group, J. Nat. Cancer Inst. (2002), 94: pp. 1,458-1,468.
23. Major P P and Cook R,"Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints", Am. J. Clin. Oncol. (2002), 25 (suppl 1): pp. S10-S18.
24. Lipton A, Small E, Saad F, et al.,"The new bisphosphonate, Zometa (r) (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate", Cancer Invest. (2002), 20 (suppl 2): pp. 45-54.
25. Saad F, Gleason D, Murray R, et al.,"Early and sustained clinical benefit of zoledronic acid in men with advanced prostate cancer (PC) metastatic to bone: comparison with pamidronate", [poster], Poster presented at: Canadian Urological Association 59th Annual Meeting; June 27 July 1, 2004;Whistler, British Columbia. Abstract 30.
26. Gleason D, Saad F, Goas A and Zheng M, "Continuing benefit of zoledronic acid in preventing skeletal complications after the first occurrence in patients with prostate cancer and bone metastases", [abstract], Proc.Am. Soc. Clin. Oncol. (2003), 22: p. 379, Abstract 1522.
27. Saad F, Gleason D, Murray R, et al., "Long-term reduction of bone pain with zoledronic acid in patients with advanced prostate cancer metastatic to bone", [poster], Poster presented at:American Urological Association Annual Meeting;April 26 May 1, 2003; Chicago, Illinois, Abstract 1473.
28. Major P P, Cook R J, Chen B-L and Zheng M, "Zoledronic acid reduces the need for radiation to bone in patients with breast or prostate cancer metastatic to bone: a survival-adjusted cumulative incidence analysis", [abstract], Proc.Am. Soc. Clin. Oncol. (2004), 23: p. 739, Abstract 8058.
29. Carroll P R, Altwein J, Brawley O, et al., "Management of disseminated prostate cancer", In: Denis L, Bartsch G, Khoury S, et al, (eds), Prostate Cancer: 3rd International Consultation on Prostate Cancer-Paris. Paris: Health Publications; (2003), pp. 251-284.
30. Smith M R, Eastham J, Gleason D M, Shasha D,Tchekmedyian S and Zinner N, "Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer", J. Urol. (2003), 169: pp. 2,008-2,012.
31.Padalecki S S, Carreon M, Grubbs B, Cui Y and Guise T A, "Androgen deprivation enhances bone loss and prostate cancer metastases to bone: prevention by zoledronic acid", Oncology (2003), 17 (suppl 3): p. 32.
