Bone Mets in Prostate Cancer

Editor's Notes

1. Key Points Prostate cancer is the most common solid tumor affecting men, with an estimated 241,740 new cases in 2012 1 Estimates indicate that there are between 60,000 and 90,000 men in the US who have ADT-resistant prostate cancer; as indicated by increasing prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT) 2 Studies have shown that over 80% of men with advanced castration-resistant prostate cancer (CRPC) develop bone metastases 3-6 Nearly half of men with CRPC developed at least one bone metastasis within 2 years 7 Results of a survey, however, have suggested that 68% of men with metastatic prostate cancer did not discuss bone metastases management with their doctor 8 References: American Cancer Society Cancer Facts and Figures 2012. Moul JW, et al. Oncol . 2007;21:1436–1445. Shah RB, et al. Cancer Res. 2004;64:9209–9216. Scher HI, et al. Clin Cancer Res . 2005;11:5223–5232. Tannock IF, et al. N Engl J Med . 2004;351:1502–1512. Petrylak DP, et al. N Engl J Med . 2004;351:1513–1520. Smith MR et al. Cancer. 2011;117:2077–2085. Tripathy D, et al. J Clin Oncol . 2011;29(suppl): Abstr e19617.
2. Key Points An analysis of enrollment data from a recent study has shown that distant metastases are common in patients believed to have nonmetastatic castration-resistant prostate cancer (CRPC) Results showed that 30% of patients had evidence of metastases confirmed by bone scans or CT/MRI at screening for study entry Background The study screened 1,756 patients for enrollment to evaluate treatment for men with nonmetastatic CRPC Patients were screened for metastatic disease by bone or CT/MRI scans and other parameters An unexpectedly high number of patients failed screening, prompting this analysis Results of the analysis showed that the primary reason for exclusion was that bone or CT/MRI scans revealed the presence of metastases in 30% of patients These data demonstrate the high frequency of asymptomatic metastases in patients believed to have nonmetastatic CRPC and the importance of periodic staging studies Reference: Yu EY, et al. J Clin Oncol . 2011;29:Abstract 135.
3. Key Points The cumulative incidence plot shows the proportion of patients with castration-resistant prostate cancer (CRPC) that developed at least 1 bone metastasis 1 Over 80% of men with advanced CRPC will develop bone metastases 2-5 At 2 years, 46% of subjects had developed at least 1 bone metastases, and 20% had died 1 Median bone metastasis-free survival was 25 months 1 Background Data were used from the placebo group (n=331) of a previously reported international randomized controlled trial of a study drug to examine the relationship between disease and host characteristics, including time to first bone metastases and death in men with CRPC and no radiographic evidence of bone metastases 1 All subjects had prostate cancer and had undergone androgen deprivation therapy (bilateral orchiectomy or medical castration) at least 3 months before randomization, and had castrate testosterone levels at screening 1 References: Smith MR et al. Cancer. 2011;117:2077–2085. Shah RB, et al. Cancer Res . 2004;64:9209–9216. Scher HI, et al. Clin Cancer Res . 2005;11:5223–5232. Tannock IF, et al. N Engl J Med . 2004;351:1502–1512. Petrylak DP, et al. N Engl J Med . 2004;351:1513–1520.
4. Key Points Bone complications can negatively impact the lives of patients in many ways Data suggest that bone metastases have a negative impact on survival of patients with prostate cancer 1 Many patients with bone metastases reported experiencing debilitating bone pain 2 Pathologic fractures and radiation are common in men with bone metastases from prostate cancer and may cause functional impairment 3-6 Patients with prostate cancer who experienced radiation to bone reported decreased health-related quality of life as a result 4 Additionally, bone complications can also contribute substantial cost of care for patients with advanced cancers 7,8 References: Sathiakumar N, et al. Prostate Cancer Prostatic Dis . 2011;14:177–183. Gralow J, et al. J Pain Symptom Manage . 2007;33:462–472. Coleman RE. Clin Cancer Res . 2006;12(Suppl 20 pt 2):6243s–6249s. Weinfurt KP, et al. Ann Oncol . 2005;16:579–584. Saad F, et al. Urol Oncol . 2006;24:4–12. Saad F, et al. J Natl Cancer Inst . 2004;96:879–992. Schulman KL, et al. Cancer . 2007;109:2334–2342. Hagiwara M, et al. Commun Oncol . 2011;8:508–515.
5. Key Points Sathiakumar and colleagues examined a combined population-based cancer registry and Medicare claims data base to assess the impact of bone metastases and skeletal-related events (SREs) on US prostate cancer patients Mortality hazard ratios (HR) were compared for prostate cancer patients without bone metastases versus patients with bone metastases, with and without SREs Prostate cancer patients with bone metastases, but without SREs, had a 6.6 times greater mortality HR versus patients without bone metastases (95% CI, 6.4-6.9) Prostate cancer patients with both bone metastases and SREs had a 10.2 times greater mortality HR versus patients without bone metastases (95% CI, 9.8-10.7) Background Study consisted of a review of data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data for the time period 1999-2006. SEER data included patient demographics, cancer diagnosis date, and cancer stage. Medicare data included demographics, claims data (service dates, ICD-9 codes), and procedure codes from hospitals and institutional and non-institutional providers. Hazard ratios were adjusted for age at cancer diagnosis, race/ethnicity, cancer stage at diagnosis, and Charlson comorbidity score Reference: Sathiakumar N, et al. Prostate Cancer Prostatic Dis . 2011;14:177–183.
6. Key Points Data has shown that up to 76% of patients with bone metastases reported moderate to severe bone pain 1 Metastatic bone pain is often chronic and required opioid therapy in addition to nonsteroidal anti-inflammatory drugs (NSAIDs) 1-4 Pain associated with bone metastases is often treatment-refractory and opioid therapy has been demonstrated to be insufficient to manage pain 1,3,4 Additionally, studies have demonstrated that patients not treated for bone metastases are at increased risk of developing skeletal complications which may further exacerbate bone pain and functional impairment 5,7,8 These data underscore the importance of the effective management of metastatic bone disease Background Data is from a survey of 534 patients with bone metastases, referred to a palliative radiation center including 117 patients with prostate cancer 1 Prior to treatment with radiation therapy, patients were asked to rate their pain intensity on a scale of 0 to 10; 0 defined as absence of pain and 10 defined as worse pain possible 1 Brief pain inventory (BPI) is a validated instrument which rates the severity of pain during the prior day using 0-10 scales. This tool uses worst pain intensity scores from 0 (no pain) to 10 (worst pain); ratings from 1 to 3 corresponded to mild pain, 4 to 7 to moderate pain, and 8 to 10 to severe pain. 9 References: Yau V, et al. J Pain Symptom Manage . 2004;27:1–2. Janjan N. Semin Onc . 2001;28(suppl 11):28–34. Twycross RG. Clin Orthopaedics Rel Res . 1995;312:187–196. Gralow J, et al. J Pain Symptom Manage. 2007;33:462–472. Lipton A, et al. Cancer . 2000;88:1082–1090. Chow E, et al. Clin Oncol . 2006;18:67–69. Saad F, et al. J Natl Cancer Inst . 2004;96:879–882. Berenson JR, et al. J Clin Oncol . 1998;16:593–602. Serlin RC, et al. Pain . 1995;61:277–284.
7. Key Points Treatment for bone metastases includes radiation therapy and narcotics 1-4 Data has shown that 33% of men with advanced castration-resistant prostate cancer (CRPC) not receiving treatment for bone metastases required radiation therapy (RT) 1,2 RT may require up to 10 hospital visits over the course of 2 weeks 3,4 Results of different study showed that 67% of patients required narcotic pain medication 3 month after receiving palliative RT to bone 3 Background Data for RT incidence is from the placebo arm of a pivotal trial in 643 patients with metastatic CRPC 1,2 Results showed that 33% of all men untreated for bone metastases (placebo arm) required RT; a total of 49% experienced a skeletal-related event 1,2 Data for narcotic usage is from a separate, prospective, randomized phase 3 study that evaluated the effectiveness of palliative RT in 898 patients with breast or prostate cancer who had painful bone metastases and moderate to severe pain. Pain data from 318 patients treated with 8 Gy radiation therapy 3 References: Saad F, et al. Urol Oncol. 2006;24:4–12. Saad F, et al. J Natl Cancer Inst. 2004;96:879–992. Hartsell WF, et al. J Natl Cancer Inst. 2005;97:798–804. Hartsell WF, et al. Clin Oncol. 2009;21:652–654.
8. Key Points Data has shown that pathologic fracture occurred in 25% of all men with advanced castration-resistant prostate cancer untreated for bone metastases 1,2 Median time to first fracture or other skeletal complication was 10.7 months 2 Background Data is from a pivotal trial in 643 patients with metastatic castration-resistant prostate cancer 1,2 Results showed that 49% of all men untreated for bone metastases (placebo arm) experienced a skeletal-related event with 25% of all men experiencing a pathologic fracture 1,2 References: Saad F, et al. Urol Oncol. 2006;24:4–12. Saad F, et al. J Natl Cancer Inst. 2004;96:879–992.
9. Key Points Men with prostate cancer who experienced a pathologic fracture commonly required hospitalization Data has shown that the average length of hospital stay for men who experienced a pathologic fracture and required hospitalization was 6.6 days Background Data from commercial and Medicare claims databases of 599 prostate cancer patients with bone metastases hospitalized for skeletal-related events between January 2001 to June 2009 Reference: Barlev A, et al. J Manag Care Pharm. 2010;16(9):693–702.
10. Key Points Data has shown that men with prostate cancer who experienced a skeletal-related event (SRE) had a clinically meaningful and statistically significant decline in quality of life; including 1 Physical well-being after radiation and pathologic fracture Functional well-being after radiation Emotional well-being after radiation and pathologic fracture Background A subset analysis was conducted to evaluate changes in quality of life for patients with advanced prostate cancer (n=248) who experienced an SRE during a multinational, randomized, double-blind, placebo controlled clinical trial 1 Health-related quality of life was measured every 90 days using the Functional Assessment of Cancer Therapy–General (FACT-G), the Brief Pain Inventory (BPI), and the EuroQol instrument 1,2 References: Weinfurt KP, et al. Ann Oncol . 2005;16:589–584. Cella DF, et al. J Clin Oncol . 1993;11:570–579.
11. Key Points Hagiwara and colleagues utilized a retrospective cohort design from 2 large US health insurance claims databases to estimate the effects of health care costs associated with bone metastases with and without skeletal-related events (SREs) in men with prostate cancer who were receiving hormonal therapy In the pre-bone metastases phase (6 months prior to bone metastases occurring), mean total healthcare costs were $23,047 per person-year For subjects advancing to bone metastases, but with no SREs, the per person-year cost escalated to $43,251, representing a cost increase of 95% over the pre-bone metastases phase When bone metastases and SREs were both present, the per person-year cost went up to $60,162, an increase of 173% versus the pre-bone metastases group Background The study sample consisted of 215,702 patients with a diagnosis of prostate cancer 8,608 subjects had evidence of bone metastases, including 4,105 patients who received hormonal therapy in the prior year 1,365 subjects met all inclusion criteria, with 579 having no SRE and 786 having one or more SRE Longitudinal multivariate regression analysis was used to compare costs during person-time with and without SREs Reference Hagiwara M, et al. Commun Oncol. 2011;8:508–515.
12. Key Points Many men with castration-resistant prostate cancer are at risk for development of bone metastases further increasing the risk of skeletal complications 1 Bone metastases are associated with increased mortality in men with prostate cancer 2 Pain from bone metastases is often debilitating and may require treatment with radiation therapy and narcotics 3-7 Physical and functional impairment has been seen in patients who experienced a fracture or received radiation to bone 8 Bone metastases are associated with increased healthcare costs 9,10 References: Coleman RE. Clin Cancer Res . 2006;12(Suppl 20 pt 2):6243s–6249s. Sathiakumar N, et al. Prostate Cancer Prostatic Dis . 2011;14:177–183. Yau V, et al. J Pain Symptom Manage . 2004;27:1–3. Gralow J, et al. J Pain Symptom Manage . 2007;33:462–472;. Saad F, et al. Urol Oncol . 2006;24:4–12. Saad F, et al. J Natl Cancer Inst . 2004;96:879–992. Hartsell WF, et al. J Natl Cancer Inst . 2005;97:798–804; Weinfurt KP, et al. Ann Oncol . 2005;16:579–584. Schulman KL, et al. Cancer . 2007;109:2334–2342. Hagiwara M, et al. Commun Oncol . 2011;8:508–515.
13. Key Points Note: Slide contains builds/animations that will advance with each mouse click Androgen deprivation therapy (ADT) is commonly used to treat clinical and/or biochemical relapse of nonmetastatic prostate cancer following surgery and/or radiation therapy 1 As prostate cancer progresses, tumors may become castration-resistant, as indicated by rising PSA despite ADT, and can metastasize to bone and other sites 2-4 Patients with castration-resistant prostate cancer (CRPC) are at increased risk of developing bone metastases 5 Data has shown that nearly half developed at least one bone metastasis within 2 years 5 Patients with bone metastases have been shown to be at increased risk of fracture and other skeletal complications 6,7 References: Freedland SJ. Cancer. 2011;117:1123–1135. Crawford ED, et al. N Engl J Med . 1989;321:419–424. Eisenberger MA, et al. N Engl J Med . 1998;339:1036–1042. Scher HI, et al. J Clin Oncol. 2008;26:1148–1159. Smith MR et al. Cancer. 2011;117:2077–2085. Saad F, et al. Urol Oncol . 2006;24:4–12. Saad F, et al. J Natl Cancer Inst . 2004;96:879–992.
14. Key Points Androgen deprivation therapy (ADT) has been shown to help delay disease progression in men with localized or locally advanced prostate cancer 1 Duration of response with ADT typically ranges between 2 to 10 years 1-3 Systematic review of clinical trials has shown that the disease-free survival rates for common treatment were: 1 5.4 years for radiation therapy (RT) + ADT > 6 years for radical prostatectomy (RP) + ADT 6 years for ADT-alone Natural history of castration-resistant prostate cancer (CRPC) suggests that it may take up to 3 years from the initial elevation of PSA until there is clinical evidence of metastatic disease 4 Background Data for duration of response with ADT was obtained from a systematic review of 35 clinical trials (n = 11,105 patients) which addressed early hormone therapy in nonmetastatic prostate cancer. Data on disease-free survival and overall survival were extracted from individual trials, summarized statistically, and analyzed. References: Antonarakis ES, et al. J Clin Oncol . 2007;25:4998–5008. Bianco FJ, et al. J Clin Oncol . 2004;22(suppl): Abstract 4552. Ross RW, et al. Cancer. 2008;112:1247–1253. Moul JW, et al. Oncol . 2007;21:1436–1445.
15. Key Points Prostate-specific antigen (PSA) levels provide a clinical tool to follow prostate cancer progression 1 Androgen deprivation therapy (ADT) has been shown to help delay disease progression; however, most tumors ultimately become resistant, indicating the development of castration-resistant prostate cancer (CRPC) 2-5 Data has shown that development of bone metastases is common with ADT resistance 6 References: Smith MR. Eur Urol Suppl . 2009;8:834–838. Antonarakis ES, et al. J Clin Oncol . 2007;25:4998–5008. Crawford ED, et al. N Engl J Med . 1989;321:419–424. Eisenberger MA, et al. N Engl J Med . 1998;339:1036–1042. Scher HI, et al. J Clin Oncol . 2008;26:1148–1159. Smith MR et al. Cancer . 2011;117:2077–2085.
16. Key Points The early identification of patients who are at high risk for bone metastases may help to reduce the risk of skeletal complications 1 Although bone pain is an important indicator of bone metastases, analyses have shown that in men with prostate cancer and rising prostate-specific antigen (PSA) levels despite androgen deprivation therapy (ADT); risk factors for the development of bone metastases include: 1-4 High absolute PSA levels (PSA > 10 ng/mL) Rapidly rising PSA levels or short PSA doubling time (PSADT) Background A retrospective analysis of 201 patients with nonmetatstatic prostate cancer and PSA progression despite ADT showed a statistically significant correlation of baseline PSA levels and increasing PSA velocity with shorter time to bone metastases 4 Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P <0.001) and PSA velocity (relative risk, 4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P <0.001) independently predicted shorter time to first bone metastasis in the reduced multivariate Cox regression model 4 References: Smith MR, et al. J Clin Oncol. 2005;23:2918– 2925. NCCN Clinical Practice Guidelines in Oncology™ Prostate Cancer. V.4.2011. Petrylak DP. Eur Urol Suppl. 2007;6:677 – 682. Moreira D, et al. J Urol . 2010:183(suppl):e335–e336.
17. Key Points Data has shown that rates of positive bone scans were linked to higher prostate-specific antigen (PSA) levels and shorter PSA doubling time (PSADT) In patients receiving androgen deprivation therapy (ADT), rates of positive bone scans for PSA > 10 ng/mL were greater than 60% and greater than 40% for PSADT < 9 months The investigators concluded that the combination of PSA levels and PSA kinetics may be used to better identify patients at risk for bone metastases Background Data from a retrospective analysis of 114 patients receiving ADT after biochemical recurrence following radical prostatectomy Reference: Moreira D, et al. J Urol . 2010:183(suppl):e335–e336.
18. Key Points Predictors of bone metastases in men with rising prostate-specific antigen (PSA) despite androgen deprivation therapy (ADT) include: 1-4 PSA levels > 10 ng/mL Rapidly rising PSA levels or short PSA doubling time (PSADT) These data help illustrate the importance of a bone scan to promptly detect bone metastases in men with rising PSA despite ADT References: Smith MR, et al. J Clin Oncol . 2005;23:2918–2925. NCCN Clinical Practice Guidelines in Oncology™ Prostate Cancer. V.4.2011. Petrylak DP. Eur Urol Suppl . 2007;6:677–682. Moreira D, et al. J Urol . 2010:183(suppl):e335–e336.
19. Key Points The “seed & soil” hypothesis describes the highly selective, complex interactions between prostate cancer cells, “the seed”, and the bone microenvironment, “the soil”, to promote development of bone metastases 1-8 Within the bone microenvironment, multiple factors released by tumor cells and bone matrix ultimately create fertile conditions for tumor growth and proliferation 1,7,8 Background Within the bone microenvironment, prostate cancer cells release a variety of growth factors, cytokines, and other proteins that stimulate excessive osteoblast and osteoclast activity resulting in destruction of bone matrix; ultimately, creating more fertile conditions for development of bone metastases 1,7,8 BMPs, FGFs, PDGFs, TGFβ, uPA, IGFs, IGFBPs, PTHrP, EGFs, VEGF, MDA-BF-1, WNT, ET-1 Bone microenvironment releases multiple factors that attract prostate cancer cells and create fertile conditions to further stimulate tumor growth and proliferation 1,7,8 PDGFs, BMPs, TGFβ, IGFs, FGFs, EGF, IL-1α, TNFα, Ca+ References: Loberg RD, et al. J Clin Oncol . 2005;23:8232–8241. Fidler IJ. Nat Rev Cancer . 2003;3:1–6. Pienta KJ, et al. Clinical Prostate Cancer . 2005;4:24–30. Chung LWK, et al. J Urol . 2005;173:10–20.. Tantivejkul K, et al. J Cell Biochem . 2004;91:706–717. Logothetis CJ, et al. Nat Rev Cancer . 2005;5:21–28. Roodman GD. N Engl J Med . 2004;350:1655–1664. Mundy GR. Nat Rev Cancer . 2002;2:584–593.
20. Key Points Note: Slide contains builds/animations that will advance with each mouse click Prostate cancer cells shed from the primary tumor enter the circulation, and release growth factors, cytokines, and other proteins which promote adhesion and proliferation to the bone 1 Circulating prostate cancer cells initially adhere to cells lining blood vessels in bone marrow 2 Tumor cells are actively recruited to the bone microenvironment by multiple factors 1-6 Tumor cells are thought to preferentially adhere to areas of increased bone turnover 1-6 References: Loberg RD, et al. J Clin Oncol . 2005;23:8232–8241. Fidler IJ. Nat Rev Cancer . 2003;3:1–6. Pienta KJ, et al. Clinical Prostate Cancer . 2005;4:24–30. Chung LWK, et al. J Urol . 2005;173:10–20. Tantivejkul K, et al. J Cell Biochem . 2004;91:706–717. Logothetis CJ, et al. Nat Rev Cancer . 2005;5:21–28.
21. Key Points Note: Slide contains builds/animations that will advance with each mouse click Tumor cells that have invaded bone secrete multiple factors that stimulate osteoblasts to overproduce growth factors 1,2 Increased levels of growth factors drive excessive osteoclast activity and bone resorption resulting in destruction of the bone matrix 1,2 Increased bone resorption releases growth factors from the bone matrix, which may further stimulate tumor growth and bone destruction leading to the further development of bone metastases 1,2 References: Roodman GD. N Engl J Med . 2004;350:1655–1664. Mundy GR. Nat Rev Cancer . 2002;2:584–593.
22. Key Points Development of bone metastases depends on complex interactions between prostate cancer cells and the bone microenvironment 1-8 Prostate cancer cells release growth factors, cytokines, and other proteins that promote adhesion and proliferation to bone 1 Multiple factors released by the bone microenvironment attract tumor cells and create a favorable environment for the development of metastases 1,7,8 Upon adhering to bone, interactions between tumor cells and the bone microenvironment result in excessive bone resorption that may further stimulate tumor growth and bone destruction leading to further development of bone metastases 1,7,8 References: Loberg RD, et al. J Clin Oncol . 2005;23:8232–8241. Fidler IJ. Nat Rev Cancer . 2003;3:1–6. Pienta KJ, et al. Clinical Prostate Cancer . 2005;4:24–30. Chung LWK, et al. J Urol . 2005;173:10–20.. Tantivejkul K, et al. J Cell Biochem . 2004;91:706–717. Logothetis CJ, et al. Nat Rev Cancer . 2005;5:21–28. Roodman GD. N Engl J Med . 2004;350:1655–1664. Mundy GR. Nat Rev Cancer . 2002;2:584–593.