Introduction
Metastasis to bone is one of the common complications associated with different types of advanced cancers, including solid tumors and multiple myeloma [ 1 ]. Patients with bone metastasis are at the risk of skeletal-related events (SREs).SREs include pathological fractures, requirement for radiation or surgery to bone to prevent or repair major structural damage, and spinal cord compression [ 2 ]. SREs represents a significant cause of morbidity including functional impairment and loss of mobility, which often lead to tremendous burden on quality of life and overall health [ 3 – 7 ].
As one of the osteoclast inhibitors, bisphosphonates have been widely used for advanced cancer patients with bone metastasis. In particular, zoledronic acid (ZA) is more effective than other bisphosphonate in delaying the first SREs [ 8 , 9 ]. ZA has been the standard choice to prevent bone metastasis-related skeletal complications for almost a decade [ 10 , 11 ]. However, side effects of ZA, including renal impairments and acute-phase reactions, limited its overall application [ 12 – 15 ]. As an alternative therapeutic option, denosumab has also been found to be effective in delaying SREs in advanced cancer. As a human monoclonal antibody, denosumab binds to receptor activator of nuclear factor kappa-B ligand (RANKL) [ 16 – 18 ], and has been shown non-inferior to ZA.
Several studies and meta-analysis [ 19 ] have been conducted to compare the efficacy and safety between denosumab and ZA. However, previous meta-analysis was performed based on several different types of advanced cancers without subgroup analysis. Specifically, solid tumors are different form multiple myeloma to a great extent. Besides, several good original manuscripts have been added. It is necessary to conduct a new review for the comparison of denosumab and ZA. Therefore, we performed a systematic review and meta-analysis to compare the efficacy and safety between denosumab and ZA for advanced cancer with bone metastasis.
Materials and methods
Inclusion criteria
Studies meeting the following criteria were included: (1) target population: patients with bone metastasis secondary to advanced solid tumors or multiple myeloma, (2) intervention: denosumab versus ZA, (3) methodological criteria: randomized controlled double-blind trials (RCTs), and (4) involved human patient populations. If the same study was published in different years or journals, then the most frequently cited report was included. Case reports and reviews were excluded from the analysis.
Search strategy
Relevant studies were identified by searching the following databases: MEDLINE, EMBASE, Web of Science, and the Cochrane Collaboration Library up to December 2020. We used the search terms “denosumab,” “zoledronic acid,” “bone metastasis,” “cancer,” “tumor,” “neoplasm,” “multiple myeloma,” and “randomized controlled trial” with different combinations of the operators “AND,” “NOT,” and “OR.” References cited in selected studies were also checked to identify additional studies. Two reviewers (L.J. and X.C.) screened the studies independently.
Data extraction
Two reviewers (L.J. and X.C.) extracted data from the eligible studies independently. Information from each study was collected in terms of the following contents: year of publication, author, study design, study time periods, and patient characteristics. The following clinical outcomes were extracted from included studies for comparison: time to first SRE (defined as the time in days from randomization date to the date of first occurrence of an on-study SRE [ 20 ]), time to first-and-subsequent SREs (defined as the time in days from randomization date to the date of a subsequent occurrence of an on-study SRE [ 20 ]), overall survival, and disease progression. Incidence of treatment-emergent adverse events (AEs) and serious AEs were extracted for comparison. All AEs were coded using Medical Dictionary for Regulatory Activities v12.0 system. In addition, safety outcomes including acute-phase reactions, renal toxicity, osteonecrosis of the jaw (ONJ), hypocalcemia, and new primary malignancy were also extracted for comparison.
Quality assessment
Quality of the included RCTs were assessed by two reviewers (L.J. and H.M.) independently using the Cochrane assessment tool. Level of agreement between the two reviewers was recorded, and disagreements between them were resolved after the discussion with the third author (X.T.).
Statistical analysis
Review Manager (Revman, version 5.3) was used for the data synthesis and analysis. Time-to-event data were pooled as hazard ratio (HR) and 95% confidence interval (CI), including time to first SRE, and time to first-and-subsequent SREs. Dichotomous data was pooled as risk ratio (RR) and 95% CI. Statistical heterogeneity was assessed using the χ 2 test. P < 0.10 or I 2 > 50% indicated significant heterogeneity. A fixed-effect model was used if low statistical heterogeneity was reported; otherwise, a random-effects model was used. P < 0.05 indicated statistically significant difference.
Results
Literature search
We identified 138 articles that could potentially be included in the analysis after search of published literature. A total of 134 articles were excluded for not meeting inclusion criteria after reviewing title, abstract, or full text, resulting in four [ 20 – 23 ] randomized controlled trials. Detailed steps of the literature search are shown in Fig. 1 . Fig. 1 Flow of studies through review
Study characteristics
Four RCTs [ 20 – 23 ] met the inclusion criteria, comparing the efficacy and safety of denosumab with ZA in advanced cancer with bone metastasis. Sample sizes of the four studies ranged from 1578 to 2033. Overall, 7201 patients were enrolled in these studies, including 3605 in the denosumab group and 3596 in the ZA group. Baseline characteristics of the four studies are provided in Table 1 . Table 1 Baseline characteristics of the studies included Study Cancer type Interventions Follow-up (mon) N (denosumab/ZA) Primary endpoint Stopeck et al. (2010) [ 22 ] Breast cancer Denosumab 120 mg SC versus ZA 4 mg IV 33 1026/1020 Time to first SRE Fizazi et al. (2011) [ 21 ] Prostate cancer Denosumab 120 mg SC versus ZA 4 mg IV 40.5 943/945 Time to first SRE Henry et al. (2014) [ 23 ] Various solid tumors Denosumab 120 mg SC versus ZA 4 mg IV 34 800/797 Time to first SRE Raje et al. (2018) [ 20 ] Multiple myeloma Denosumab 120 mg SC versus ZA 4 mg IV 50 859/859 Time to first SRE
Table 1
Baseline characteristics of the studies included
| Study | Cancer type | Interventions | Follow-up (mon) | N (denosumab/ZA) | Primary endpoint |
| Stopeck et al. (2010) [ 22 ] | Breast cancer | Denosumab 120 mg SC versus ZA 4 mg IV | 33 | 1026/1020 | Time to first SRE |
| Fizazi et al. (2011) [ 21 ] | Prostate cancer | Denosumab 120 mg SC versus ZA 4 mg IV | 40.5 | 943/945 | Time to first SRE |
| Henry et al. (2014) [ 23 ] | Various solid tumors | Denosumab 120 mg SC versus ZA 4 mg IV | 34 | 800/797 | Time to first SRE |
| Raje et al. (2018) [ 20 ] | Multiple myeloma | Denosumab 120 mg SC versus ZA 4 mg IV | 50 | 859/859 | Time to first SRE |
Quality assessment
All the included four RCTs were phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer. Quality of the included studies was evaluated using the Cochrane assessment tool. The assessment of various items revealed a low risk of bias among the included four studies (Fig. 2 ). Fig. 2 Quality assessment of the 4 randomized controlled trials included
Assessing efficacy
All the four studies presented information about time to first and first-and-subsequent SREs, overall survival improvement, and time to disease progression. In the study by Henry et al. [ 23 ], the median time to first on-study SRE was 21.4 and 15.4 months in patients receiving denosumab (n = 800) and ZA (n = 797) respectively (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68–0.96; P = 0.017). In the study by Fizazi et al. [ 21 ], the median time to first on-study SRE was 20.7 and 17.1 months in patients receiving denosumab (n = 950) and ZA (n = 951) respectively (HR 0.82; 95% CI 0.71-0.95; P = 0.0002). In the study by Raje et al. [ 20 ], the median time to first on-study SRE was 22.8 and 24.0 months in patients receiving denosumab (n = 859) and ZA (n = 859) respectively (HR 0.98; 95% CI 0.85-1.14; P = 0.010). The pooled result showed that denosumab was significantly superior to ZA in delaying time to first SRE (HR 0.86; 95% CI 0.80–0.93; P < 0.01), and time to first-and-subsequent SREs (risk ratio (RR) 0.87; 95% CI 0.81–0.93; P < 0.01). No significant differences were found between two groups in overall survival (HR 0.96; 95% CI 0.89–1.04; P = 0.33), or time to disease progression (HR 0.98; 95% CI 0.93–1.05; P = 0.61) (Fig. 3 ). Fig. 3 Overall analysis of denosumab versus ZA. Forest plots of time to first SRE ( A ), time to first-and-subsequent SREs ( B ), overall survival ( C ), and time to disease progression ( D )
Excluding multiple myeloma, subgroup analysis was carried out between denosumab and ZA in solid tumors with bone metastasis. Pooled results showed that denosumab was superior to ZA in delaying time to first SRE (HR 0.82; 95% CI 0.75–0.89; P < 0.01) and time to first-and-subsequent SREs (RR 0.81; 95% CI 0.74–0.88; P < 0.01). There were no significant differences between two groups in overall survival (HR 0.97; 95% CI 0.90–1.05; P = 0.45), or time to disease progression (HR 1.01; 95% CI 0.94–1.07; P = 0.86) (Fig. 4 ). Fig. 4 Subgroup analysis of denosumab versus ZA in solid tumors. Forest plots of time to first SRE ( A ), time to first-and-subsequent SREs ( B ), overall survival ( C ), and time to disease progression ( D )
Assessing safety
All the included four studies presented information about overall AE, serious AEs, acute-phase reactions, renal toxicity, ONJ, and hypocalcemia. No significant differences were found in the incidence of AE (RR 0.99; 95% CI 0.99–1.00; P = 0.17), serious AEs (RR 0.98; 95% CI 0.94–1.02; P = 0.32) between denosumab and ZA. Pooled results showed that denosumab was associated with lower incidence of renal toxicity (RR 0.69; 95% CI 0.54–0.87; P < 0.01), and acute phase reaction (RR 0.47; 95% CI 0.38–0.56; P < 0.01). However, denosumab was also associated with higher incidence of hypocalcemia (RR 1.78; 95% CI 1.33–2.38; P < 0.01), and ONJ (RR 1.41; 95% CI 1.01–1.95; P = 0.04). Two studies [ 21 , 22 ] presented information about incidence of new primary malignancy. No significant differences were found between denosumab and ZA (RR 1.53; 95% CI 0.80–2.93; P = 0.20) (Figs. 5 and 6 ). Fig. 5 Overall analysis of denosumab versus ZA. Forest plots of incidence of AE ( A ), serious AEs ( B ), and renal toxicity ( C ) Fig. 6 Overall analysis of denosumab versus ZA. Forest plots of incidence of acute phase reaction ( A ), hypocalcaemia ( B ), ONJ ( C ), and new primary malignancy ( D )
Subgroup analysis between two groups in solid tumors with bone metastasis also showed no significant differences in AE (RR 0.99; 95% CI 0.98–1.00; P = 0.29) or serious AEs (RR 0.98; 95% CI 0.91–1.06; P = 0.58). Denosumab was related to lower incidence of renal toxicity (RR 0.73; 95% CI 0.55–0.97; P = 0.03) and acute phase reaction (RR 0.43; 95% CI 0.37–0.49; P < 0.01), and higher incidence of hypocalcemia (RR 2.05; 95% CI 1.64–2.58; P < 0.01). Unlike the overall analysis, subgroup analysis showed no significant differences in the incidence of ONJ (RR 1.37; 95% CI 0.89–2.11; P = 0.16) (Figs. 7 and 8 ). Fig. 7 Subgroup analysis of denosumab versus ZA in solid tumors. Forest plots of incidence of AE ( A ), serious AEs ( B ), and renal toxicity ( C ) Fig. 8 Subgroup analysis of denosumab versus ZA in solid tumors. Forest plots of incidence of acute phase reaction ( A ), hypocalcaemia ( B ), and ONJ ( C )
Discussion
For years, ZA has been regarded as the standard of care for advanced cancer with bone metastasis to prevent SREs [ 24 , 25 ]. However, SREs continue to occur, albeit at a reduced rate. There are also several limitations and inconveniences for ZA use, including need for intravenous access, monitoring of renal function, need for dose adjustment in patients with renal impairment, and management of acute phase reactions. By contrast, denosumab does not have these limitations, which is given subcutaneously, and not associated with renal toxicity or acute phase reactions [ 26 – 29 ].
In this meta-analysis, four RCTs [ 20 – 23 ] of 7201 patients with high quality were included. All the included four RCTs were phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer. With respect to time to first SRE and time to first-and-subsequent SREs, pooled results showed that denosumab was significantly superior to ZA in delaying time to first SRE and time to first-and-subsequent SREs. This finding was consistent with three RCTs [ 21 – 23 ] except the study by Raje et al. [ 20 ]. In the RCT by Raje et al. [ 20 ] with 1718 multiple myeloma patients, no significant differences were found between denosumab and ZA in time to first SRE or first-and-subsequent SREs. Subgroup analysis was consistent with the overall analysis.
With regard to overall survival and time to disease progression, both overall analysis and subgroup analysis showed no differences between denosumab and ZA. One thing to note is that Raje et al. [ 20 ] reported superiority of denosumab to ZA in delaying time to disease progression, which was different from the other three studies. As multiple myeloma is different from solid tumor, it is important to conduct subgroup analysis.
As to safety assessment in this meta-analysis, both overall analysis and subgroup analysis showed no differences between denosumab and ZA in overall AE or serious AEs. Pooled results showed that denosumab was associated with lower incidence of renal toxicity and acute-phase reactions. Subgroup analysis showed similar results. Pooled results also showed that denosumab was associated with higher incidence of hypocalcemia and ONJ. Interestingly, all the included four studies [ 20 – 23 ] showed no significant difference in the incidence of ONJ, which was inconsistent with the pooled result. And subgroup analysis based on solid tumor showed no difference in the incidence of ONJ. So, further analysis with more studies is needed for the comparison of incidence of ONJ. As reported, ONJ was usually related with previously reported risk factors, such as tooth extraction [ 30 ]. Probably due to its higher antiresorptive potency over ZA, denosumab was associated with higher incidence of hypocalcemia, which was consistent with all the included studies [ 20 – 23 ]. As to the incidence of new primary malignancy, Chen and Pu [ 31 ] reported denosumab was associated with higher incidence, which was inconsistent with the three studies included [ 21 , 32 , 33 ]. However, our meta-analysis showed no significant difference between denosumab and ZA, which was consistent with the two studies included [ 21 , 22 ]. More studies are needed for further analysis.
Based on this systematic review and meta-analysis, denosumab is associated with delayed first and subsequent SREs, lower incidence of renal toxicity, and acute-phase reactions, but higher incidence of hypocalcemia and ONJ. Small number of included studies is the main limitation of this meta-analysis. Further analysis with more studies is needed for the comparison of denosumab and ZA for advanced cancer with bone metastasis.
Abbreviations
Skeletal-related events
Zoledronic acid
Adverse events
Osteonecrosis of the jaw
Hazard ratio
Confidence interval
Risk ratio
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Acknowledgements
Authors are grateful to the authors of the included studies and all the patients included in the studies.
Authors’ contributions
LH.J was responsible for the data collation and primary manuscript generation. LH.J, XH.C, and HN.M were responsible for manuscript editing and contributed to data collection. XS.T contributed to study design. The authors read and approved the final manuscript.
Funding
No funding was provided for this study.
Availability of data and materials
The data and materials contributing to this article may be made available upon request by sending an e-mail to the first author.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Consent for publication was obtained from the participant.
Competing interests
All authors declare no competing interests.
References
1. Coleman RE Clinical features of metastatic bone disease and risk of skeletal morbidity Clin Cancer Res 2006 12 20 Pt 2 6243s 6249s 10.1158/1078-0432.CCR-06-0931 17062708
2. Coleman RE Skeletal complications of malignancy Cancer 1997 80 8 Suppl 1588 1594 10.1002/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G 9362426
3. Oefelein MG Ricchiuti V Conrad W Resnick MI Skeletal fractures negatively correlate with overall survival in men with prostate cancer J Urol 2002 168 3 1005 1007 10.1016/S0022-5347(05)64561-2 12187209
4. Schulman KL Kohles J Economic burden of metastatic bone disease in the U.S Cancer 2007 109 11 2334 2342 10.1002/cncr.22678 17450591
5. Tosi P Diagnosis and treatment of bone disease in multiple myeloma: spotlight on spinal involvement Scientifica. 2013 2013 104546 10.1155/2013/104546 24381787 PMC3870870
6. Weinfurt KP Castel LD Li Y Timbie JW Glendenning GA Schulman KA Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions Med Care 2004 42 2 164 175 10.1097/01.mlr.0000108746.69256.45 14734954
7. Noguchi M Kikuchi H Ishibashi M Noda S Percentage of the positive area of bone metastasis is an independent predictor of disease death in advanced prostate cancer Br J Cancer 2003 88 2 195 201 10.1038/sj.bjc.6600715 12610502 PMC2377050
8. Lipton A Small E Saad F Gleason D Gordon D Smith M Rosen L Ortu Kowalski M Reitsma D Seaman J The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate Cancer Investig 2002 20 Suppl 2 45 54 10.1081/CNV-120014886 12442349
9. Major PP Lipton A Berenson J Hortobagyi G Oral bisphosphonates: a review of clinical use in patients with bone metastases Cancer 2000 88 1 6 14 10.1002/(SICI)1097-0142(20000101)88:1<6::AID-CNCR3>3.0.CO;2-D 10618600
10. Grávalos C Rodríguez C Sabino A Seguí M Virizuela JA Carmona A SEOM Clinical Guideline for bone metastases from solid tumours (2016) Clin Transl Oncol 2016 18 12 1243 1253 10.1007/s12094-016-1590-1 27896639 PMC5138247
11. Terpos E Kleber M Engelhardt M Zweegman S Gay F Kastritis E van de Donk NWCJ Bruno B Sezer O Broijl A Bringhen S Beksac M Larocca A Hajek R Musto P Johnsen HE Morabito F Ludwig H Cavo M Einsele H Sonneveld P Dimopoulos MA Palumbo A on behalf of the European Myeloma Network European Myeloma Network guidelines for the management of multiple myeloma-related complications Haematologica. 2015 100 10 1254 1266 10.3324/haematol.2014.117176 26432383 PMC4591757
12. Smith MR Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence Cancer Treat Rev 2005 31 Suppl 3 19 25 10.1016/j.ctrv.2005.09.004 16229955
13. Chang JT Green L Beitz J Renal failure with the use of zoledronic acid N Engl J Med 2003 349 17 1676 1679 10.1056/NEJM200310233491721 14573746
14. Markowitz GS Fine PL Stack JI Kunis CL Radhakrishnan J Palecki W Park J Nasr SH Hoh S Siegel DS D'Agati VD Toxic acute tubular necrosis following treatment with zoledronate (Zometa) Kidney Int 2003 64 1 281 289 10.1046/j.1523-1755.2003.00071.x 12787420
15. Oh WK Proctor K Nakabayashi M Evan C Tormey LK Daskivich T The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid Cancer 2007 109 6 1090 1096 10.1002/cncr.22504 17311345
16. Lipton A Goessl C Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis Bone. 2011 48 1 96 99 10.1016/j.bone.2010.10.161 20950721
17. Brown JE Coleman RE Denosumab in patients with cancer-a surgical strike against the osteoclast. Nature reviews Clin Oncol 2012 9 2 110 118 10.1038/nrclinonc.2011.197 22231759
18. Body JJ Denosumab for the management of bone disease in patients with solid tumors Expert Rev Anticancer Ther 2012 12 3 307 322 10.1586/era.11.204 22192269
19. Zheng GZ, Chang B, Lin FX, Xie D, Hu QX, Yu GY, et al. Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours. Eur J Cancer Care. 2017;26(6). 10.1111/ecc.12541. 10.1111/ecc.12541 27430483
20. Raje N Terpos E Willenbacher W Shimizu K García-Sanz R Durie B Legieć W Krejčí M Laribi K Zhu L Cheng P Warner D Roodman GD Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study Lancet Oncol 2018 19 3 370 381 10.1016/S1470-2045(18)30072-X 29429912
21. Fizazi K Carducci M Smith M Damião R Brown J Karsh L Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study Lancet 2011 377 9768 813 822 10.1016/S0140-6736(10)62344-6 21353695 PMC3090685
22. Stopeck AT Lipton A Body JJ Steger GG Tonkin K de Boer RH Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study J Clin Oncol 2010 28 35 5132 5139 10.1200/JCO.2010.29.7101 21060033
23. Henry D Vadhan-Raj S Hirsh V von Moos R Hungria V Costa L Woll PJ Scagliotti G Smith G Feng A Jun S Dansey R Yeh H Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors Support Care Cancer 2014 22 3 679 687 10.1007/s00520-013-2022-1 24162260
24. Lee RJ Saylor PJ Smith MR Treatment and prevention of bone complications from prostate cancer Bone. 2011 48 1 88 95 10.1016/j.bone.2010.05.038 20621630 PMC3010497
25. Saad F Gleason DM Murray R Tchekmedyian S Venner P Lacombe L 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 11 879 882 10.1093/jnci/djh141 15173273
26. Smith MR Egerdie B Hernández Toriz N Feldman R Tammela TL Saad F Denosumab in men receiving androgen-deprivation therapy for prostate cancer N Engl J Med 2009 361 8 745 755 10.1056/NEJMoa0809003 19671656 PMC3038121
27. Lipton A Steger GG Figueroa J Alvarado C Solal-Celigny P Body JJ Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases J Clin Oncol 2007 25 28 4431 4437 10.1200/JCO.2007.11.8604 17785705
28. Ellis GK Bone HG Chlebowski R Paul D Spadafora S Smith J Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer J Clin Oncol 2008 26 30 4875 4882 10.1200/JCO.2008.16.3832 18725648
29. Fizazi K Lipton A Mariette X Body JJ Rahim Y Gralow JR Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates J Clin Oncol 2009 27 10 1564 1571 10.1200/JCO.2008.19.2146 19237632
30. Walter C Al-Nawas B Grötz KA Thomas C Thüroff JW Zinser V Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate Eur Urol 2008 54 5 1066 1072 10.1016/j.eururo.2008.06.070 18602738
31. Chen F Pu F Safety of denosumab versus zoledronic acid in patients with bone metastases: a meta-analysis of randomized controlled trials Oncol Res Treat 2016 39 7-8 453 459 10.1159/000447372 27487236
32. Lipton A Fizazi K Stopeck AT Henry DH Brown JE Yardley DA Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials Eur J Cancer 2012 48 16 3082 3092 10.1016/j.ejca.2012.08.002 22975218
33. Henry DH Costa L Goldwasser F Hirsh V Hungria V Prausova J Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma J Clin Oncol 2011 29 9 1125 1132 10.1200/JCO.2010.31.3304 21343556