EURURO-5611; No. of Pages 2 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer Janet E. Brown a,*, Steven L. Wood b a
Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Sheffield, UK; b Cancer Research UK Manchester Institute, The University
of Manchester, Withington, Manchester, UK
In the last decade, an improved understanding of the molecular mechanisms underlying renal cell carcinoma (RCC) has resulted in the development of targeted therapies revolutionising the treatment of advanced or metastatic RCC (mRCC), leading to improved overall survival (OS). These therapies include tyrosine kinase inhibitors (TKIs) such as sunitinib and pazopanib (targeting vascular endothelial growth factor) and mammalian target of rapamycin (mTOR) inhibitors (targeting the mTOR pathway). Approximately a third of patients with mRCC present with or develop bone metastasis (BM), an aggressive lytic process causing substantial morbidity through the development of skeletal complications, sometimes termed skeletal-related events (SREs). These SREs occur in a high proportion of mRCC patients with BM and include radiotherapy for bone pain, surgery to bone, pathologic fractures, and spinal cord/nerve root compression. Hypercalcaemia secondary to BM may also be included. This definition of SREs, in terms of the type of events included, is very widely accepted [1]. The distribution of SRE types in mRCC is broadly similar to that in other cancers giving rise to lytic BMs (irradiation to bone being a very frequent SRE), except that spinal cord/nerve root compression appears to be more common in mRCC [2]. Several recent studies have highlighted the importance of BM in RCC management [3]. The retrospective study reported by Woodward et al. [2] showed that OS of mRCC patients with BM after the occurrence of a first SRE is highly dependent on the type of that SRE, as demonstrated in Figure 1. Hypercalcaemia and spinal cord/nerve root compression carry a poor prognosis, radiotherapy to bone carries an intermediate prognosis, and patients with surgery to bone
and fracture as first SRE have the best prognosis. Although this study was carried out largely before the era of targeted therapy, it showed that prognosis is poor once BM is confirmed, except in patients who had bone-only metastases throughout the course of their disease, in whom OS was significantly better. A small study on RCC patients with BM treated between 2009 and 2011 showed a significant association between high levels of bone biomarkers and OS [4]. Notably, the very recent large study (n = 1970) published in European Urology [5] that related only to patients receiving targeted therapy confirmed that the presence of bone and liver metastases has a negative impact on survival in patients with clear cell histology and good performance status. Although survival of mRCC patients following the onset of BM is not yet comparable with that for breast and prostate cancer patients (often several years), we may expect that management of BM in mRCC patients will become an increasingly significant component of clinical practice. The paper by McKay and colleagues in this issue of European Urology [6] is a further welcome contribution to this increased focus. Although it is not the first clinical database to evaluate the impact of BM and bisphosphonates in mRCC patients, as implied by the authors (eg, see references 1, 2, and 5), the database in the paper is the largest to date (n = 2749) and includes a population treated by modern targeted agents. In the absence of prospective studies, this database is potentially one of the most powerful tools to address increasingly important questions and establish hypotheses for testing prospectively. The principal finding—that the presence of BMs in patients was associated with shorter OS compared with patients without BMs (13.2
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.02.040. * Corresponding author. Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Witham Road, Sheffield S10 2SJ, UK. Tel. +44 114 2265235; Fax: +44 114 2265364. E-mail address: j.e.brown@sheffield.ac.uk (J.E. Brown). http://dx.doi.org/10.1016/j.eururo.2014.03.042 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Brown JE, Wood SL. Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.042
EURURO-5611; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Cumulative % Surviving
100 FRACTURE: N = 53 HYPERCALC: N = 31 SCC+NERVE ROOT: N = 67
80
RT: N = 198 SURGERY: N = 72
60 40
χ24 = 26.18 P < .001
20
2
4
6
8
10
Time (Years) Fig. 1 – Survival after occurrence of skeletal-related event (SRE) by type of SRE, using the first example of that type of SRE only. (The curve shows survival from first use of radiotherapy, first fracture, and so on.) Hypercalc = hypercalcaemia; RT = radiotherapy; SCC = spinal cord compression. Reproduced with permission from Elsevier [2].
vs 20.2 mo; p < 0.0001) and shorter progression-free survival (5.1 vs 6.7 mo; p < 0.0008)—confirms earlier studies [2] in this larger population but, it is important to note, applies to a population receiving modern targeted therapy. This is a substantial and important addition to knowledge in this field. The reported rate of SREs is lower than in previously reported studies and, as the authors point out, may reflect the improved efficacy of modern targeted therapies. However, this idea cannot be proven because the authors have defined SREs as including only pathologic fractures and spinal cord compression and have not included irradiation or surgery to bone, which account for a high proportion of the SREs in RCC patients with BM [1,2]. The suggestion in this paper that bisphosphonate users with BM did not have a decreased rate of SREs compared with nonusers cannot be justified because major SRE components are not included in the analysis. Data on these missing SREs should be available, as irradiation and surgery to bone would be expected to be recorded in the relevant trials. It would be extremely valuable if the complete SRE analyses could be performed. This study has other limitations. Bisphosphonates are often started in patients after the occurrence of an SRE, and it is well established that a first SRE is a very strong predictor for further SREs [7]. This situation is likely to significantly bias the analysis against bisphosphonate benefit (the authors do not give prior SRE details for the bisphosphonate and nonbisphosphonate groups). The data include only patients with clear cell histology (approximately 80% of RCCs) and with good performance status; they do not include patients with bone-only metastases, who often have better survival. The targeted agent studies to date have not been prospectively designed to capture response in bone with sequential bone imaging and assessment of bone pain. Phase 3 studies of bisphosphonates and denosumab that have included RCC patients [1,8,9] do not have these limitations and show significant benefit from the use of anti–bone-resorptive agents in reducing SREs. What these studies do not show, however, is the potential benefit of the targeted agents themselves in reducing bone tumour burden.
McKay et al. [6] correctly point out the problem of osteonecrosis of the jaw (ONJ) with anti–bone-resorptive agents used in association with TKIs, although there is no indication from their data whether ONJ occurrence was formally validated by dental experts against standard criteria or what severity of ONJ was experienced. ONJ remains an issue, although it is now often more manageable and preventable with appropriate advice [10]. It is also not clear whether the hypocalcaemia mentioned was biochemical only and asymptomatic or was symptomatic and requiring treatment. In other bisphosphonate studies, the benefits of reducing hypercalcaemia outweigh any problems of hypocalcaemia. It is entirely plausible from mechanistic considerations that targeted agents themselves may reduce bone tumour burden, and this presumably is the rationale that stimulated the work of McKay et al. Their paper bringing further attention to this important area is welcomed as further support for the need for prospective measurement of response in bone and appropriate patient stratification in future randomised trials of targeted agents. Conflicts of interest: Janet E. Brown has served on advisory boards for Bayer, GlaxoSmithKline, Amgen, Novartis, and Bristol-Myers Squibb.
References [1] Lipton A, Zhen M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962–9. [2] Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cell cancer patients with bone metastases. Bone 2011;48:160–6. [3] Wood SL, Brown JE. Skeletal metastasis in renal cell carcinoma: current and future management options. Cancer Treat Rev 2012; 38:284–91. [4] Alcaraz A, Gonza´lez-Lo´pez R, Morote J, et al. Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: the TUGAMO study. Br J Cancer 2013;109: 121–30. [5] McKay R, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014;65:577–84. [6] McKay RR, Lin X, Perkins JJ, et al. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2014.02.040. [7] Brown JE, Cook RJ, Lipton A, et al. Prognostic factors for skeletal complications from metastatic bone disease in breast cancer. Breast Cancer Res Treat 2010;123:767–79. [8] Henry DH, Costa L, Goldwasser F, et al. 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;29:1125–32. [9] Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumours: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–7. [10] Ripamonti CI, Maniezzo M, Campat T, et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates: the experience of the National Cancer Institute of Milan. Ann Oncol 2009;20:137–45.
Please cite this article in press as: Brown JE, Wood SL. Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.042
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer Janet E. Brown a,*, Steven L. Wood b a
Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Sheffield, UK; b Cancer Research UK Manchester Institute, The University
of Manchester, Withington, Manchester, UK
In the last decade, an improved understanding of the molecular mechanisms underlying renal cell carcinoma (RCC) has resulted in the development of targeted therapies revolutionising the treatment of advanced or metastatic RCC (mRCC), leading to improved overall survival (OS). These therapies include tyrosine kinase inhibitors (TKIs) such as sunitinib and pazopanib (targeting vascular endothelial growth factor) and mammalian target of rapamycin (mTOR) inhibitors (targeting the mTOR pathway). Approximately a third of patients with mRCC present with or develop bone metastasis (BM), an aggressive lytic process causing substantial morbidity through the development of skeletal complications, sometimes termed skeletal-related events (SREs). These SREs occur in a high proportion of mRCC patients with BM and include radiotherapy for bone pain, surgery to bone, pathologic fractures, and spinal cord/nerve root compression. Hypercalcaemia secondary to BM may also be included. This definition of SREs, in terms of the type of events included, is very widely accepted [1]. The distribution of SRE types in mRCC is broadly similar to that in other cancers giving rise to lytic BMs (irradiation to bone being a very frequent SRE), except that spinal cord/nerve root compression appears to be more common in mRCC [2]. Several recent studies have highlighted the importance of BM in RCC management [3]. The retrospective study reported by Woodward et al. [2] showed that OS of mRCC patients with BM after the occurrence of a first SRE is highly dependent on the type of that SRE, as demonstrated in Figure 1. Hypercalcaemia and spinal cord/nerve root compression carry a poor prognosis, radiotherapy to bone carries an intermediate prognosis, and patients with surgery to bone
and fracture as first SRE have the best prognosis. Although this study was carried out largely before the era of targeted therapy, it showed that prognosis is poor once BM is confirmed, except in patients who had bone-only metastases throughout the course of their disease, in whom OS was significantly better. A small study on RCC patients with BM treated between 2009 and 2011 showed a significant association between high levels of bone biomarkers and OS [4]. Notably, the very recent large study (n = 1970) published in European Urology [5] that related only to patients receiving targeted therapy confirmed that the presence of bone and liver metastases has a negative impact on survival in patients with clear cell histology and good performance status. Although survival of mRCC patients following the onset of BM is not yet comparable with that for breast and prostate cancer patients (often several years), we may expect that management of BM in mRCC patients will become an increasingly significant component of clinical practice. The paper by McKay and colleagues in this issue of European Urology [6] is a further welcome contribution to this increased focus. Although it is not the first clinical database to evaluate the impact of BM and bisphosphonates in mRCC patients, as implied by the authors (eg, see references 1, 2, and 5), the database in the paper is the largest to date (n = 2749) and includes a population treated by modern targeted agents. In the absence of prospective studies, this database is potentially one of the most powerful tools to address increasingly important questions and establish hypotheses for testing prospectively. The principal finding—that the presence of BMs in patients was associated with shorter OS compared with patients without BMs (13.2
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.02.040. * Corresponding author. Academic Unit of Clinical Oncology, University of Sheffield, Weston Park Hospital, Witham Road, Sheffield S10 2SJ, UK. Tel. +44 114 2265235; Fax: +44 114 2265364. E-mail address: j.e.brown@sheffield.ac.uk (J.E. Brown). http://dx.doi.org/10.1016/j.eururo.2014.03.042 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Brown JE, Wood SL. Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.042
EURURO-5611; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Cumulative % Surviving
100 FRACTURE: N = 53 HYPERCALC: N = 31 SCC+NERVE ROOT: N = 67
80
RT: N = 198 SURGERY: N = 72
60 40
χ24 = 26.18 P < .001
20
2
4
6
8
10
Time (Years) Fig. 1 – Survival after occurrence of skeletal-related event (SRE) by type of SRE, using the first example of that type of SRE only. (The curve shows survival from first use of radiotherapy, first fracture, and so on.) Hypercalc = hypercalcaemia; RT = radiotherapy; SCC = spinal cord compression. Reproduced with permission from Elsevier [2].
vs 20.2 mo; p < 0.0001) and shorter progression-free survival (5.1 vs 6.7 mo; p < 0.0008)—confirms earlier studies [2] in this larger population but, it is important to note, applies to a population receiving modern targeted therapy. This is a substantial and important addition to knowledge in this field. The reported rate of SREs is lower than in previously reported studies and, as the authors point out, may reflect the improved efficacy of modern targeted therapies. However, this idea cannot be proven because the authors have defined SREs as including only pathologic fractures and spinal cord compression and have not included irradiation or surgery to bone, which account for a high proportion of the SREs in RCC patients with BM [1,2]. The suggestion in this paper that bisphosphonate users with BM did not have a decreased rate of SREs compared with nonusers cannot be justified because major SRE components are not included in the analysis. Data on these missing SREs should be available, as irradiation and surgery to bone would be expected to be recorded in the relevant trials. It would be extremely valuable if the complete SRE analyses could be performed. This study has other limitations. Bisphosphonates are often started in patients after the occurrence of an SRE, and it is well established that a first SRE is a very strong predictor for further SREs [7]. This situation is likely to significantly bias the analysis against bisphosphonate benefit (the authors do not give prior SRE details for the bisphosphonate and nonbisphosphonate groups). The data include only patients with clear cell histology (approximately 80% of RCCs) and with good performance status; they do not include patients with bone-only metastases, who often have better survival. The targeted agent studies to date have not been prospectively designed to capture response in bone with sequential bone imaging and assessment of bone pain. Phase 3 studies of bisphosphonates and denosumab that have included RCC patients [1,8,9] do not have these limitations and show significant benefit from the use of anti–bone-resorptive agents in reducing SREs. What these studies do not show, however, is the potential benefit of the targeted agents themselves in reducing bone tumour burden.
McKay et al. [6] correctly point out the problem of osteonecrosis of the jaw (ONJ) with anti–bone-resorptive agents used in association with TKIs, although there is no indication from their data whether ONJ occurrence was formally validated by dental experts against standard criteria or what severity of ONJ was experienced. ONJ remains an issue, although it is now often more manageable and preventable with appropriate advice [10]. It is also not clear whether the hypocalcaemia mentioned was biochemical only and asymptomatic or was symptomatic and requiring treatment. In other bisphosphonate studies, the benefits of reducing hypercalcaemia outweigh any problems of hypocalcaemia. It is entirely plausible from mechanistic considerations that targeted agents themselves may reduce bone tumour burden, and this presumably is the rationale that stimulated the work of McKay et al. Their paper bringing further attention to this important area is welcomed as further support for the need for prospective measurement of response in bone and appropriate patient stratification in future randomised trials of targeted agents. Conflicts of interest: Janet E. Brown has served on advisory boards for Bayer, GlaxoSmithKline, Amgen, Novartis, and Bristol-Myers Squibb.
References [1] Lipton A, Zhen M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962–9. [2] Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cell cancer patients with bone metastases. Bone 2011;48:160–6. [3] Wood SL, Brown JE. Skeletal metastasis in renal cell carcinoma: current and future management options. Cancer Treat Rev 2012; 38:284–91. [4] Alcaraz A, Gonza´lez-Lo´pez R, Morote J, et al. Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: the TUGAMO study. Br J Cancer 2013;109: 121–30. [5] McKay R, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014;65:577–84. [6] McKay RR, Lin X, Perkins JJ, et al. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2014.02.040. [7] Brown JE, Cook RJ, Lipton A, et al. Prognostic factors for skeletal complications from metastatic bone disease in breast cancer. Breast Cancer Res Treat 2010;123:767–79. [8] Henry DH, Costa L, Goldwasser F, et al. 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;29:1125–32. [9] Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumours: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–7. [10] Ripamonti CI, Maniezzo M, Campat T, et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates: the experience of the National Cancer Institute of Milan. Ann Oncol 2009;20:137–45.
Please cite this article in press as: Brown JE, Wood SL. Assessment of the Impact of Targeted Therapy on Metastatic Bone Disease in Renal Cancer. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.042
