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Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and treatment options

Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and... Background: We surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This multicenter retrospective observational study included 135 patients. Histological subtype, characteristics of bone metastases, treatment, skeletal related events (SREs) and disease outcome were recorded. Results: The most represented histological subtypes were leiomyosarcoma (27%) angiosarcoma (13%) and undifferentiated sarcoma (8%). Axial skeleton was the most common site for bone involvement (70%). In 27% of cases, bone metastases were present at the time of diagnosis. Fifty-four (40%) patients developed SREs and the median time to first SRE was 4 months (range 1–9). The most common SRE was the need for radiotherapy (28%) followed by pathological fracture (22%). Median survival after bone progression was 6 months (range 1–14). SREs were associated with decreased overall survival (OS) (P = 0.04). A subgroup analysis revealed that bisphosphonates significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002) while they did not determine an improvement in OS, although a favourable trend was identified (median: 7 versus 5 months; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of bisphosphonates in this setting. Keywords: Bone metastases, Soft tissue sarcoma, Skeletal related events, Biphosphonate Introduction lungs, and those arising from the abdominal cavity, usu- Soft tissue sarcomas (STS) are a group of rare and hetero- ally metastasizing to liver and peritoneum. geneous cancers, accounting for less than 1% of all human Even if no extensive data are currently available on the tumors. Their biological behavior is characterized by local skeletal involvement in STS patients, the daily clinical prac- aggressiveness and tendency to hematogenous spreading. tice suggests that the development of bone metastases and Almost 50% of STS patients develop metastatic disease the subsequent occurrence of skeletal related events (SREs) [1], mainly within three years from initial diagnosis. The (namely pathological fracture, hypercalcaemia, spinal cord distribution of metastases from STS varies, depending on compression, need for surgery or palliative radiotherapy the primary site and histological subtype. For example, for refractory pain) [2] can be part of the natural history those arising from the extremities mainly spread to the of this disease, can significantly modified a patient’sper- formance status and deeply affect quality of life. Further- more, the role of bisphosphonates therapy, known to be * Correspondence: a.frezza@unicampus.it 1 effective in preventing or delaying SREs and in relieving Department of Medical Oncology, Universita’ Campus Bio-Medico, Rome, from bone pain in different human tumors [3,4], has never Italy Department of Oncology, London Sarcoma Service, University College been assessed in STS patients. Hospital, London, UK Full list of author information is available at the end of the article © 2013 Vincenzi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 2 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 The aim of this retrospective multicenter observational analysis. A P value of less than .05 indicated statistical study was to better define the natural history of skeletal significance. metastases from STS, to investigate their possible prog- nostic value and to explore different treatment options Results which might guide future practice. Patient population Among the enrolled 135 patients 53% were male (71/135). The median age was 52 years (range 23 to 86). All patients Patients and methods were affected by a histologically proven sarcoma of the Patient population soft tissue and all the diagnoses were centrally reviewed by Almost 1250 patients affected by metastatic soft tissue a pathologist with expertise in this field. Leiomyosarcoma sarcoma have been screened. Among these, 135 patients was diagnosed in 27% (36/135) of the patients while with radiologically (plain films, CT scan, MRI scan) proven 14% (19/135) were affected by undifferentiated pleo- bone metastases from STS have been selected and retro- morphic sarcoma, 13% (17/135) by angiosarcoma, 7% spectively included in the present analysis. All patients (10/135) by liposarcoma, 7% (9/135) by malignant epithe- were diagnosed and treated between 1999 and 2011 at lioid hemangioendothelioma, 6% (8/135) by malignant University College Hospital (London Sarcoma Service), peripheral nerve sheet tumor (MPNST), 5% (7/135) by University Campus Bio-Medico (Rome), Ospedale Santa synovial sarcoma and 21% (29/135) by other different Chiara (Pisa), Policlinico P. Giaccone (Palemo), Istituto histological subtypes. The histological grade was G1 in 4% Oncologico Veneto (Padova), Universita’ Politecnica delle (6/135) of patients, G2 (28/135) in 21% of patients, and Marche (Ancona), and Ospedale Giovanni XXIII (Bari). G3 in 75% (101/135). The primary site of the disease was limbs or limb girdles in 50% (67/135) of patients, body Data collection cavity in 33% (45/135) and trunk in 17% (23/135). Patient The following clinical data have been retrospectively col- characteristics are summarized in Table 1. lected: age, gender, primary histological subtype (classified according to 2002 World Health Organization classifica- Natural history of bone metastases from soft tion of the tumors [5]), grade (according to the French tissue sarcoma federation of Cancer Centre Sarcoma Group [6]), primary In 27% (36/135) of cases, bone metastases were present at site, presence of bone metastases at the time of diagnosis, the time of diagnosis. Less than 5 bone metastases were number (equal or less than 5, more than 5) and site of detected in 60% (81/135) of patients while more than 5 bone metastases, treatments received for bone lesions were present in the remaining 40% (54/135). Among the (chemotherapy, zoledronic acid, palliative radiotherapy or analyzed patients, the spine was involved in 51% (69/135) surgery), presence of SREs, time to first SREs and survival of cases, being the most common skeletal site; hip/pelvis from the time of skeletal disease diagnosis. The clinical was involved in 20% (27/135) of patients, long bones in data were both manually and electronically extracted. The 15% (20/135) and other sites 14% (19/135). A SRE devel- completeness of the series of each centre was based on oped in 40% (54/135) of patients and median time to first the contribution of each author. The study has been SRE was 4 months (range: 1–9). The most common SRE conducted in compliance with the Helsinki Declaration was the need for radiotherapy occurring in 28% (38/135) and has been approved by the ethic committee at Univer- of patients followed by pathologic fracture (22%, 30/135), sity Campus Bio-Medico. need for surgery (21%, 29/135), cord compression (13%, 18/135) and hypercalcaemia occurring only in 3% (4/135) Statistical analysis of patients. These results are summarized in Table 2. In the univariate model all the clinical variables were evaluated as predictors for shorter time to bone metasta- Prognostic value of bone metastases and treatment sis, higher risk of skeletal morbidity (SREs), and shorter options time from SREs to death. Patients who did not have a Patients survived for a median of 6 months after diagnosis recorded date for a specific event were censored after of bone metastases (range: 1–14). The number of bone the date of last follow-up. All survival intervals were de- metastases did not significantly correlate with survival in termined by the Kaplan-Meier product-limit method [7] STS patients (P = 0.63), while both the occurrence of SREs while differences in survival according to clinical pa- and an early time to first SRE were associated with a de- rameters or treatment were evaluated by the log-rank creased overall survival (OS) (P = 0.04 and P = 0.002). test [8] and described by the Kaplan-Meier method. The Among the enrolled patients, 72% (97/135) received last follow-up for patients included in the analysis was chemotherapy. The median number of treatment lines November 2011 and the event was death. SPSS software was 2 (range: 0–4) and the most wildly used drugs in- (version 17.00, SPSS, Chicago) was used for statistical cluded doxorubicin, ifosfamide, gemcitabine, docetaxel Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 3 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 Table 1 Patient characteristics Table 2 Natural history of bone metastases from soft tissue sarcoma Characteristic N patients (%) N patients (%) Median age (years) 52 (range: 23–86) Bone metastases onset Gender � Time of diagosis 36 (27) � Male 71 (53) � After diagnosis 99 (73) � Female 64 (47) Number of bone metastases Histology � ≤ 5 81 (60) � Leiomyosarcoma 36 (27) � > 5 54 (40) � Undifferentiated pleomorphic sarcoma 19 (14) Bone metastases site � Angiosarcoma 17 (13) � Spine 69 (51) � Liposarcoma 10 (7) � Hip/pelvis 27 (20) � Malignant epithelioid hemangioendothelioma 9 (7) � Long bones 20 (15) � MPNST 8 (6) � Others 19 (14) � Synovial sarcoma 7 (5) SRE development � Others 29 (21) � Yes 54 (40) Tumour grade � No 81 (60) � G1 6 (4) � Median time to first SRE (months) 4 (range: 1–9) � G2 21 (28) SRE type � G3 101 (75) � Palliative radiotherapy 28 (38) Primary site � Pathological fracture 30 (22) � Limbs or limb girdles 67 (50) � Cord compression 18 (13) � Body cavity 45 (33) � Hypercalcaemia 4 (3) � Trunk 23 (17) � Palliative surgery 29 (21) and paclitaxel. Only 60% (81/135) were started on bisphosphonates at the time of bone metastasis diagnosis. the histological subtypes. From previous smaller reports Radiotherapy was given to 31% (42/135) of the patients, [10,11], angiosarcoma, dedifferentiated liposarcoma and 21% (29/135) were treated with surgery and 2% (3/135) alveolar soft part sarcoma showed the higher incidence of with other local approaches. On the contrary, 39% (52/ skeletal metastases with a percentage of bone involvement 135) did not receive any specific treatment. These results of almost 50%. The axial skeleton is the most common were summarized in Table 3. A subgroup analysis re- site of localization while the involvement of long bones is vealed that bisphosphonates significantly prolonged me- rarer and usually limited to diaphyses. Radiologically, dian time to first SRE (5 versus 2 months; P = 0.002). bone metastases from STS are described as lytic in more Conversely, bisphosphonate therapy did not determine an than 80% of cases [12] and the detection of a pathological improvement in terms of OS, even if a favorable trend fracture by radiography is not an uncommon finding. was identified for treated patients (median, 7 versus 5 Although our dataset confirmed the variability in bone months, respectively; P = 0.105). These results are sum- metastases incidence among different subtypes of sarcoma, marized in Table 4. leiomyosarcoma, undifferentiated pleomorphic sarcoma and angiosarcoma were the most common histotypes Discussion associated with bone involvement. As expected, high The skeleton is the third most frequent site of metasta- Table 3 Treatment options for bone metastases from soft ses from solid tumors and the vast majority of bone me- tissue sarcoma tastases affect patients with primary breast, lung or Treatment N patients (%) prostate cancer. However, the development of metastatic � Biphosphonates 81 (60) bone disease and the occurrence of SREs can complicate several different malignancies, causing a worsening of � Radiotherapy 42 (31) patient’s quality of life and requiring a complex manage- � Surgery 29 (21) ment which significantly impact on health resources [9]. � Other 3 (2) Among patients affected by STSs, bone metastases � No specific treatment 52 (39) occur in almost 10%, with a great variability depending on Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 4 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 Table 4 Impact of bisphosphonate therapy on overall delay demonstrated in the time to the first SRE, the use of survival and time to first skeletal related events bisphosphonates in this setting should be considered. Bisphosphonate No bisphosphonate P value Further studies are warranted which aim to corrobor- ate these results and to properly explore the impact of Median overall 7 5 0.105 survival (months) bisphosphonates therapy on survival of STS patients. Median time to first 5 2 0.002 SRE (months) Abbreviations STS: Soft tissue sarcoma; SREs: Skeletal related events; MPNST: Malignant peripheral nerve sheet tumor; OS: Overall survival. histological grade and a primary tumor arising from limbs Competing interests The authors have no competing interests to declare. or limb girdles were both found to be risk factors for the development of bone metastases. Concordantly with pre- Authors’ contributions vious findings, the axial skeleton was involved in 70% of BV, GT, DS, AMF conceived the study and the design. AMF, GB, GGB, SZ, RB, the enrolled patients while long bones only in 15%. More- MT, RT and FB carried out data collection and BV performed statistical over, for the first time in the present study, the rate of analysis. AMF, GS, FS, APD, MS, PD, DD and JW helped to draft the manuscript. All authors read and approved the final manuscript. SREs was assessed and they have been found to occur in 40% of the included patients. The most common Acknowledgements SREs were represented by the need for radiotherapy, Anyone who contributed in the article was included among the authors. The mainly in the context of pain management, and patho- study did not require any fundings. logical fractures. Interestingly, as already known for breast Author details [13] and prostate [14] cancer patients, the occurrence of Department of Medical Oncology, Universita’ Campus Bio-Medico, Rome, 2 3 SREs, especially within six months from the diagnosis of Italy. Breast Unit, Royal Marsden Hospital, London, UK. Department of Oncology, London Sarcoma Service, University College Hospital, London, UK. bone metastases, strongly correlates with a decreased OS 4 5 Department of Medicine, Universita’ di Verona, Verona, Italy. Department of (P = 0.002). Medical Oncology, Policlinico P. Giaccone, Palemo, Italy. Department of Despite these results, which clearly describe the extent Medical Oncology, Ospedale Santa Chiara, Pisa, Italy. Department of Medical Oncology, Istituto Oncologico Veneto, Padova, Italy. Department of Medical of this problem and its relevance in terms of prognosis Oncology, Universita’ Politecnica delle Marche, Ancona, Italy. Department of and quality of life, there are currently no clear guidelines Biomedical Sciences and Medical Oncology, University of Bari ‘Aldo Moro’, regarding the management of bone metastases from Bari, Italy. Department of Pathology, Royal National Orthopaedic Hospital, London, UK. Department of Medical Oncology, Daniel den Hoed Cancer STS. This issue is confirmed by the extreme heterogen- Center, Erasmus University Medical Center, Rotterdam, The Netherlands. eity of treatment approaches observed in this population. Department of Pathology, General Hospital, Treviso, Italy. Radiotherapy was used in almost one third of the pa- Received: 1 January 2013 Accepted: 8 April 2013 tients in our dataset, mainly to improve pain control or Published: 17 April 2013 to reduce the risk of a pathological fracture, while the use of surgery was limited to 21% of the cases. References It is interesting to underline that 60% of the patients were 1. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, Leahy started on bisphosphonates at thetimeof bonemetastasis M, Van Coevorden F, Verweij J, Hogendoorn PC, Ouali M, Marreaud S, Bramwell VH, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group diagnosis, including pamidronate or zoledronic acid. The and the NCIC Clinical Trials Group Sarcoma Disease Site Committee: selection criteria for administration of bisphosphonates Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim are not clear but are mainly dependent on institutional for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012, 13(10):1045–1054. practice. The results from the present analysis show how 2. Clemons M, Gelmon KA, Pritchard KI, Paterson AH: Bone-targeted agents the use of bisphosphonates in patients with bone metasta- and skeletal-related events in breast cancer patients with bone ses from STS significantly delays the first SRE (P = 0.002) metastases: the state of the art. Curr Oncol 2012, 19(5):259–268. 3. Pavlakis N, Schmidt RL, Stockler MR: Bisphosphonates for breast cancer. and seems to be associated with a favorable trend in terms Cochrane Database Syst Rev 2005(3):CD003474. doi:10.1002/14651858. of survival, although the statistical significance was not CD003474.pub2. reached (P = 0.105) in this cohort. 4. Yuen KK, Shelley M, Sze WM, Wilt TJ, Mason M: Bisphosphonates for advanced prostate cancer. Cochrane Database Syst Rev 2006(4):CD006250. doi:10.1002/14651858.CD006250. 5. Fletcher CD: The evolving classification of soft tissue tumours: an update Conclusions based on the new WHO classification. Histopathology 2006, 48(1):3–12. 6. Guillou L, Coindre JM, Bonichon F, Nguyen BB, Terrier P, Collin F, Vilain MO, On the basis of the present study, the need for a Mandard AM, Le Doussal V, Leroux A, Jacquemier J, Duplay H, Sastre-Garau standardization of bone metastases treatment in STS X, Costa J: Comparative study of the National Cancer Institute and patients is recommended in order to improve quality French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol of life and perhaps impact on survival. 1997, 15(1):350–362. Although the value of our results is limited by the retro- 7. Kaplan E, Meier P: Nonparametric estimation from incomplete spective nature of the study we believe that, given the observations. J Am Stat Assoc 1958, 53:457–481. Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 5 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 8. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Analysis and examples. Br J Cancer 1977, 35:1–39. 9. Decroisette C, Monnet I, Berard H, Quere G, Le Caer H, Bota S, Audigier- Valette C, Geriniere L, Vernejoux JM, Chouaid C, Groupe Français de Pneumo-Cancérologie 0601 Team: Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601). J Thorac Oncol 2011, 6(3):576–582. 10. Yoshikawa H, Myoui A, Ochi T, Araki N, Ueda T, Kudawara I, Nakanishi K, Tanaka H, Nakamura H: Bone Metastases from Soft Tissue Sarcomas. Semin Musculoskelet Radiol 1999, 3(2):183–190. 11. Yoshikawa H, Ueda T, Mori S, Araki N, Kuratsu S, Uchida A, Ochi T: Skeletal metastases from soft-tissue sarcomas. Incidence, patterns, and radiological features. J Bone Joint Surg Br 1997, 79(4):548–552. 12. Wong WS, Kaiser LR, Gold RH, Fon GT: Radiographic features of osseous metastases of soft-tissue sarcomas. Radiology 1982, 143(1):71–74. 13. Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, Blackburn J, Arora T, Brill I, Kilgore ML: Mortality following bone metastasis and skeletal-related events among women with breast cancer: a population- based analysis of U.S. Medicare beneficiaries, 1999–2006. Breast Cancer Res Treat 2012, 131(1):231–238. Epub 2011 Aug 13. 14. Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, Blackburn J, Arora T, Kilgore ML: Mortality following bone metastasis and skeletal- related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 2011, 14(2):177–183. Epub 2011 March 15. doi:10.1186/2045-3329-3-6 Cite this article as: Vincenzi et al.: Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and treatment options. 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Abstract

Background: We surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This multicenter retrospective observational study included 135 patients. Histological subtype, characteristics of bone metastases, treatment, skeletal related events (SREs) and disease outcome were recorded. Results: The most represented histological subtypes were leiomyosarcoma (27%) angiosarcoma (13%) and undifferentiated sarcoma (8%). Axial skeleton was the most common site for bone involvement (70%). In 27% of cases, bone metastases were present at the time of diagnosis. Fifty-four (40%) patients developed SREs and the median time to first SRE was 4 months (range 1–9). The most common SRE was the need for radiotherapy (28%) followed by pathological fracture (22%). Median survival after bone progression was 6 months (range 1–14). SREs were associated with decreased overall survival (OS) (P = 0.04). A subgroup analysis revealed that bisphosphonates significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002) while they did not determine an improvement in OS, although a favourable trend was identified (median: 7 versus 5 months; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of bisphosphonates in this setting. Keywords: Bone metastases, Soft tissue sarcoma, Skeletal related events, Biphosphonate Introduction lungs, and those arising from the abdominal cavity, usu- Soft tissue sarcomas (STS) are a group of rare and hetero- ally metastasizing to liver and peritoneum. geneous cancers, accounting for less than 1% of all human Even if no extensive data are currently available on the tumors. Their biological behavior is characterized by local skeletal involvement in STS patients, the daily clinical prac- aggressiveness and tendency to hematogenous spreading. tice suggests that the development of bone metastases and Almost 50% of STS patients develop metastatic disease the subsequent occurrence of skeletal related events (SREs) [1], mainly within three years from initial diagnosis. The (namely pathological fracture, hypercalcaemia, spinal cord distribution of metastases from STS varies, depending on compression, need for surgery or palliative radiotherapy the primary site and histological subtype. For example, for refractory pain) [2] can be part of the natural history those arising from the extremities mainly spread to the of this disease, can significantly modified a patient’sper- formance status and deeply affect quality of life. Further- more, the role of bisphosphonates therapy, known to be * Correspondence: a.frezza@unicampus.it 1 effective in preventing or delaying SREs and in relieving Department of Medical Oncology, Universita’ Campus Bio-Medico, Rome, from bone pain in different human tumors [3,4], has never Italy Department of Oncology, London Sarcoma Service, University College been assessed in STS patients. Hospital, London, UK Full list of author information is available at the end of the article © 2013 Vincenzi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 2 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 The aim of this retrospective multicenter observational analysis. A P value of less than .05 indicated statistical study was to better define the natural history of skeletal significance. metastases from STS, to investigate their possible prog- nostic value and to explore different treatment options Results which might guide future practice. Patient population Among the enrolled 135 patients 53% were male (71/135). The median age was 52 years (range 23 to 86). All patients Patients and methods were affected by a histologically proven sarcoma of the Patient population soft tissue and all the diagnoses were centrally reviewed by Almost 1250 patients affected by metastatic soft tissue a pathologist with expertise in this field. Leiomyosarcoma sarcoma have been screened. Among these, 135 patients was diagnosed in 27% (36/135) of the patients while with radiologically (plain films, CT scan, MRI scan) proven 14% (19/135) were affected by undifferentiated pleo- bone metastases from STS have been selected and retro- morphic sarcoma, 13% (17/135) by angiosarcoma, 7% spectively included in the present analysis. All patients (10/135) by liposarcoma, 7% (9/135) by malignant epithe- were diagnosed and treated between 1999 and 2011 at lioid hemangioendothelioma, 6% (8/135) by malignant University College Hospital (London Sarcoma Service), peripheral nerve sheet tumor (MPNST), 5% (7/135) by University Campus Bio-Medico (Rome), Ospedale Santa synovial sarcoma and 21% (29/135) by other different Chiara (Pisa), Policlinico P. Giaccone (Palemo), Istituto histological subtypes. The histological grade was G1 in 4% Oncologico Veneto (Padova), Universita’ Politecnica delle (6/135) of patients, G2 (28/135) in 21% of patients, and Marche (Ancona), and Ospedale Giovanni XXIII (Bari). G3 in 75% (101/135). The primary site of the disease was limbs or limb girdles in 50% (67/135) of patients, body Data collection cavity in 33% (45/135) and trunk in 17% (23/135). Patient The following clinical data have been retrospectively col- characteristics are summarized in Table 1. lected: age, gender, primary histological subtype (classified according to 2002 World Health Organization classifica- Natural history of bone metastases from soft tion of the tumors [5]), grade (according to the French tissue sarcoma federation of Cancer Centre Sarcoma Group [6]), primary In 27% (36/135) of cases, bone metastases were present at site, presence of bone metastases at the time of diagnosis, the time of diagnosis. Less than 5 bone metastases were number (equal or less than 5, more than 5) and site of detected in 60% (81/135) of patients while more than 5 bone metastases, treatments received for bone lesions were present in the remaining 40% (54/135). Among the (chemotherapy, zoledronic acid, palliative radiotherapy or analyzed patients, the spine was involved in 51% (69/135) surgery), presence of SREs, time to first SREs and survival of cases, being the most common skeletal site; hip/pelvis from the time of skeletal disease diagnosis. The clinical was involved in 20% (27/135) of patients, long bones in data were both manually and electronically extracted. The 15% (20/135) and other sites 14% (19/135). A SRE devel- completeness of the series of each centre was based on oped in 40% (54/135) of patients and median time to first the contribution of each author. The study has been SRE was 4 months (range: 1–9). The most common SRE conducted in compliance with the Helsinki Declaration was the need for radiotherapy occurring in 28% (38/135) and has been approved by the ethic committee at Univer- of patients followed by pathologic fracture (22%, 30/135), sity Campus Bio-Medico. need for surgery (21%, 29/135), cord compression (13%, 18/135) and hypercalcaemia occurring only in 3% (4/135) Statistical analysis of patients. These results are summarized in Table 2. In the univariate model all the clinical variables were evaluated as predictors for shorter time to bone metasta- Prognostic value of bone metastases and treatment sis, higher risk of skeletal morbidity (SREs), and shorter options time from SREs to death. Patients who did not have a Patients survived for a median of 6 months after diagnosis recorded date for a specific event were censored after of bone metastases (range: 1–14). The number of bone the date of last follow-up. All survival intervals were de- metastases did not significantly correlate with survival in termined by the Kaplan-Meier product-limit method [7] STS patients (P = 0.63), while both the occurrence of SREs while differences in survival according to clinical pa- and an early time to first SRE were associated with a de- rameters or treatment were evaluated by the log-rank creased overall survival (OS) (P = 0.04 and P = 0.002). test [8] and described by the Kaplan-Meier method. The Among the enrolled patients, 72% (97/135) received last follow-up for patients included in the analysis was chemotherapy. The median number of treatment lines November 2011 and the event was death. SPSS software was 2 (range: 0–4) and the most wildly used drugs in- (version 17.00, SPSS, Chicago) was used for statistical cluded doxorubicin, ifosfamide, gemcitabine, docetaxel Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 3 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 Table 1 Patient characteristics Table 2 Natural history of bone metastases from soft tissue sarcoma Characteristic N patients (%) N patients (%) Median age (years) 52 (range: 23–86) Bone metastases onset Gender � Time of diagosis 36 (27) � Male 71 (53) � After diagnosis 99 (73) � Female 64 (47) Number of bone metastases Histology � ≤ 5 81 (60) � Leiomyosarcoma 36 (27) � > 5 54 (40) � Undifferentiated pleomorphic sarcoma 19 (14) Bone metastases site � Angiosarcoma 17 (13) � Spine 69 (51) � Liposarcoma 10 (7) � Hip/pelvis 27 (20) � Malignant epithelioid hemangioendothelioma 9 (7) � Long bones 20 (15) � MPNST 8 (6) � Others 19 (14) � Synovial sarcoma 7 (5) SRE development � Others 29 (21) � Yes 54 (40) Tumour grade � No 81 (60) � G1 6 (4) � Median time to first SRE (months) 4 (range: 1–9) � G2 21 (28) SRE type � G3 101 (75) � Palliative radiotherapy 28 (38) Primary site � Pathological fracture 30 (22) � Limbs or limb girdles 67 (50) � Cord compression 18 (13) � Body cavity 45 (33) � Hypercalcaemia 4 (3) � Trunk 23 (17) � Palliative surgery 29 (21) and paclitaxel. Only 60% (81/135) were started on bisphosphonates at the time of bone metastasis diagnosis. the histological subtypes. From previous smaller reports Radiotherapy was given to 31% (42/135) of the patients, [10,11], angiosarcoma, dedifferentiated liposarcoma and 21% (29/135) were treated with surgery and 2% (3/135) alveolar soft part sarcoma showed the higher incidence of with other local approaches. On the contrary, 39% (52/ skeletal metastases with a percentage of bone involvement 135) did not receive any specific treatment. These results of almost 50%. The axial skeleton is the most common were summarized in Table 3. A subgroup analysis re- site of localization while the involvement of long bones is vealed that bisphosphonates significantly prolonged me- rarer and usually limited to diaphyses. Radiologically, dian time to first SRE (5 versus 2 months; P = 0.002). bone metastases from STS are described as lytic in more Conversely, bisphosphonate therapy did not determine an than 80% of cases [12] and the detection of a pathological improvement in terms of OS, even if a favorable trend fracture by radiography is not an uncommon finding. was identified for treated patients (median, 7 versus 5 Although our dataset confirmed the variability in bone months, respectively; P = 0.105). These results are sum- metastases incidence among different subtypes of sarcoma, marized in Table 4. leiomyosarcoma, undifferentiated pleomorphic sarcoma and angiosarcoma were the most common histotypes Discussion associated with bone involvement. As expected, high The skeleton is the third most frequent site of metasta- Table 3 Treatment options for bone metastases from soft ses from solid tumors and the vast majority of bone me- tissue sarcoma tastases affect patients with primary breast, lung or Treatment N patients (%) prostate cancer. However, the development of metastatic � Biphosphonates 81 (60) bone disease and the occurrence of SREs can complicate several different malignancies, causing a worsening of � Radiotherapy 42 (31) patient’s quality of life and requiring a complex manage- � Surgery 29 (21) ment which significantly impact on health resources [9]. � Other 3 (2) Among patients affected by STSs, bone metastases � No specific treatment 52 (39) occur in almost 10%, with a great variability depending on Vincenzi et al. Clinical Sarcoma Research 2013, 3:6 Page 4 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/6 Table 4 Impact of bisphosphonate therapy on overall delay demonstrated in the time to the first SRE, the use of survival and time to first skeletal related events bisphosphonates in this setting should be considered. Bisphosphonate No bisphosphonate P value Further studies are warranted which aim to corrobor- ate these results and to properly explore the impact of Median overall 7 5 0.105 survival (months) bisphosphonates therapy on survival of STS patients. Median time to first 5 2 0.002 SRE (months) Abbreviations STS: Soft tissue sarcoma; SREs: Skeletal related events; MPNST: Malignant peripheral nerve sheet tumor; OS: Overall survival. histological grade and a primary tumor arising from limbs Competing interests The authors have no competing interests to declare. or limb girdles were both found to be risk factors for the development of bone metastases. Concordantly with pre- Authors’ contributions vious findings, the axial skeleton was involved in 70% of BV, GT, DS, AMF conceived the study and the design. AMF, GB, GGB, SZ, RB, the enrolled patients while long bones only in 15%. More- MT, RT and FB carried out data collection and BV performed statistical over, for the first time in the present study, the rate of analysis. AMF, GS, FS, APD, MS, PD, DD and JW helped to draft the manuscript. All authors read and approved the final manuscript. SREs was assessed and they have been found to occur in 40% of the included patients. The most common Acknowledgements SREs were represented by the need for radiotherapy, Anyone who contributed in the article was included among the authors. The mainly in the context of pain management, and patho- study did not require any fundings. logical fractures. Interestingly, as already known for breast Author details [13] and prostate [14] cancer patients, the occurrence of Department of Medical Oncology, Universita’ Campus Bio-Medico, Rome, 2 3 SREs, especially within six months from the diagnosis of Italy. Breast Unit, Royal Marsden Hospital, London, UK. Department of Oncology, London Sarcoma Service, University College Hospital, London, UK. bone metastases, strongly correlates with a decreased OS 4 5 Department of Medicine, Universita’ di Verona, Verona, Italy. Department of (P = 0.002). Medical Oncology, Policlinico P. Giaccone, Palemo, Italy. Department of Despite these results, which clearly describe the extent Medical Oncology, Ospedale Santa Chiara, Pisa, Italy. Department of Medical Oncology, Istituto Oncologico Veneto, Padova, Italy. Department of Medical of this problem and its relevance in terms of prognosis Oncology, Universita’ Politecnica delle Marche, Ancona, Italy. Department of and quality of life, there are currently no clear guidelines Biomedical Sciences and Medical Oncology, University of Bari ‘Aldo Moro’, regarding the management of bone metastases from Bari, Italy. Department of Pathology, Royal National Orthopaedic Hospital, London, UK. Department of Medical Oncology, Daniel den Hoed Cancer STS. This issue is confirmed by the extreme heterogen- Center, Erasmus University Medical Center, Rotterdam, The Netherlands. eity of treatment approaches observed in this population. Department of Pathology, General Hospital, Treviso, Italy. Radiotherapy was used in almost one third of the pa- Received: 1 January 2013 Accepted: 8 April 2013 tients in our dataset, mainly to improve pain control or Published: 17 April 2013 to reduce the risk of a pathological fracture, while the use of surgery was limited to 21% of the cases. References It is interesting to underline that 60% of the patients were 1. 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Wong WS, Kaiser LR, Gold RH, Fon GT: Radiographic features of osseous metastases of soft-tissue sarcomas. Radiology 1982, 143(1):71–74. 13. Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, Blackburn J, Arora T, Brill I, Kilgore ML: Mortality following bone metastasis and skeletal-related events among women with breast cancer: a population- based analysis of U.S. Medicare beneficiaries, 1999–2006. Breast Cancer Res Treat 2012, 131(1):231–238. Epub 2011 Aug 13. 14. Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V, Blackburn J, Arora T, Kilgore ML: Mortality following bone metastasis and skeletal- related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 2011, 14(2):177–183. Epub 2011 March 15. doi:10.1186/2045-3329-3-6 Cite this article as: Vincenzi et al.: Bone metastases in soft tissue sarcoma: a survey of natural history, prognostic value and treatment options. 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Clinical Sarcoma ResearchSpringer Journals

Published: Apr 17, 2013

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