Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of bone between 2000 and 2013

Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of... Background: The majority of patients with chondrosarcoma of bone have an excellent overall survival after local therapy. However, in case of unresectable locally advanced or metastatic disease the outcome is poor and limited treatment options exist. Therefore we conducted a survey of clinical phase I or II trials and retrospective studies that described systemic therapy for chondrosarcoma patients. Materials and methods: Using PubMed, clinicaltrials.gov, the Cochrane controlled trial register and American Society of Clinical Oncology (ASCO) abstracts a literature survey was conducted. From the identified items, data were collected by a systematic analysis. We limited our search to semi-recent studies published between 2000 and 2013 to include modern drugs, imaging techniques and disease evaluations. Results: A total of 31 studies were found which met the criteria: 9 phase I trials, 11 phase II and 8 retrospective studies. In these studies 855 chondrosarcoma patients were reported. The tested drugs were mostly non-cytotoxic, either alone or in combination with another non-cytotoxic agent or chemotherapy. Currently two phase I trials, one phase IB/II trial and three phase II trials are enrolling chondrosarcoma patients. Conclusion: Because chondrosarcoma of bone is an orphan disease it is difficult to conduct clinical trials. The meagre outcome data for locally advanced or metastatic patients indicate that new treatment options are needed. For the phase I trials it is difficult to draw conclusions because of the low numbers of chondrosarcoma patients enrolled, and at different dose levels. Some phase II trials show promising results which support further research. Retrospective studies are encouraged as they could add to the limited data available. Efforts to increase the number of studies for this orphan disease are urgently needed. Keywords: Chondrosarcoma, Systemic treatment, Clinical trial Background features including clear cell, mesenchymal and dediffer- Chondrosarcoma (CS) is the second most common pri- entiated CS [3]. The prognosis for patients with CS is mary bone sarcoma in humans, but with an estimated very diverse with a very good prognosis for atypical car- incidence of 0.2 in 100.000 patients per year it is still a tilaginous tumour/CS grade I which are slow growing very rare disease [1]. CS mostly affects adults between and do not metastasize and a poor prognosis for grade the age of 20 and 60 [2]. CS belong to a very diverse III CS which have a high risk, up to 70%, for local recur- group of tumors having in common the production of rence and metastasis [4,5]. Currently the most com- cartilaginous matrix. Almost 90% of the CS are of the monly used treatment option for atypical cartilaginous conventional subtype, but there are also the more rare tumour/CS grade I is curettage with local adjuvants subtypes with their own distinct histological and clinical which is usually enough to cure the patient. However, for grade II and grade III CS en bloc resection is re- quired. If a patient has unresectable or metastasized dis- * Correspondence: a.j.gelderblom@lumc.nl 1 ease the current treatment options are very limited. CS Department of Clinical Oncology, Leiden University Medical Centre, has always been considered to be chemotherapy and Albinusdreef 2, 2333 ZA Leiden, The Netherlands Full list of author information is available at the end of the article © 2014 van Maldegem 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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 2 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 radiotherapy resistant and it was assumed that patients the search method for clinical trials included in this ana- would not benefit from non-surgical treatment. However, lysis. Figure 2 shows a timetable with the number and new preclinical work and retrospective studies show that type of clinical trials that met our criteria and their time there may be a place for non-cytotoxic, chemo- and radio- of publication showing an increasing number of publica- therapy in the treatment of CS [6,7]. In the last decades tions from 2004 onwards. The data from the trials that more knowledge has become available about the molecu- were included in this study are shown in Table 1 for the lar background of the different CS subtypes (for review phase I trials, Table 2 for phase II trials and Table 3 for see [8-10]). Investigators have been trying to find new sys- the results of the retrospective studies. In the clinical tri- temic treatment options for these patients through phase I als that were identified a total of 1927 patients were in- and II clinical trials (no phase III studies were ever con- cluded of which 855 are patients with CS. Histological ducted). Because CS is such a rare disease, and high grade subtypes included were conventional, dedifferentiated metastatic or unresectable disease is even more uncom- and mesenchymal. The actual number of patients with mon, the number of patients in these trials is however low CS may be higher because in some of the phase I trials and thereby it is difficult to give a clear answer to the only the CS patients who had an objective response or question whether a new drug improves outcome or not. stable disease were reported but more may have been Here we report an overview of a survey we conducted on enrolled. The drugs that were being tested were mostly published and presented phase I and II clinical trials and non-cytotoxic in the phase I trials, either alone or in retrospective studies on systemic therapy enrolling CS pa- combination with another non-cytotoxic agent or con- tients, published from 2000 until 2013. We also include ventional chemotherapy in the phase II trials. For the the studies that are enrolling patients at this moment. retrospective studies all treatments were conventional chemotherapy based. In the phase I trials of the 13 in- Material and methods cluded CS patients there were no complete response Search strategy (CR), 2 (15%) partial response (PR) and 7 (54%) stable To collect phase I and II and retrospective studies which disease (SD). For the phase II trials 156 CS patients were included CS patients we used the search machines enrolled with 2 (1.3%) CR, 2 (1.3%) PR and 21 (13.4%) PubMed, clinicaltrials.gov, the Cochrane controlled trial SD. The results on the clinicaltrials.gov website for register and American Society of Clinical Oncology current trials are shown in Table 4. Two phase I trials, (ASCO) abstracts. For the search criteria we used the one phase IB/II trial and three phase II trials were found. terms [chondrosarcoma] AND [phase I OR phase II OR There are no phase III trials that are currently or were retrospective] AND [clinical trial]. To check for missed ever recruiting CS patients. articles we widened the search to [sarcoma] AND [phase I OR phase II] AND [clinical trial] and compared the re- Discussion sults. When multiple reports from the same trial were CS is a primary bone cancer that in most patients can published we only used the article with the longest fol- be cured by local treatment alone. When tumors are low up time. Publications were used if they 1) described unresectable, either because of locally advanced or meta- results from an early phase clinical trial in which CS pa- static disease, systemic treatment options are very lim- tients were included, either prospective or retrospective, ited due to the current view that non-surgical treatment 2) were written in English. The latest search was per- options have no benefit. Currently for advanced CS pa- formed in December 2013. Studies on extraskeletal myx- tients the outcome is poor with an overall survival of oid CS were excluded. less than two years [5,40,41]. Data were collected from trials published between The general insensitivity to chemotherapy in CS may be 2000 and 2013 to include modern drugs, imaging tech- due to activation of anti-apoptotic and pro-survival path- niques and disease evaluations. Data extraction was done ways and therefore future treatment of advanced CS pa- by one of the authors (A.v.M) and a systemic analysis tients could benefit from targeted agents that specifically was applied that is normally used for meta-analysis [11]. interfere with these pathways, rendering the tumours From all reports author name, year of publication, num- more sensitive to the conventional chemotherapeutic ber of patients, intervention and outcome data were agents [8,9,40]. For instance, the anti-apoptotic proteins noted. Bcl-2 and Bcl-XL are highly expressed in all CS subtypes and the BH-3 mimetic ABT-737 renders CS cell lines sen- Results sitive to the conventional chemotherapeutic agents doxo- From 2000 until 2013 a total of 31 phase I, II or retro- rubicin and cisplatin [10,40]. Survivin, a member of the spective clinical trials were reported that enrolled 1 or inhibitor of apoptosis protein family, is expressed in CS more CS patients: 11 phase I, 11 phase II and 8 retro- samples and RNA interference targeted on survivin results spective studies. Figure 1 shows a flow-chart indicating in cell cycle arrest and increased apoptotic rates in CS cell van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 3 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 106 potential relevant reports identified after initial search 62 PubMed 35 Clinicaltrials.gov 4 Cochrane library 5 ASCO abstracts 70 Reports excluded on the basis of abstract, title or no results published 36 Reports retrieved in full text 6 Reports excluded on the basisof full text search 30 Reports included in the analysis Figure 1 Flow-chart showing the search method to identify the relevant clinical reports for our analysis. lines [42]. However, despite promising results in vitro, Two recent retrospective studies as well as animal some novel approaches never make it to a clinical trial. studies suggested that a subgroup of the patients may An example of this is the combination treatment of the benefit from non-cytotoxic agents, chemotherapy, radio- Bcl-2 inhibitor ABT-737 and doxorubicin. Drug compan- therapy or a combination [6,7,41]. In systemic treatment, ies were not interested to supply drug for a clinical trial so being either a doxorubicin-containing chemotherapy regi- it remains unclear if this combination is beneficial to pa- men or non-cytotoxic drugs as imatinib and sirolimus, sig- tient outcome. nificantly improved survival compared to no treatment in Figure 2 Overview of the number of clinical trials included in the analysis according to the year of publication with phase I trials in blue, phase II trials in red and the retrospective trials in green. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 4 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 1 Phase I trials included in the analysis showing the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome Author Year No of patients Intervention Outcome for CS patients Serrone et al. [12] 2001 44 advanced sarcoma (2 CS) Group A: IFOS short infusion + EPI Not mentioned Group B: IFOS continuous infusion + EPI Schwartz et al. [13] 2005 38 advanced solid tumors with 6 sarcoma LY293111 (Leucotriene-B4 receptor 1SD with at least 1 CS antagonist) Levine et al. [14] 2006 51 advanced malignancies with 7 sarcoma Veglin (VEGF antisense oligodeoxynucleotide) 1 SD with at least 1 CS Lockhart et al. [15] 2007 18 advanced malignancies (1 CS) MAC-321 (analogue of docetaxel) 1 SD Chawla et al. [16] 2009 20 advanced sarcoma (1 CS) Rexin-G (tumor-targeted retrovector) Not mentioned Group A: 2 times a week Group B: 3 times a week Camidge et al. [17] 2010 50 advanced malignancies with 11 sarcoma PRO95780 (death receptor 5 antibody) 1 SD with at least 1 CS Herbst et al. [18] 2010 71 advanced malignancies with 9 sarcoma rhApo2L/TRAIL (death receptor activator) 2 PR with at least 2 CS Cohort 1: dose escalation Cohort 2: treated at MTD Olmos et al. [19] 2010 29 advanced sarcoma (1 CS) Figitumumab (IGF1R antibody) 1 SD Qeuk et al. [20] 2010 21 advanced solid tumors (1 CS) Everolimus (mTOR inhibitor) and figitumumab 1SD (IGF1R antibody) Stroppa et al. [21] 2010 8 advanced sarcoma (1 CS) Doxorubicin + IFOS Not mentioned Pacey et al. [22] 2011 25 advanced solid tumors with at least 1 CS Alvespimycin (heat shock protein 90 inhibitor) 1 SD CS chondrosarcoma, EPI epirubicin, IFOS ifosfamide, PR partial response, SD stable disease. Table 2 Phase II trials included in the analysis with the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome Author Year No of patients Intervention Outcome for CS patients Merimsky et al. [23] 2000 18 advanced sarcoma (3 CS) Gemcitabine 2 SD Skubitz et al. [24] 2003 47 advanced sarcoma (1 CS) Pegylated-liposomal doxorubicin Not mentioned Nooij et al. [25] 2005 37 bone sarcoma (16 CS) Doxorubicin + cisplatin 2 CR Group A: operable, non-metastatic (4 CS) 3 SD Group B: inoperable, metastatic (12 CS) Maki et al. [26] 2009 145 advanced sarcoma (2 CS) Sorafenib (multi-tyrosine kinase inhibitor) Not mentioned Pacey et al. [27] 2009 26 advanced sarcoma (2 CS) Sorafenib(multi-tyrosine kinase inhibitor) 1 SD Grignani et al. [28] 2011 26 advanced chondrosarcoma Imatinib mesylate (c-kit/PDGFR inhibitor) 8 SD OS 11 months Fox et al. [29] 2012 53 advanced sarcoma (25 CS) Gemcitabine + docetaxel 2 PR Italiano et al. [30] 2012 40 advanced CS GDC-0449/vismodegib (hedgehog inhibitor) 4 SD (of first 17 patients) Schuetze et al. [31] 2012 49 advanced sarcoma (2 CS) Sirolimus (mTOR inhibitor) + cyclophosphamide 1 SD Ha et al. [32] 2013 36 advanced sarcoma Cetuximab (EGFR antibody) PD Group A: EGFR+ Group B: EGFR- (1 CS) Schwartz et al. [33] 2013 388 advanced sarcoma Cixutumumab (IGF1R antibody) + temsirolimus Not mentioned (mTOR-inhibitor) Group A: IGF-1R + soft tissue sarcoma Group B: IGF-1R + bone sarcoma (20 CS) Group C: IGF-1R- sarcoma (18 CS) CR complete response, CS chondrosarcoma, OS overall survival, PD progressive disease, PFS progression free survival, PR partial response, SD stable disease. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 5 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 3 Retrospective trials included in the analysis showing the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome First author Year of No of patients Intervention and number of patients Outcome of systemic therapy publication Mitchell [34] 2000 22 resectable dediff CS Doxorubicin based chemotherapy + 1/5 > 90% necrosis after preoperative surgery chemo 5 preoperative chemotherapy and 6 5 year OS with chemotherapy 36%, postoperative, 11 no chemotherapy without 0% Dickey [35] 2004 42 local or advanced 15 Surgery 5 year OS and median OS: with surgery dediff CS 11.8% and 6.4 months 22 surgery and chemotherapy 5 other With surgery and chemotherapy 4% and 8.4 months Staals [36] 2006 102 local or advanced 68 Surgery Median survival 18 vs 23 months dediff central CS (not significant) 25 surgery + chemotherapy 9 palliative care Cesari [7] 2007 24 local or advanced 24 surgery of which: 10 year OS: mesenchymal CS 5 + RT Surgical remission 27% 12 + chemotherapy Non-surgical remission 0% Complete surgical remission 10 year DFS: With chemotherapy 76%, without 17% Grimer [37] 2008 266 local and 71 207 Surgery Local disease advanced dediff CS 90 chemotherapy 5 year OS: 40 surgery + chemotherapy With chemotherapy 33%, without 25% (p = 0.11) Advanced disease Median OS: With chemotherapy 7 months, without 3 months (not significant) Dantonello [38] 2008 14 local mesenchymal CS 12 Surgery + chemotherapy 10 year OS 64% 2 surgery + RT Bernstein-Molho [39] 2012 9 advanced CS Sirolimus + cyclophosphamide OR 11% SD 56% PFS 15 months Italiano [5] 2012 98 advanced CS Doxorubicin based chemotherapy OR 14% SD 31% PFS 5.3 months OS 19 months CS chondrosarcoma, Dediff dedifferentiated, DFS disease free survival, OR objective response, OS overall survival, PFS progression free survival, RT radiotherapy, SD stable disease. central CS patients with unresectable disease was shown inhibition in both newly planted as well as established [41]. For patients with only locally advanced disease radio- CS tumours with a mean of 43% [30]. Because of the therapy may be a good therapeutic option with a signifi- strong preclinical results a randomized phase II trial cant survival benefit compared to no treatment. Patients studying the effect of IPI-926 compared to placebo in with mesenchymal or dedifferentiated CS may also benefit metastatic or locally advanced CS patients was con- from systemic treatment [6], and further clinical studies ducted (NCT01310816). The study showed that IPI-926 are warranted looking at specific CS subtypes. is well tolerated but there was no difference in PFS or Recently also new treatment options were tested in OS compared to placebo. However a small subset of pa- clinical trials such as the hedgehog (Hh) inhibitor IPI- tients had minor reductions in tumour size. Another Hh 926. Hedgehog signaling was previously shown to be im- inhibitor that was tested in a phase II trial including ad- portant in CS genesis [43-45]. CS xenograft models were vanced CS patients was GDC-0449, also called vismode- treated with IPI-926 and showed a downregulation of gib (NCT01267955). This study did not meet its primary the Hh pathway in the tumors and a significant growth endpoint, but the results suggested activity of the drug van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 6 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 4 Overview of the trials currently recruiting chondrosarcoma patients, showing the clinicaltrials.gov number, title of the study and the phase Clinicaltrials.gov number Title Phase NCT01522820 Vaccine therapy with or without sirolimus in treating patients with NY-ESO-1 expressing solid tumors I NCT01643278 Dasatinib and ipilimumab in treating patients with gastrointestinal stromal tumors or other sarcomas that I cannot be removed by surgery or are metastatic NCT01154452 Vismodegib and gamma-secretase/notch signalling pathway inhibitor RO4929097 in treating patients with IB/II advanced or metastatic sarcoma NCT01330966 Study of pazopanib in the treatment of surgically unresectable or metastatic chondrosarcoma II NCT00928525 Imatinib in patients with desmoid tumor and chondrosarcoma II NCT01653028 Alisertib in treating patients with advanced or metastatic sarcoma II Not yet assigned A phase 2, single arm, multi center trial evaluating the efficacy of the combination of sirolimus and II cyclophosphamide in metastatic or unresectable myxoid liposarcoma and chondrosarcoma. in a subset of patients with progressive grade 1 or 2 con- in the abstracts are very difficult to find. Some of the ventional CS [46]. Despite the fact that in both studies phase I trials could be found by using the Cochrane Con- only a small subset showed benefit, it is important to do trolled Trial Register or the clinicaltrials.gov database, al- these trials even if the results do not seem promising for though not all trials are registered in these databases. In the whole patient group. By studying the tumor tissue of the phase I trials, with an average of 34 recruited patients, the small subset of responders, we may learn to better only a small number of CS patients were enrolled at vari- understand the mode of action. Moreover, this will en- ous dose levels which make it difficult to conclude on the able the identification of biomarkers to predict which effect of these new treatment options specifically for CS patients do respond to the treatment to improve patient patients. For the phase II trials sarcoma patients were en- selection in future trials. rolled in different strata. Some strata included CS patients According to the clinicaltrials.gov website currently 6 while the studies by Grignani and Italiano were restricted clinical phase I or II trials are enrolling CS patients, in to CS patients only [46,47]. all of these trials non-cytotoxic agents are being tested For the retrospective studies it was difficult to make either alone or in combination. These treatments are definite conclusions on the effect of systemic therapy be- based on preclinical work that has been conducted over cause many different chemotherapy treatment regimens the last years and which shows promising results. An ex- were used in patients with different stages of disease and ample of this is the mTOR pathway. Dysregulation of different CS subtypes. As the biological behavior of the mTOR signaling can be found in many tumor types, subtypes differs much with therefore expected different however in clinical trials inhibitors of mTOR so far show outcomes it is hard to conclude from studies where the only modest results, which may be due to activation of specific subtype is not reported. The study by Cesari the PI3K/Akt pathway. In CS, both mTOR and AKT [48] is very interesting because it shows that mesenchy- were shown to be activated [28,42]. Dual inhibition using mal CS patients who had a complete surgical remission BEZ235 dramatically decreased growth of CS cell lines may benefit from adjuvant chemotherapy with a 10 year and xenografts [28]. The euroSARC consortium, www. disease free survival that improves from 10% without eurosarc.eu, is starting a phase II study in unresectable chemotherapy to 76% with chemotherapy. This is in line conventional, dedifferentiated and mesenchymal CS with with previous studies and the current opinion is that the combination of sirolimus and cyclofosfamide. An ex- mesenchymal CS is a chemotherapy sensitive tumor and that patients therefore benefit from chemotherapy ploratory analysis of the mTOR pathway is foreseen in this study with pharmacokinetic assays on tumour biop- treatment [25,29]. For the other CS subtypes it has sies taken before and after treatment (www.eurosarc.eu). generally been thought that they are insensitive to con- ventional chemotherapy, although for dedifferentiated We conducted a search for all clinical phase I or II tri- als and retrospective studies that included CS patients. CS activity was shown in individual cases and it is still Because we intended to include modern imaging and undefined if chemotherapy treatment is effective [3,12,49]. A retrospective study with 337 dedifferentiated CS study designs the survey was limited to the period from 2000 until 2013. The list of the phase I trials that met patients shows that the prognosis remains dismal, our search criteria is probably not completely reflecting however an improvement of survival, not significant, in patients receiving chemotherapy who are under the actual number of CS patients enrolled in phase I clin- ical trials, which is caused by the search strategy by which 60 years of age and had limb salvage treatment was trials that included CS patients without mentioning them found [13]. Also for conventional CS more evidence is van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 7 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 currently found that systemic treatment does improve sur- Daugaard S, Hogendoorn PC, Bovee JV: Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma vival [41]. reveals Bcl-2 family members and TGFbeta as potential targets. Am J Pathol In conclusion, CS is a difficult patient population to 2013, 182:1347–1356. study in clinical trials. It is a very rare disease and most 10. Hamada C: The role of meta-analysis in cancer clinical trials. Int J Clin Oncol 2009, 14:90–94. patients can be cured by surgery alone, which makes the 11. van Oosterwijk JG, Herpers B, Meijer D, Briaire-de Bruijn IH, Cleton-Jansen AM, group of patients that might need adjuvant or palliative Gelderblom H, van de Water B, Bovee JV: Restoration of chemosensitivity for treatment even smaller. This is also one of the reasons doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol 2012, 23:1617–1626. why it is very difficult to receive funding for these stud- 12. Serrone L, Zeuli M, Papaldo P, Nardoni C, Pacetti U, Cognetti F: Ifosfamide ies. However, from the current poor prognosis of non- and epirubicin combination in untreated sarcomas: two treatment resectable locally advanced or metastatic CS patients it schedules. Onkologie 2001, 24:465–468. 13. Schwartz GK,WeitzmanA,O'ReillyE,Brail L, de AlwisDP, Cleverly A, is very clear that there is an unmet medical need and Barile-Thiem B, Vinciguerra V, Budman DR: Phase I and pharmacokinetic new treatment options are warranted. To improve the study of LY293111, an orally bioavailable LTB4 receptor antagonist, in number of new treatment options for these patients it is patients with advanced solid tumors. JClin Oncol 2005, 23:5365–5373. 14. Levine AM, Tulpule A, Quinn DI, Gorospe G III, Smith DL, Hornor L, Boswell essential to collaborate and share data on research so WD, Espina BM, Groshen SG, Masood R, Gill PS: Phase I study of antisense that future clinical trials have a sound biological ration- oligonucleotide against vascular endothelial growth factor: decrease in ale and can be conducted with as few patients as pos- plasma vascular endothelial growth factor with potential clinical efficacy. J Clin Oncol 2006, 24:1712–1719. sible in a short timeframe. 15. Lockhart AC, Bukowski R, Rothenberg ML, Wang KK, Cooper W, Grover J, Appleman L, Mayer PR, Shapiro M, Zhu AX: Phase I trial of oral MAC-321 in Competing interests subjects with advanced malignant solid tumors. Cancer Chemother The authors declare that they have no competing interests. Pharmacol 2007, 60:203–209. 16. Chawla SP, Chua VS, Fernandez L, Quon D, Saralou A, Blackwelder WC, Hall Authors’ contributions FL, Gordon EM: Phase I/II and phase II studies of targeted gene delivery HG conceived the study. AVM collected data. AVM and HG wrote the paper in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and and JB made comments. All authors read and approved the final manuscript. osteosarcoma. Mol Ther 2009, 17:1651–1657. 17. Camidge DR, Herbst RS, Gordon MS, Eckhardt SG, Kurzrock R, Durbin B, Ing J, Acknowledgement Tohnya TM, Sager J, Ashkenazi A, Bray G, Mendelson D: A phase I safety and The research leading to these results has received funding from the pharmacokinetic study of the death receptor 5 agonistic antibody European Union Seventh Framework Programme (FP7/2007-2013) under PRO95780 in patients with advanced malignancies. Clin Cancer Res 2010, grant agreement n° 278742 (Eurosarc). 16:1256–1263. 18. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O'Dwyer PJ, Gordon MS, Author details Novotny W, Goldwasser MA, Tohnya TM, Lum BL, Ashkenazi A, Jubb AM, Department of Clinical Oncology, Leiden University Medical Centre, Mendelson DS: Phase I dose-escalation study of recombinant human Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Department of Pathology, Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with Leiden University Medical Centre, Leiden, The Netherlands. advanced cancer. J Clin Oncol 2010, 28:2839–2846. 19. Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Received: 10 July 2014 Accepted: 1 August 2014 Batzel GN, Yin D, Pritchard-Jones K, Judson I, Worden FP, Gualberto A, Scurr M, Published: 12 August 2014 de Bono JS, Haluska P: Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma References and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010, 1. Damron TA, Ward WG, Stewart A: Osteosarcoma, chondrosarcoma, and 11:129–135. Ewing's sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res 20. Quek R, Wang Q, Morgan JA, Shapiro GI, Butrynski JE, Ramaiya N, Huftalen T, 2007, 459:40–47. Jederlinic N, Manola J, Wagner AJ, Demetri GD, George S: Combination 2. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab Taminiau AH, Bovee JV: The clinical approach towards chondrosarcoma. in patients with advanced sarcomas and other solid tumors. Clin Cancer Oncologist 2008, 13:320–329. Res 2011, 17:871–879. 3. Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P: Clinical 21. Stroppa E, Bertuzzi A, Di CG, Mussi C, Lutman RF, Barbato A, Santoro A: outcome of central conventional chondrosarcoma. J Surg Oncol 2012, Phase I study of non-pegylated liposomal doxorubicin in combination 106:929–937. with ifosfamide in adult patients with metastatic soft tissue sarcomas. 4. Evans HL, Ayala AG, Romsdahl MM: Prognostic factors in chondrosarcoma Invest New Drugs 2010, 28:834–838. of bone: a clinicopathologic analysis with emphasis on histologic 22. Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, grading. Cancer 1977, 40:818–831. Arkenau HT, Moreno-Farre J, Banerji U,Roels B, PeacheyH,AherneW, 5. Italiano A, Mir O, Cioffi A, Palmerini E, Piperno-Neumann S, Perrin C, de Bono JS,Raynaud F, WorkmanP,JudsonI: A phase I study of the Chaigneau L, Penel N, Duffaud F, Kurtz JE, Collard O, Bertucci F, Bompas E, heat shock protein 90 inhibitor alvespimycin (17-DMAG) given Le Cesne A, Maki RG, Ray Coquard I, Blay JY: Advanced chondrosarcomas: intravenously to patients with advanced solid tumors. Clin Cancer Res role of chemotherapy and survival. Ann Oncol 2013, 24:2916–2922. 2011, 17:1561–1570. 6. Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, 23. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, Blay JY, Dutor A: Inhibition of chondrosarcoma growth by mTOR inhibitor Fenig E, Neuman G, Sapir D, Ariad S, Inbar M: Gemcitabine in soft tissue or in an in vivo syngeneic rat model. PLoS One 2012, 7:e32458. bone sarcoma resistant to standard chemotherapy: a phase II study. 7. Bovee JV, Hogendoorn PC, Wunder JS, Alman BA: Cartilage tumours and Cancer Chemother Pharmacol 2000, 45:177–181. bone development: molecular pathology and possible therapeutic 24. Skubitz KM: Phase II trial of pegylated-liposomal doxorubicin (Doxil) in targets. Nat Rev Cancer 2010, 10:481–488. sarcoma. Cancer Invest 2003, 21:167–176. 8. van Oosterwijk JG, Anninga JK, Gelderblom H, Cleton-Jansen AM, Bovee JV: 25. Nooij MA, Whelan J, Bramwell VH, Taminiau AT, Cannon S, Hogendoorn PC, Update on targets and novel treatment options for high-grade osteosarcoma Pringle J, Uscinska BM, Weeden S, Kirkpatrick A, Glabbeke M, Craft AW: and chondrosarcoma. Hematol Oncol Clin North Am 2013, 27:1021–1048. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell 9. van Oosterwijk JG, Meijer D, van Ruler MA, van den Akker BE, Oosting J, sarcomas of the bone, other than osteosarcoma or malignant fibrous Krenacs T, Picci P, Flanagan AM, Liegl-Atzwanger B, Leithner A, Athanasou N, van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 8 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 histiocytoma: a European Osteosarcoma Intergroup Study. Eur J chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol 2006, Cancer 2005, 41:225–230. 168:321–330. 26. Maki RG, D'Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD, 42. Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, Livingston MB, Cooney MM, Hensley ML, Mita MM, Takimoto CH, Kraft AS, Buhnemann C, Hassan AB, Demitri GD, Bovee JV, Wagner AJ: Functional Elias AD, Brockstein B, Blachère NE, Edgar MA, Schwartz LH, Qin LX, profiling of receptor tyrosine kinases and downstream signaling in Antonescu CR, Schwartz GK: Phase II study of sorafenib in patients with human chondrosarcomas identifies pathways for rational targeted metastatic or recurrent sarcomas. J Clin Oncol 2009, 27:3133–3140. therapy. Clin Cancer Res 2013, 19:3796–3807. 27. Pacey S, Ratain MJ, Flaherty KT, Kaye SB, Cupit L, Rowinsky EK, Xia C, 43. Bovee JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC: Up-regulation O'Dwyer PJ, Judson IR: Efficacy and safety of sorafenib in a subset of of PTHrP and Bcl-2 expression characterizes the progression of patients with advanced soft tissue sarcoma from a Phase II randomized osteochondroma towards peripheral chondrosarcoma and is a late event discontinuation trial. Invest New Drugs 2011, 29:481–488. in central chondrosarcoma. Lab Invest 2000, 80:1925–1934. 28. Grignani G, Palmerini E, Stacchiotti S, Boglione A, Ferraresi V, Frustaci S, 44. Ng JM, Curran T: The Hedgehog's tale: developing strategies for targeting Comandone A, Casali PG, Ferrari S, Aglietta M: A phase 2 trial of imatinib cancer. Nat Rev Cancer 2011, 11:493–501. mesylate in patients with recurrent nonresectable chondrosarcomas 45. Campbell VT, Nadesan P, Ali SA, Wang CY, Whetstone H, Poon R, Wei Q, expressing platelet-derived growth factor receptor-alpha or -beta: An Keilty J, Proctor J, Wang LW, Apte SS, McGovern K, Alman BA, Wunder JS: Italian Sarcoma Group study. Cancer 2011, 117:826–831. Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth. Mol 29. Fox E, Patel S, Wathen JK, Schuetze S, Chawla S, Harmon D, Reinke D, Cancer Ther 2014, 13:1259. Chugh R, Benjamin RS, Helman LJ: Phase II study of sequential 46. Schrage YM, Briaire-de Bruijn IH, de Miranda NF, van Oosterwijk J, Taminiau AH, gemcitabine followed by docetaxel for recurrent Ewing sarcoma, van Wezel T, Hogendoorn PC, Bovee JV: Kinome profiling of chondrosarcoma osteosarcoma, or unresectable or locally recurrent chondrosarcoma: reveals SRC-pathway activity and dasatinib as option for treatment. Cancer results of Sarcoma Alliance for Research Through Collaboration Study Res 2009, 69:6216–6222. 003. Oncologist 2012, 17:321. 47. Cesari M, Bertoni F, Bacchini P, Mercuri M, Palmerini E, Ferrari S: 30. Italiano A, Le CA, Bellera C, Piperno-Neumann S, Duffaud F, Penel N, Cassier P, Mesenchymal chondrosarcoma. An analysis of patients treated at a Domont J, Takebe N, Kind M, Coindre JM, Blay JY, Bui B: GDC-0449 in patients single institution. Tumori 2007, 93:423–427. with advanced chondrosarcomas: a French Sarcoma Group/US and French 48. Huvos AG, Rosen G, Dabska M, Marcove RC: Mesenchymal National Cancer Institute Single-Arm Phase II Collaborative Study. Ann Oncol chondrosarcoma. A clinicopathologic analysis of 35 patients with 2013, 24:2922–2926. emphasis on treatment. Cancer 1983, 51:1230–1237. 31. Schuetze SM, Zhao L, Chugh R, Thomas DG, Lucas DR, Metko G, Zalupski 49. Yokota K, Sakamoto A, Matsumoto Y, Matsuda S, Harimaya K, Oda Y, MM, Baker LH: Results of a phase II study of sirolimus and Iwamoto Y: Clinical outcome for patients with dedifferentiated cyclophosphamide in patients with advanced sarcoma. Eur J Cancer 2012, chondrosarcoma: a report of 9 cases at a single institute. J Orthop Surg 48:1347–1353. Res 2012, 7:38. 32. Ha HT, Griffith KA, Zalupski MM, Schuetze SM, Thomas DG, Lucas DR, Baker LH, Chugh R: Phase II trial of cetuximab in patients with metastatic or doi:10.1186/2045-3329-4-11 locally advanced soft tissue or bone sarcoma. Am J Clin Oncol 2013, Cite this article as: van Maldegem et al.: Comprehensive analysis of 36:77–82. published studies involving systemic treatment for chondrosarcoma of 33. Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, bone between 2000 and 2013. Clinical Sarcoma Research 2014 4:11. Agulnik M, Schuetze SM, Reed DR, Okuno SH, Ludwig JA, Keedy V, Rietschel P, Kraft AS, Adkins D, Van Tine BA, Brockstein B, Yim V, Bitas C, Abdullah A, Antonescu CR, Condy M, Dickson MA, Vasudeva SD, Ho AL, Doyle LA, Chen HX, Maki RG: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 2013, 14:371–382. 34. Mitchell AD, Ayoub K, Mangham DC, Grimer RJ, Carter SR, Tillman RM: Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Joint Surg Br 2000, 82:55–61. 35. Dickey ID, Rose PS, Fuchs B, Wold LE, Okuno SH, Sim FH, Scully SP: Dedifferentiated chondrosarcoma: the role of chemotherapy with updated outcomes. J Bone Joint Surg Am 2004, 86-A:2412–2418. 36. Staals EL, Bacchini P, Bertoni F: Dedifferentiated central chondrosarcoma. Cancer 2006, 106:2682–2691. 37. Grimer RJ, Gosheger G, Taminiau A, Biau D, Matejovsky Z, Kollender Y, San-Julian M, Gherlinzoni F, Ferrari C: Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group. Eur J Cancer 2007, 43:2060–2065. 38. Dantonello TM, Int-Veen C, Leuschner I, Schuck A, Furtwaengler R, Claviez A, Schneider DT, Klingebiel T, Bielack SS, Koscielniak E: Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. Submit your next manuscript to BioMed Central Cancer 2008, 112:2424–2431. and take full advantage of: 39. Bernstein-Molho R, Kollender Y, Issakov J, Bickels J, Dadia S, Flusser G, Meller I, Sagi-Eisenberg R, Merimsky O: Clinical activity of mTOR inhibition in • Convenient online submission combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol 2012, • Thorough peer review 70:855–860. • No space constraints or color figure charges 40. van Maldegem AM, Gelderblom H, Palmerini E, Dijkstra SD, Gambarotti M, • Immediate publication on acceptance Ruggieri P, Nout RA, van de Sande MA, Ferarri C, Ferrari S, Bovee JV, Picci P: Outcome of advanced, unresectable conventional central • Inclusion in PubMed, CAS, Scopus and Google Scholar chondrosarcoma. Cancer 2014. doi:10.1002/cncr.28845. [Epub ahead of • Research which is freely available for redistribution print]. 41. Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Submit your manuscript at Alman BA, Wunder JS: Constitutive hedgehog signaling in www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of bone between 2000 and 2013

Download PDF
8 pages

Loading next page...
 
/lp/springer-journals/comprehensive-analysis-of-published-studies-involving-systemic-hgQb1xMMAG

References (52)

Publisher
Springer Journals
Copyright
Copyright © 2014 by van Maldegem et al.; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
eISSN
2045-3329
DOI
10.1186/2045-3329-4-11
pmid
25126409
Publisher site
See Article on Publisher Site

Abstract

Background: The majority of patients with chondrosarcoma of bone have an excellent overall survival after local therapy. However, in case of unresectable locally advanced or metastatic disease the outcome is poor and limited treatment options exist. Therefore we conducted a survey of clinical phase I or II trials and retrospective studies that described systemic therapy for chondrosarcoma patients. Materials and methods: Using PubMed, clinicaltrials.gov, the Cochrane controlled trial register and American Society of Clinical Oncology (ASCO) abstracts a literature survey was conducted. From the identified items, data were collected by a systematic analysis. We limited our search to semi-recent studies published between 2000 and 2013 to include modern drugs, imaging techniques and disease evaluations. Results: A total of 31 studies were found which met the criteria: 9 phase I trials, 11 phase II and 8 retrospective studies. In these studies 855 chondrosarcoma patients were reported. The tested drugs were mostly non-cytotoxic, either alone or in combination with another non-cytotoxic agent or chemotherapy. Currently two phase I trials, one phase IB/II trial and three phase II trials are enrolling chondrosarcoma patients. Conclusion: Because chondrosarcoma of bone is an orphan disease it is difficult to conduct clinical trials. The meagre outcome data for locally advanced or metastatic patients indicate that new treatment options are needed. For the phase I trials it is difficult to draw conclusions because of the low numbers of chondrosarcoma patients enrolled, and at different dose levels. Some phase II trials show promising results which support further research. Retrospective studies are encouraged as they could add to the limited data available. Efforts to increase the number of studies for this orphan disease are urgently needed. Keywords: Chondrosarcoma, Systemic treatment, Clinical trial Background features including clear cell, mesenchymal and dediffer- Chondrosarcoma (CS) is the second most common pri- entiated CS [3]. The prognosis for patients with CS is mary bone sarcoma in humans, but with an estimated very diverse with a very good prognosis for atypical car- incidence of 0.2 in 100.000 patients per year it is still a tilaginous tumour/CS grade I which are slow growing very rare disease [1]. CS mostly affects adults between and do not metastasize and a poor prognosis for grade the age of 20 and 60 [2]. CS belong to a very diverse III CS which have a high risk, up to 70%, for local recur- group of tumors having in common the production of rence and metastasis [4,5]. Currently the most com- cartilaginous matrix. Almost 90% of the CS are of the monly used treatment option for atypical cartilaginous conventional subtype, but there are also the more rare tumour/CS grade I is curettage with local adjuvants subtypes with their own distinct histological and clinical which is usually enough to cure the patient. However, for grade II and grade III CS en bloc resection is re- quired. If a patient has unresectable or metastasized dis- * Correspondence: a.j.gelderblom@lumc.nl 1 ease the current treatment options are very limited. CS Department of Clinical Oncology, Leiden University Medical Centre, has always been considered to be chemotherapy and Albinusdreef 2, 2333 ZA Leiden, The Netherlands Full list of author information is available at the end of the article © 2014 van Maldegem 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/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 2 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 radiotherapy resistant and it was assumed that patients the search method for clinical trials included in this ana- would not benefit from non-surgical treatment. However, lysis. Figure 2 shows a timetable with the number and new preclinical work and retrospective studies show that type of clinical trials that met our criteria and their time there may be a place for non-cytotoxic, chemo- and radio- of publication showing an increasing number of publica- therapy in the treatment of CS [6,7]. In the last decades tions from 2004 onwards. The data from the trials that more knowledge has become available about the molecu- were included in this study are shown in Table 1 for the lar background of the different CS subtypes (for review phase I trials, Table 2 for phase II trials and Table 3 for see [8-10]). Investigators have been trying to find new sys- the results of the retrospective studies. In the clinical tri- temic treatment options for these patients through phase I als that were identified a total of 1927 patients were in- and II clinical trials (no phase III studies were ever con- cluded of which 855 are patients with CS. Histological ducted). Because CS is such a rare disease, and high grade subtypes included were conventional, dedifferentiated metastatic or unresectable disease is even more uncom- and mesenchymal. The actual number of patients with mon, the number of patients in these trials is however low CS may be higher because in some of the phase I trials and thereby it is difficult to give a clear answer to the only the CS patients who had an objective response or question whether a new drug improves outcome or not. stable disease were reported but more may have been Here we report an overview of a survey we conducted on enrolled. The drugs that were being tested were mostly published and presented phase I and II clinical trials and non-cytotoxic in the phase I trials, either alone or in retrospective studies on systemic therapy enrolling CS pa- combination with another non-cytotoxic agent or con- tients, published from 2000 until 2013. We also include ventional chemotherapy in the phase II trials. For the the studies that are enrolling patients at this moment. retrospective studies all treatments were conventional chemotherapy based. In the phase I trials of the 13 in- Material and methods cluded CS patients there were no complete response Search strategy (CR), 2 (15%) partial response (PR) and 7 (54%) stable To collect phase I and II and retrospective studies which disease (SD). For the phase II trials 156 CS patients were included CS patients we used the search machines enrolled with 2 (1.3%) CR, 2 (1.3%) PR and 21 (13.4%) PubMed, clinicaltrials.gov, the Cochrane controlled trial SD. The results on the clinicaltrials.gov website for register and American Society of Clinical Oncology current trials are shown in Table 4. Two phase I trials, (ASCO) abstracts. For the search criteria we used the one phase IB/II trial and three phase II trials were found. terms [chondrosarcoma] AND [phase I OR phase II OR There are no phase III trials that are currently or were retrospective] AND [clinical trial]. To check for missed ever recruiting CS patients. articles we widened the search to [sarcoma] AND [phase I OR phase II] AND [clinical trial] and compared the re- Discussion sults. When multiple reports from the same trial were CS is a primary bone cancer that in most patients can published we only used the article with the longest fol- be cured by local treatment alone. When tumors are low up time. Publications were used if they 1) described unresectable, either because of locally advanced or meta- results from an early phase clinical trial in which CS pa- static disease, systemic treatment options are very lim- tients were included, either prospective or retrospective, ited due to the current view that non-surgical treatment 2) were written in English. The latest search was per- options have no benefit. Currently for advanced CS pa- formed in December 2013. Studies on extraskeletal myx- tients the outcome is poor with an overall survival of oid CS were excluded. less than two years [5,40,41]. Data were collected from trials published between The general insensitivity to chemotherapy in CS may be 2000 and 2013 to include modern drugs, imaging tech- due to activation of anti-apoptotic and pro-survival path- niques and disease evaluations. Data extraction was done ways and therefore future treatment of advanced CS pa- by one of the authors (A.v.M) and a systemic analysis tients could benefit from targeted agents that specifically was applied that is normally used for meta-analysis [11]. interfere with these pathways, rendering the tumours From all reports author name, year of publication, num- more sensitive to the conventional chemotherapeutic ber of patients, intervention and outcome data were agents [8,9,40]. For instance, the anti-apoptotic proteins noted. Bcl-2 and Bcl-XL are highly expressed in all CS subtypes and the BH-3 mimetic ABT-737 renders CS cell lines sen- Results sitive to the conventional chemotherapeutic agents doxo- From 2000 until 2013 a total of 31 phase I, II or retro- rubicin and cisplatin [10,40]. Survivin, a member of the spective clinical trials were reported that enrolled 1 or inhibitor of apoptosis protein family, is expressed in CS more CS patients: 11 phase I, 11 phase II and 8 retro- samples and RNA interference targeted on survivin results spective studies. Figure 1 shows a flow-chart indicating in cell cycle arrest and increased apoptotic rates in CS cell van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 3 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 106 potential relevant reports identified after initial search 62 PubMed 35 Clinicaltrials.gov 4 Cochrane library 5 ASCO abstracts 70 Reports excluded on the basis of abstract, title or no results published 36 Reports retrieved in full text 6 Reports excluded on the basisof full text search 30 Reports included in the analysis Figure 1 Flow-chart showing the search method to identify the relevant clinical reports for our analysis. lines [42]. However, despite promising results in vitro, Two recent retrospective studies as well as animal some novel approaches never make it to a clinical trial. studies suggested that a subgroup of the patients may An example of this is the combination treatment of the benefit from non-cytotoxic agents, chemotherapy, radio- Bcl-2 inhibitor ABT-737 and doxorubicin. Drug compan- therapy or a combination [6,7,41]. In systemic treatment, ies were not interested to supply drug for a clinical trial so being either a doxorubicin-containing chemotherapy regi- it remains unclear if this combination is beneficial to pa- men or non-cytotoxic drugs as imatinib and sirolimus, sig- tient outcome. nificantly improved survival compared to no treatment in Figure 2 Overview of the number of clinical trials included in the analysis according to the year of publication with phase I trials in blue, phase II trials in red and the retrospective trials in green. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 4 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 1 Phase I trials included in the analysis showing the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome Author Year No of patients Intervention Outcome for CS patients Serrone et al. [12] 2001 44 advanced sarcoma (2 CS) Group A: IFOS short infusion + EPI Not mentioned Group B: IFOS continuous infusion + EPI Schwartz et al. [13] 2005 38 advanced solid tumors with 6 sarcoma LY293111 (Leucotriene-B4 receptor 1SD with at least 1 CS antagonist) Levine et al. [14] 2006 51 advanced malignancies with 7 sarcoma Veglin (VEGF antisense oligodeoxynucleotide) 1 SD with at least 1 CS Lockhart et al. [15] 2007 18 advanced malignancies (1 CS) MAC-321 (analogue of docetaxel) 1 SD Chawla et al. [16] 2009 20 advanced sarcoma (1 CS) Rexin-G (tumor-targeted retrovector) Not mentioned Group A: 2 times a week Group B: 3 times a week Camidge et al. [17] 2010 50 advanced malignancies with 11 sarcoma PRO95780 (death receptor 5 antibody) 1 SD with at least 1 CS Herbst et al. [18] 2010 71 advanced malignancies with 9 sarcoma rhApo2L/TRAIL (death receptor activator) 2 PR with at least 2 CS Cohort 1: dose escalation Cohort 2: treated at MTD Olmos et al. [19] 2010 29 advanced sarcoma (1 CS) Figitumumab (IGF1R antibody) 1 SD Qeuk et al. [20] 2010 21 advanced solid tumors (1 CS) Everolimus (mTOR inhibitor) and figitumumab 1SD (IGF1R antibody) Stroppa et al. [21] 2010 8 advanced sarcoma (1 CS) Doxorubicin + IFOS Not mentioned Pacey et al. [22] 2011 25 advanced solid tumors with at least 1 CS Alvespimycin (heat shock protein 90 inhibitor) 1 SD CS chondrosarcoma, EPI epirubicin, IFOS ifosfamide, PR partial response, SD stable disease. Table 2 Phase II trials included in the analysis with the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome Author Year No of patients Intervention Outcome for CS patients Merimsky et al. [23] 2000 18 advanced sarcoma (3 CS) Gemcitabine 2 SD Skubitz et al. [24] 2003 47 advanced sarcoma (1 CS) Pegylated-liposomal doxorubicin Not mentioned Nooij et al. [25] 2005 37 bone sarcoma (16 CS) Doxorubicin + cisplatin 2 CR Group A: operable, non-metastatic (4 CS) 3 SD Group B: inoperable, metastatic (12 CS) Maki et al. [26] 2009 145 advanced sarcoma (2 CS) Sorafenib (multi-tyrosine kinase inhibitor) Not mentioned Pacey et al. [27] 2009 26 advanced sarcoma (2 CS) Sorafenib(multi-tyrosine kinase inhibitor) 1 SD Grignani et al. [28] 2011 26 advanced chondrosarcoma Imatinib mesylate (c-kit/PDGFR inhibitor) 8 SD OS 11 months Fox et al. [29] 2012 53 advanced sarcoma (25 CS) Gemcitabine + docetaxel 2 PR Italiano et al. [30] 2012 40 advanced CS GDC-0449/vismodegib (hedgehog inhibitor) 4 SD (of first 17 patients) Schuetze et al. [31] 2012 49 advanced sarcoma (2 CS) Sirolimus (mTOR inhibitor) + cyclophosphamide 1 SD Ha et al. [32] 2013 36 advanced sarcoma Cetuximab (EGFR antibody) PD Group A: EGFR+ Group B: EGFR- (1 CS) Schwartz et al. [33] 2013 388 advanced sarcoma Cixutumumab (IGF1R antibody) + temsirolimus Not mentioned (mTOR-inhibitor) Group A: IGF-1R + soft tissue sarcoma Group B: IGF-1R + bone sarcoma (20 CS) Group C: IGF-1R- sarcoma (18 CS) CR complete response, CS chondrosarcoma, OS overall survival, PD progressive disease, PFS progression free survival, PR partial response, SD stable disease. van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 5 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 3 Retrospective trials included in the analysis showing the name of the author, year of publication, number of patients enrolled in the trial, the intervention that was tested and the outcome First author Year of No of patients Intervention and number of patients Outcome of systemic therapy publication Mitchell [34] 2000 22 resectable dediff CS Doxorubicin based chemotherapy + 1/5 > 90% necrosis after preoperative surgery chemo 5 preoperative chemotherapy and 6 5 year OS with chemotherapy 36%, postoperative, 11 no chemotherapy without 0% Dickey [35] 2004 42 local or advanced 15 Surgery 5 year OS and median OS: with surgery dediff CS 11.8% and 6.4 months 22 surgery and chemotherapy 5 other With surgery and chemotherapy 4% and 8.4 months Staals [36] 2006 102 local or advanced 68 Surgery Median survival 18 vs 23 months dediff central CS (not significant) 25 surgery + chemotherapy 9 palliative care Cesari [7] 2007 24 local or advanced 24 surgery of which: 10 year OS: mesenchymal CS 5 + RT Surgical remission 27% 12 + chemotherapy Non-surgical remission 0% Complete surgical remission 10 year DFS: With chemotherapy 76%, without 17% Grimer [37] 2008 266 local and 71 207 Surgery Local disease advanced dediff CS 90 chemotherapy 5 year OS: 40 surgery + chemotherapy With chemotherapy 33%, without 25% (p = 0.11) Advanced disease Median OS: With chemotherapy 7 months, without 3 months (not significant) Dantonello [38] 2008 14 local mesenchymal CS 12 Surgery + chemotherapy 10 year OS 64% 2 surgery + RT Bernstein-Molho [39] 2012 9 advanced CS Sirolimus + cyclophosphamide OR 11% SD 56% PFS 15 months Italiano [5] 2012 98 advanced CS Doxorubicin based chemotherapy OR 14% SD 31% PFS 5.3 months OS 19 months CS chondrosarcoma, Dediff dedifferentiated, DFS disease free survival, OR objective response, OS overall survival, PFS progression free survival, RT radiotherapy, SD stable disease. central CS patients with unresectable disease was shown inhibition in both newly planted as well as established [41]. For patients with only locally advanced disease radio- CS tumours with a mean of 43% [30]. Because of the therapy may be a good therapeutic option with a signifi- strong preclinical results a randomized phase II trial cant survival benefit compared to no treatment. Patients studying the effect of IPI-926 compared to placebo in with mesenchymal or dedifferentiated CS may also benefit metastatic or locally advanced CS patients was con- from systemic treatment [6], and further clinical studies ducted (NCT01310816). The study showed that IPI-926 are warranted looking at specific CS subtypes. is well tolerated but there was no difference in PFS or Recently also new treatment options were tested in OS compared to placebo. However a small subset of pa- clinical trials such as the hedgehog (Hh) inhibitor IPI- tients had minor reductions in tumour size. Another Hh 926. Hedgehog signaling was previously shown to be im- inhibitor that was tested in a phase II trial including ad- portant in CS genesis [43-45]. CS xenograft models were vanced CS patients was GDC-0449, also called vismode- treated with IPI-926 and showed a downregulation of gib (NCT01267955). This study did not meet its primary the Hh pathway in the tumors and a significant growth endpoint, but the results suggested activity of the drug van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 6 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 Table 4 Overview of the trials currently recruiting chondrosarcoma patients, showing the clinicaltrials.gov number, title of the study and the phase Clinicaltrials.gov number Title Phase NCT01522820 Vaccine therapy with or without sirolimus in treating patients with NY-ESO-1 expressing solid tumors I NCT01643278 Dasatinib and ipilimumab in treating patients with gastrointestinal stromal tumors or other sarcomas that I cannot be removed by surgery or are metastatic NCT01154452 Vismodegib and gamma-secretase/notch signalling pathway inhibitor RO4929097 in treating patients with IB/II advanced or metastatic sarcoma NCT01330966 Study of pazopanib in the treatment of surgically unresectable or metastatic chondrosarcoma II NCT00928525 Imatinib in patients with desmoid tumor and chondrosarcoma II NCT01653028 Alisertib in treating patients with advanced or metastatic sarcoma II Not yet assigned A phase 2, single arm, multi center trial evaluating the efficacy of the combination of sirolimus and II cyclophosphamide in metastatic or unresectable myxoid liposarcoma and chondrosarcoma. in a subset of patients with progressive grade 1 or 2 con- in the abstracts are very difficult to find. Some of the ventional CS [46]. Despite the fact that in both studies phase I trials could be found by using the Cochrane Con- only a small subset showed benefit, it is important to do trolled Trial Register or the clinicaltrials.gov database, al- these trials even if the results do not seem promising for though not all trials are registered in these databases. In the whole patient group. By studying the tumor tissue of the phase I trials, with an average of 34 recruited patients, the small subset of responders, we may learn to better only a small number of CS patients were enrolled at vari- understand the mode of action. Moreover, this will en- ous dose levels which make it difficult to conclude on the able the identification of biomarkers to predict which effect of these new treatment options specifically for CS patients do respond to the treatment to improve patient patients. For the phase II trials sarcoma patients were en- selection in future trials. rolled in different strata. Some strata included CS patients According to the clinicaltrials.gov website currently 6 while the studies by Grignani and Italiano were restricted clinical phase I or II trials are enrolling CS patients, in to CS patients only [46,47]. all of these trials non-cytotoxic agents are being tested For the retrospective studies it was difficult to make either alone or in combination. These treatments are definite conclusions on the effect of systemic therapy be- based on preclinical work that has been conducted over cause many different chemotherapy treatment regimens the last years and which shows promising results. An ex- were used in patients with different stages of disease and ample of this is the mTOR pathway. Dysregulation of different CS subtypes. As the biological behavior of the mTOR signaling can be found in many tumor types, subtypes differs much with therefore expected different however in clinical trials inhibitors of mTOR so far show outcomes it is hard to conclude from studies where the only modest results, which may be due to activation of specific subtype is not reported. The study by Cesari the PI3K/Akt pathway. In CS, both mTOR and AKT [48] is very interesting because it shows that mesenchy- were shown to be activated [28,42]. Dual inhibition using mal CS patients who had a complete surgical remission BEZ235 dramatically decreased growth of CS cell lines may benefit from adjuvant chemotherapy with a 10 year and xenografts [28]. The euroSARC consortium, www. disease free survival that improves from 10% without eurosarc.eu, is starting a phase II study in unresectable chemotherapy to 76% with chemotherapy. This is in line conventional, dedifferentiated and mesenchymal CS with with previous studies and the current opinion is that the combination of sirolimus and cyclofosfamide. An ex- mesenchymal CS is a chemotherapy sensitive tumor and that patients therefore benefit from chemotherapy ploratory analysis of the mTOR pathway is foreseen in this study with pharmacokinetic assays on tumour biop- treatment [25,29]. For the other CS subtypes it has sies taken before and after treatment (www.eurosarc.eu). generally been thought that they are insensitive to con- ventional chemotherapy, although for dedifferentiated We conducted a search for all clinical phase I or II tri- als and retrospective studies that included CS patients. CS activity was shown in individual cases and it is still Because we intended to include modern imaging and undefined if chemotherapy treatment is effective [3,12,49]. A retrospective study with 337 dedifferentiated CS study designs the survey was limited to the period from 2000 until 2013. The list of the phase I trials that met patients shows that the prognosis remains dismal, our search criteria is probably not completely reflecting however an improvement of survival, not significant, in patients receiving chemotherapy who are under the actual number of CS patients enrolled in phase I clin- ical trials, which is caused by the search strategy by which 60 years of age and had limb salvage treatment was trials that included CS patients without mentioning them found [13]. Also for conventional CS more evidence is van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 7 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 currently found that systemic treatment does improve sur- Daugaard S, Hogendoorn PC, Bovee JV: Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma vival [41]. reveals Bcl-2 family members and TGFbeta as potential targets. Am J Pathol In conclusion, CS is a difficult patient population to 2013, 182:1347–1356. study in clinical trials. It is a very rare disease and most 10. Hamada C: The role of meta-analysis in cancer clinical trials. Int J Clin Oncol 2009, 14:90–94. patients can be cured by surgery alone, which makes the 11. van Oosterwijk JG, Herpers B, Meijer D, Briaire-de Bruijn IH, Cleton-Jansen AM, group of patients that might need adjuvant or palliative Gelderblom H, van de Water B, Bovee JV: Restoration of chemosensitivity for treatment even smaller. This is also one of the reasons doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol 2012, 23:1617–1626. why it is very difficult to receive funding for these stud- 12. Serrone L, Zeuli M, Papaldo P, Nardoni C, Pacetti U, Cognetti F: Ifosfamide ies. However, from the current poor prognosis of non- and epirubicin combination in untreated sarcomas: two treatment resectable locally advanced or metastatic CS patients it schedules. Onkologie 2001, 24:465–468. 13. Schwartz GK,WeitzmanA,O'ReillyE,Brail L, de AlwisDP, Cleverly A, is very clear that there is an unmet medical need and Barile-Thiem B, Vinciguerra V, Budman DR: Phase I and pharmacokinetic new treatment options are warranted. To improve the study of LY293111, an orally bioavailable LTB4 receptor antagonist, in number of new treatment options for these patients it is patients with advanced solid tumors. JClin Oncol 2005, 23:5365–5373. 14. Levine AM, Tulpule A, Quinn DI, Gorospe G III, Smith DL, Hornor L, Boswell essential to collaborate and share data on research so WD, Espina BM, Groshen SG, Masood R, Gill PS: Phase I study of antisense that future clinical trials have a sound biological ration- oligonucleotide against vascular endothelial growth factor: decrease in ale and can be conducted with as few patients as pos- plasma vascular endothelial growth factor with potential clinical efficacy. J Clin Oncol 2006, 24:1712–1719. sible in a short timeframe. 15. Lockhart AC, Bukowski R, Rothenberg ML, Wang KK, Cooper W, Grover J, Appleman L, Mayer PR, Shapiro M, Zhu AX: Phase I trial of oral MAC-321 in Competing interests subjects with advanced malignant solid tumors. Cancer Chemother The authors declare that they have no competing interests. Pharmacol 2007, 60:203–209. 16. Chawla SP, Chua VS, Fernandez L, Quon D, Saralou A, Blackwelder WC, Hall Authors’ contributions FL, Gordon EM: Phase I/II and phase II studies of targeted gene delivery HG conceived the study. AVM collected data. AVM and HG wrote the paper in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and and JB made comments. All authors read and approved the final manuscript. osteosarcoma. Mol Ther 2009, 17:1651–1657. 17. Camidge DR, Herbst RS, Gordon MS, Eckhardt SG, Kurzrock R, Durbin B, Ing J, Acknowledgement Tohnya TM, Sager J, Ashkenazi A, Bray G, Mendelson D: A phase I safety and The research leading to these results has received funding from the pharmacokinetic study of the death receptor 5 agonistic antibody European Union Seventh Framework Programme (FP7/2007-2013) under PRO95780 in patients with advanced malignancies. Clin Cancer Res 2010, grant agreement n° 278742 (Eurosarc). 16:1256–1263. 18. Herbst RS, Eckhardt SG, Kurzrock R, Ebbinghaus S, O'Dwyer PJ, Gordon MS, Author details Novotny W, Goldwasser MA, Tohnya TM, Lum BL, Ashkenazi A, Jubb AM, Department of Clinical Oncology, Leiden University Medical Centre, Mendelson DS: Phase I dose-escalation study of recombinant human Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Department of Pathology, Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with Leiden University Medical Centre, Leiden, The Netherlands. advanced cancer. J Clin Oncol 2010, 28:2839–2846. 19. Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Received: 10 July 2014 Accepted: 1 August 2014 Batzel GN, Yin D, Pritchard-Jones K, Judson I, Worden FP, Gualberto A, Scurr M, Published: 12 August 2014 de Bono JS, Haluska P: Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma References and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010, 1. Damron TA, Ward WG, Stewart A: Osteosarcoma, chondrosarcoma, and 11:129–135. Ewing's sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res 20. Quek R, Wang Q, Morgan JA, Shapiro GI, Butrynski JE, Ramaiya N, Huftalen T, 2007, 459:40–47. Jederlinic N, Manola J, Wagner AJ, Demetri GD, George S: Combination 2. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab Taminiau AH, Bovee JV: The clinical approach towards chondrosarcoma. in patients with advanced sarcomas and other solid tumors. Clin Cancer Oncologist 2008, 13:320–329. Res 2011, 17:871–879. 3. Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P: Clinical 21. Stroppa E, Bertuzzi A, Di CG, Mussi C, Lutman RF, Barbato A, Santoro A: outcome of central conventional chondrosarcoma. J Surg Oncol 2012, Phase I study of non-pegylated liposomal doxorubicin in combination 106:929–937. with ifosfamide in adult patients with metastatic soft tissue sarcomas. 4. Evans HL, Ayala AG, Romsdahl MM: Prognostic factors in chondrosarcoma Invest New Drugs 2010, 28:834–838. of bone: a clinicopathologic analysis with emphasis on histologic 22. Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, grading. Cancer 1977, 40:818–831. Arkenau HT, Moreno-Farre J, Banerji U,Roels B, PeacheyH,AherneW, 5. Italiano A, Mir O, Cioffi A, Palmerini E, Piperno-Neumann S, Perrin C, de Bono JS,Raynaud F, WorkmanP,JudsonI: A phase I study of the Chaigneau L, Penel N, Duffaud F, Kurtz JE, Collard O, Bertucci F, Bompas E, heat shock protein 90 inhibitor alvespimycin (17-DMAG) given Le Cesne A, Maki RG, Ray Coquard I, Blay JY: Advanced chondrosarcomas: intravenously to patients with advanced solid tumors. Clin Cancer Res role of chemotherapy and survival. Ann Oncol 2013, 24:2916–2922. 2011, 17:1561–1570. 6. Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, 23. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, Blay JY, Dutor A: Inhibition of chondrosarcoma growth by mTOR inhibitor Fenig E, Neuman G, Sapir D, Ariad S, Inbar M: Gemcitabine in soft tissue or in an in vivo syngeneic rat model. PLoS One 2012, 7:e32458. bone sarcoma resistant to standard chemotherapy: a phase II study. 7. Bovee JV, Hogendoorn PC, Wunder JS, Alman BA: Cartilage tumours and Cancer Chemother Pharmacol 2000, 45:177–181. bone development: molecular pathology and possible therapeutic 24. Skubitz KM: Phase II trial of pegylated-liposomal doxorubicin (Doxil) in targets. Nat Rev Cancer 2010, 10:481–488. sarcoma. Cancer Invest 2003, 21:167–176. 8. van Oosterwijk JG, Anninga JK, Gelderblom H, Cleton-Jansen AM, Bovee JV: 25. Nooij MA, Whelan J, Bramwell VH, Taminiau AT, Cannon S, Hogendoorn PC, Update on targets and novel treatment options for high-grade osteosarcoma Pringle J, Uscinska BM, Weeden S, Kirkpatrick A, Glabbeke M, Craft AW: and chondrosarcoma. Hematol Oncol Clin North Am 2013, 27:1021–1048. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell 9. van Oosterwijk JG, Meijer D, van Ruler MA, van den Akker BE, Oosting J, sarcomas of the bone, other than osteosarcoma or malignant fibrous Krenacs T, Picci P, Flanagan AM, Liegl-Atzwanger B, Leithner A, Athanasou N, van Maldegem et al. Clinical Sarcoma Research 2014, 4:11 Page 8 of 8 http://www.clinicalsarcomaresearch.com/content/4/1/11 histiocytoma: a European Osteosarcoma Intergroup Study. Eur J chondrosarcoma up-regulates tumor cell proliferation. Am J Pathol 2006, Cancer 2005, 41:225–230. 168:321–330. 26. Maki RG, D'Adamo DR, Keohan ML, Saulle M, Schuetze SM, Undevia SD, 42. Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, Livingston MB, Cooney MM, Hensley ML, Mita MM, Takimoto CH, Kraft AS, Buhnemann C, Hassan AB, Demitri GD, Bovee JV, Wagner AJ: Functional Elias AD, Brockstein B, Blachère NE, Edgar MA, Schwartz LH, Qin LX, profiling of receptor tyrosine kinases and downstream signaling in Antonescu CR, Schwartz GK: Phase II study of sorafenib in patients with human chondrosarcomas identifies pathways for rational targeted metastatic or recurrent sarcomas. J Clin Oncol 2009, 27:3133–3140. therapy. Clin Cancer Res 2013, 19:3796–3807. 27. Pacey S, Ratain MJ, Flaherty KT, Kaye SB, Cupit L, Rowinsky EK, Xia C, 43. Bovee JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC: Up-regulation O'Dwyer PJ, Judson IR: Efficacy and safety of sorafenib in a subset of of PTHrP and Bcl-2 expression characterizes the progression of patients with advanced soft tissue sarcoma from a Phase II randomized osteochondroma towards peripheral chondrosarcoma and is a late event discontinuation trial. Invest New Drugs 2011, 29:481–488. in central chondrosarcoma. Lab Invest 2000, 80:1925–1934. 28. Grignani G, Palmerini E, Stacchiotti S, Boglione A, Ferraresi V, Frustaci S, 44. Ng JM, Curran T: The Hedgehog's tale: developing strategies for targeting Comandone A, Casali PG, Ferrari S, Aglietta M: A phase 2 trial of imatinib cancer. Nat Rev Cancer 2011, 11:493–501. mesylate in patients with recurrent nonresectable chondrosarcomas 45. Campbell VT, Nadesan P, Ali SA, Wang CY, Whetstone H, Poon R, Wei Q, expressing platelet-derived growth factor receptor-alpha or -beta: An Keilty J, Proctor J, Wang LW, Apte SS, McGovern K, Alman BA, Wunder JS: Italian Sarcoma Group study. Cancer 2011, 117:826–831. Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth. Mol 29. Fox E, Patel S, Wathen JK, Schuetze S, Chawla S, Harmon D, Reinke D, Cancer Ther 2014, 13:1259. Chugh R, Benjamin RS, Helman LJ: Phase II study of sequential 46. Schrage YM, Briaire-de Bruijn IH, de Miranda NF, van Oosterwijk J, Taminiau AH, gemcitabine followed by docetaxel for recurrent Ewing sarcoma, van Wezel T, Hogendoorn PC, Bovee JV: Kinome profiling of chondrosarcoma osteosarcoma, or unresectable or locally recurrent chondrosarcoma: reveals SRC-pathway activity and dasatinib as option for treatment. Cancer results of Sarcoma Alliance for Research Through Collaboration Study Res 2009, 69:6216–6222. 003. Oncologist 2012, 17:321. 47. Cesari M, Bertoni F, Bacchini P, Mercuri M, Palmerini E, Ferrari S: 30. Italiano A, Le CA, Bellera C, Piperno-Neumann S, Duffaud F, Penel N, Cassier P, Mesenchymal chondrosarcoma. An analysis of patients treated at a Domont J, Takebe N, Kind M, Coindre JM, Blay JY, Bui B: GDC-0449 in patients single institution. Tumori 2007, 93:423–427. with advanced chondrosarcomas: a French Sarcoma Group/US and French 48. Huvos AG, Rosen G, Dabska M, Marcove RC: Mesenchymal National Cancer Institute Single-Arm Phase II Collaborative Study. Ann Oncol chondrosarcoma. A clinicopathologic analysis of 35 patients with 2013, 24:2922–2926. emphasis on treatment. Cancer 1983, 51:1230–1237. 31. Schuetze SM, Zhao L, Chugh R, Thomas DG, Lucas DR, Metko G, Zalupski 49. Yokota K, Sakamoto A, Matsumoto Y, Matsuda S, Harimaya K, Oda Y, MM, Baker LH: Results of a phase II study of sirolimus and Iwamoto Y: Clinical outcome for patients with dedifferentiated cyclophosphamide in patients with advanced sarcoma. Eur J Cancer 2012, chondrosarcoma: a report of 9 cases at a single institute. J Orthop Surg 48:1347–1353. Res 2012, 7:38. 32. Ha HT, Griffith KA, Zalupski MM, Schuetze SM, Thomas DG, Lucas DR, Baker LH, Chugh R: Phase II trial of cetuximab in patients with metastatic or doi:10.1186/2045-3329-4-11 locally advanced soft tissue or bone sarcoma. Am J Clin Oncol 2013, Cite this article as: van Maldegem et al.: Comprehensive analysis of 36:77–82. published studies involving systemic treatment for chondrosarcoma of 33. Schwartz GK, Tap WD, Qin LX, Livingston MB, Undevia SD, Chmielowski B, bone between 2000 and 2013. Clinical Sarcoma Research 2014 4:11. Agulnik M, Schuetze SM, Reed DR, Okuno SH, Ludwig JA, Keedy V, Rietschel P, Kraft AS, Adkins D, Van Tine BA, Brockstein B, Yim V, Bitas C, Abdullah A, Antonescu CR, Condy M, Dickson MA, Vasudeva SD, Ho AL, Doyle LA, Chen HX, Maki RG: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 2013, 14:371–382. 34. Mitchell AD, Ayoub K, Mangham DC, Grimer RJ, Carter SR, Tillman RM: Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Joint Surg Br 2000, 82:55–61. 35. Dickey ID, Rose PS, Fuchs B, Wold LE, Okuno SH, Sim FH, Scully SP: Dedifferentiated chondrosarcoma: the role of chemotherapy with updated outcomes. J Bone Joint Surg Am 2004, 86-A:2412–2418. 36. Staals EL, Bacchini P, Bertoni F: Dedifferentiated central chondrosarcoma. Cancer 2006, 106:2682–2691. 37. Grimer RJ, Gosheger G, Taminiau A, Biau D, Matejovsky Z, Kollender Y, San-Julian M, Gherlinzoni F, Ferrari C: Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group. Eur J Cancer 2007, 43:2060–2065. 38. Dantonello TM, Int-Veen C, Leuschner I, Schuck A, Furtwaengler R, Claviez A, Schneider DT, Klingebiel T, Bielack SS, Koscielniak E: Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. Submit your next manuscript to BioMed Central Cancer 2008, 112:2424–2431. and take full advantage of: 39. Bernstein-Molho R, Kollender Y, Issakov J, Bickels J, Dadia S, Flusser G, Meller I, Sagi-Eisenberg R, Merimsky O: Clinical activity of mTOR inhibition in • Convenient online submission combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol 2012, • Thorough peer review 70:855–860. • No space constraints or color figure charges 40. van Maldegem AM, Gelderblom H, Palmerini E, Dijkstra SD, Gambarotti M, • Immediate publication on acceptance Ruggieri P, Nout RA, van de Sande MA, Ferarri C, Ferrari S, Bovee JV, Picci P: Outcome of advanced, unresectable conventional central • Inclusion in PubMed, CAS, Scopus and Google Scholar chondrosarcoma. Cancer 2014. doi:10.1002/cncr.28845. [Epub ahead of • Research which is freely available for redistribution print]. 41. Tiet TD, Hopyan S, Nadesan P, Gokgoz N, Poon R, Lin AC, Yan T, Andrulis IL, Submit your manuscript at Alman BA, Wunder JS: Constitutive hedgehog signaling in www.biomedcentral.com/submit

Journal

Clinical Sarcoma Research – Springer Journals

Published: Aug 12, 2014

There are no references for this article.