Response of conventional chondrosarcoma to gemcitabine alone: a case report
© Provenzano et al.; licensee BioMed Central. 2015
Received: 12 January 2015
Accepted: 3 March 2015
Published: 15 March 2015
Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide.
KeywordsSarcoma Bone sarcoma Chondrosarcoma Gemcitabine Chemotherapy
The skeletal chondrosarcoma family represents a heterogeneous group of malignant bone mesenchymal tumours characterised by the production of a chondroid matrix. They are the third bone sarcoma in incidence, and the most frequent in adults. There are three main subtypes: conventional, mesenchymal, and clear-cell. A “dedifferentiated” chondrosarcoma develops in 10-15% of conventional chondrosarcomas, while mesenchymal chondrosarcoma is a high-grade, aggressive neoplasm with a natural history and chemosensitivity that might be close to Ewing sarcoma, and clear-cell chondrosarcoma is a low-grade variant .
In conventional chondrosarcoma (cCS), the histological malignancy grade is the main prognostic factor . Grade 1 cCS are characterised by a very low metastatic potential, and some authors have quite recently suggested a re-classification of these types as “atypical cartilaginous tumours” . Grade 2 and 3 cCS are marked by a higher metastatic potential, with a 10-year survival of 64-86% and 29-55% respectively [3,4].
CCSs are also categorised according to their location in the bone: a central chondrosarcoma onsets in the medullary cavity, a small percentage of them from a pre-existing benign lesion known as enchondroma, while a peripheral variant arises from the surface of the bone, as a result of malignant progression of a pre-existing benign (solitary or hereditary) osteochondroma.
Surgery is the mainstay of the treatment of localized disease. While curettage is acceptable for grade 1 cCS, wide excision is usually required for higher grade cCS, with the exception of skull base cCS which may be treated with radiotherapy. In particular, hadrons can play an important role in the management of skull base cCS, and very good outcomes are reported .
In surgically treated patients, the benefit of adding radiotherapy and chemotherapy remains unclear, due to a lack of prospective trials. Adjuvant radiotherapy and/or chemotherapy may be proposed to high-risk patients in conditions of uncertainty. When cCS is advanced, and a medical therapy is the only option, regimens commonly used in other bone sarcomas are employed . Traditionally, chemotherapy has been considered poorly effective , but the low number of cases and the inclusion in available series of conventional (both central and peripheral), dedifferentiated, mesenchymal, clear-cell histotypes does not help to understand the actual chemo-responsiveness of the disease. Recently, responses to gemcitabine in combination with docetaxel have been reported in advanced chondrosarcomas .
Hereby, we describe the case of a young woman with a metastatic, pretreated cCS treated with gemcitabine as a single agent, after failing to anthracyclines, ifosfamide, cisplatin, etoposide.
Patient characteristics and medical history
Front-line surgery was ruled out because of the extent of the disease, the major blood vessels and nerves being involved. In February 2010, chemotherapy with full-dose doxorubicin plus ifosfamide was administered for 3 cycles, but tumour progression ensued. In April 2010, definitive external beam radiotherapy (total dose 72 Gy) achieved a minor dimensional response and symptom control.
Neutropenia G1-G2 was recorded as the only side effect to gemcitabine.
In September 2013, chemotherapy was interrupted after 9 cycles as for patient request. Tumour response was maintained until February 2014 when, after a-14 month progression-free survival, a disease progression was observed to the liver and to the abdomen, with the new appearance of multiple peritoneal metastases. In May 2014, gemcitabine was restarted, with progression at the following evaluation in September 2014.
This is the first report of a response to gemcitabine as single agent, in a patient with a heavily pre-treated advanced cCS. The response was marked by a regression of the tumour and symptomatic improvement. While high-grade chondrosarcoma subtypes (mesenchymal and dedifferentiated) can be sensitive to chemotherapy , cCS is usually described as a chemo-refractory disease . Indeed, in high-grade chondrosarcomas responses to chemotherapy have been reported to anthracycline-based chemotherapy combinations, and they are usually treated with regimens commonly used in high-grade osteosarcomas, also including cisplatin [7,11-13].
Trials with targeted-therapy have not proven efficacy so far. The initial enthusiasm on hedgehog inhibitors coming from pre-clinical studies, on the basis of a strong activation of the hedgehog pathway in chondrosarcomas, has been cut down after the results of a phase 2 trial in which no objective responses were observed .
Summary of available studies reporting on gemcitabine in the treatment of chondrosarcomas (all histotypes)
Though a single case, this is the first report of responsiveness of cCS to gemcitabine alone. This patient was experiencing a progressive disease with worsening symptoms before gemcitabine. After starting gemcitabine, pain and walking impairment quickly improved. Tumour response was a RECIST partial response to the site of liver metastasis, and a minor tumour shrinkage of the primary, pretreated with RT, lesion. Response was long lasting. Interestingly, this patient had not responded to any of the drugs used previously.
To be noted, the patient described in this case report carried a secondary peripheral chondrosarcoma. Differently from central variant, secondary peripheral chondrosarcomas have distinct molecular features. In fact, solitary osteochondromas are characterised by homozygous deletion of EXT-1 (exostosin) gene, which is involved in heparan sulfate biosynthesis. This alteration may lead to a dysregulation of downstream signalling pathways and, eventually, progression to secondary peripheral chondrosarcoma [22,23]. On this basis, different targets as compared to primary central chondrosarcoma have been identified  in secondary peripheral chondrosarcoma and a different chemosensitivity cannot be excluded. Even if, at least of our knowledge, there are no data to sustain at present a higher sensitivity to gemcitabine in presence of an EXT-1 deletion and the available reports on the activity of gemcitabine/docetaxel in chondrosarcoma do not go into details on the chondrosarcoma subtype, this cannot be ruled out.
We add to anecdotal evidence that gemcitabine-based chemotherapy may be active in cCS. This needs to be confirmed through prospective studies targeted to cCS, without the confounding factor of other histotypes. Whether the combination of docetaxel and gemcitabine can be more active than gemcitabine single agent in cCS is left to understand, considering the extra-toxicity implied by the combination in comparison to single-agent gemcitabine.
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors thank the patient and her family. We also thank Mireya Fernandez-Fournier for English revision.
NH has received a research grant from the Spanish Society of Medical Oncology SEOM.
- Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013.Google Scholar
- Björnsson J, McLeod RA, Unni KK, Ilstrup DM, Pritchard DJ. Primary chondrosarcoma of long bones and limb girdles. Cancer. 1998;83:2105–19.View ArticlePubMedGoogle Scholar
- Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol. 2012;106:929–37.View ArticlePubMedGoogle Scholar
- Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977;40:818–31.View ArticlePubMedGoogle Scholar
- Uhl M, Mattke M, Welzel T, Oelmann J, Habl G, Jensen AD, et al. High control rate in patients with chondrosarcoma of the skull base after carbon ion therapy: first report of long-term results. Cancer. 2014;120:1579–85.View ArticlePubMedGoogle Scholar
- The ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Supplement 3):113–23.View ArticleGoogle Scholar
- Italiano A, Mir O, Cioffi A, Palmerini E, Piperno-Neumann S, Perrin C, et al. Advanced chondrosarcomas: role of chemotherapy and survival. Ann Oncol. 2013;24:2916–22.View ArticlePubMed CentralPubMedGoogle Scholar
- Fox E, Patel S, Wathen JK, Schuetze S, Chawla S, Harmon D, et al. Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma Alliance for Research Through Collaboration Study 003. Oncologist. 2012;17:321.View ArticlePubMed CentralPubMedGoogle Scholar
- Frezza AM, Cesari M, Baumhoer D, Biau D, Bielack S, Campanacci DA, et al. Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. Eur J Cancer. 2015;51:374–81.View ArticlePubMedGoogle Scholar
- Van Maldegem AM, Bovée JV, Gelderblom H. Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of bone between 2000 and 2013. Clin Sarcoma Res. 2014;4:11.View ArticlePubMed CentralPubMedGoogle Scholar
- La Rocca RV, Morgan KW, Paris K, Baeker TR. Recurrent chondrosarcoma of the cranial base: a durable response to ifosfamide-doxorubicin chemotherapy. J Neurooncol. 1999;41:281–3.View ArticlePubMedGoogle Scholar
- Nooij MA, Whelan J, Bramwell VHC, Taminiau AT, Cannon S, Hogendoorn PCW, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study. Eur J Cancer. 2005;41:225–30.View ArticlePubMedGoogle Scholar
- Van Maldegem AM, Gelderblom H, Palmerini E, Dijkstra SD, Gambarotti M, Ruggieri P, et al. Outcome of advanced, unresectable conventional central chondrosarcoma. Cancer. 2014;120:3159–64.View ArticlePubMedGoogle Scholar
- Italiano A, Le Cesne A, Bellera C, Piperno-Neumann S, Duffaud F, Penel N, et al. GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study. Ann Oncol. 2013;24:2922–6.View ArticlePubMed CentralPubMedGoogle Scholar
- Lund B, Kristjansen PE, Hansen HH. Clinical and preclinical activity of 2’,2'-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev. 1993;19:45–55.View ArticlePubMedGoogle Scholar
- Stacchiotti S, Palassini E, Sanfilippo R, Vincenzi B, Arena MG, Bochicchio AM, et al. Gemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network. Ann Oncol. 2012;23:501–8.View ArticlePubMedGoogle Scholar
- Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol. 2007;25:2755–63.View ArticlePubMedGoogle Scholar
- Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002;20:2824–31.View ArticlePubMedGoogle Scholar
- Pautier P, Floquet A, Penel N, Piperno-Neumann S, Isambert N, Rey A, et al. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group. Oncologist. 2012;17:1213–20.View ArticlePubMed CentralPubMedGoogle Scholar
- Lee EM, Rha SY, Lee J, Park KH, Ahn J-H. Phase II study of weekly docetaxel and fixed dose rate gemcitabine in patients with previously treated advanced soft tissue and bone sarcoma. Cancer Chemother Pharmacol. 2012;69:635–42.View ArticlePubMedGoogle Scholar
- Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, et al. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008;113:419–25.View ArticlePubMedGoogle Scholar
- Bovée JVMG, Hogendoorn PCW, Wunder JS, Alman B. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat Rev Cancer. 2010;10:481–8.View ArticlePubMedGoogle Scholar
- De Andrea CE, Reijnders CMA, Kroon HM, de Jong D, Hogendoorn PCW, Szuhai K, et al. Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene. 2012;31(9):1095–104.View ArticlePubMedGoogle Scholar
- Gelderblom H, Hogendoorn PCW, Dijkstra SD, van Rijswijk CS, Krol a. D, Taminiau a. HM, Bovee JVMG. The clinical approach towards chondrosarcoma. Oncologist. 2008;13:320–9.View ArticlePubMedGoogle Scholar
- Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, et al. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol. 2000;45:177–81.View ArticlePubMedGoogle Scholar
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.