Chondrosarcoma is a heterogeneous group of primary bone sarcoma with an excellent overall survival after local therapy; however, a small percentage of patients have metastatic disease, which has no surgical treatment options. This article describes data from patients diagnosed with unresectable chondrosarcoma in four major sarcoma centers, comparing progression free survival for the different treatment regimens used for four chondrosarcoma subtypes.
Keywords: Chondrosarcoma, Unresectable, Progression‐free survival, Systemic treatment, Retrospective
Abstract
Background.
Chondrosarcoma is a heterogeneous group of primary bone sarcoma with an excellent overall survival after local therapy. However, the small percentage of patients who have no surgical treatment options have a very poor prognosis. We retrospectively collected data from these patients in four sarcoma centers and compared the progression‐free survival (PFS) for the different treatment regimens used for the four chondrosarcoma subtypes.
Materials and Methods.
Patients diagnosed with unresectable chondrosarcoma in all four major sarcoma centers were included, and data on first‐line systemic therapy were retrospectively collected for analysis.
Results.
A total of 112 patients were enrolled in this retrospective analysis: 50 conventional, 25 mesenchymal, 34 dedifferentiated, and 3 clear cell chondrosarcoma patients. In conventional chondrosarcoma patients, the longest mean PFS (6.7 months) was found in the group treated with antihormonal therapy. Patients diagnosed with mesenchymal chondrosarcoma were all treated with multidrug chemotherapy, and the mean PFS was 6.7 months. Doxorubicin monotherapy seems to have an unexplained better PFS than doxorubicin‐based combination therapy in patients with dedifferentiated chondrosarcoma (5.5 vs. 2.8 months, respectively; p = .275).
Conclusion.
Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the diagnosed subtype and improve survival.
Implications for Practice.
Currently, there are no uniform treatment lines for advanced chondrosarcoma patients, which results in a very diverse group of treatment regimens being used. In this study, the data of 112 patients was collected. It was concluded that some treatment regimens seem to have a better progression‐free survival compared with others, and that these results also differ between the chondrosarcoma subtypes. Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the diagnosed histological subtype to improve their survival.
Introduction
Chondrosarcoma (CS) consists of a heterogeneous group of tumors that share the common feature of cartilage matrix production [1]. Conventional chondrosarcoma is the most common (90%) subtype; the remaining 10% are mesenchymal, dedifferentiated, and clear cell chondrosarcoma. For conventional chondrosarcoma, metastatic disease is rare, and most patients can be cured with surgical interventions. Overall survival (OS) depends on the subtype, with dedifferentiated and mesenchymal chondrosarcoma being the more aggressive with a worse overall survival [2], [3], [4], [5]. Retrospective studies have shown that these patients may benefit from (neo‐) adjuvant chemotherapy or radiotherapy, but large prospective studies still need to be conducted [2], [5], [6], [7]. The small percentage of patients who present or develop metastatic disease for which no surgical options are available still have a very poor prognosis and limited treatment options [8]. The first line of treatment for any chondrosarcoma is surgery, as this is currently the only treatment option to cure a patient. For patients with metastatic disease, it remains unclear what the best chemotherapy regimen is and if chemotherapy has any benefit on overall survival. Recent data on mesenchymal chondrosarcoma patients with localized disease show a significant reduction in local disease recurrence with (neo) adjuvant chemotherapy [9]. For patients with metastatic disease, the numbers were too small to make any recommendations. The data from another retrospective study including advanced chondrosarcoma patients suggest that chemotherapy results in a better progression‐free survival (PFS) for patients with mesenchymal and dedifferentiated chondrosarcoma. No effect on overall survival was seen [10].
Here, we retrospectively collected the data from patients diagnosed with unresectable chondrosarcoma in four major sarcoma treatment centers. The data was shown separately for the four chondrosarcoma subtypes—conventional, mesenchymal, dedifferentiated, and clear cell. The progression‐free survival after different treatment regimens was calculated and compared.
Materials and Methods
Patients diagnosed with unresectable chondrosarcoma in one of four centers (Leiden University Medical Centre, Leiden, The Netherlands; University of Texas MD Anderson Cancer Center, Houston, TX; Maria Sklodowska‐Curie Institute – Oncology Center, Warsaw, Poland; and Radboud University Medical Centre, Nijmegen, The Netherlands) receiving palliative systemic treatment between 1980 and 2016 were selected. Information was collected retrospectively regarding date of birth, gender, date of last contact or death, histological subtype, grade, tumor location at onset, tumor location of unresectable disease, received treatments, overall survival, and progression‐free survival. Patients were regarded as unresectable if complete resection of the primary tumor and/or metastatic sites was viewed as technically not possible due to the size or (multiple) location(s) of the tumor or if complete resection would lead to unacceptable morbidity for the patient as assessed in multidisciplinary team meetings in centers of expertise.
The PFS after the first treatment line is compared between the different treatment regimens for each chondrosarcoma subtype.
The PFS was calculated from start of first treatment line until disease progression, death, or the last follow‐up examination. The survival curves were calculated according to the Kaplan‐Meier method and compared using the log‐rank test.
Results
Patients
A total of 112 patients were enrolled in this study, of whom 50 (45%) had conventional, 25 (22%) mesenchymal, 34 (30%) dedifferentiated, and 3 (3%) clear cell chondrosarcoma. The patients' characteristics are described in Table 1. All patient data are shown in supplemental online Table 1.
Table 1. Patient characteristics.
Six of these patients were also included in the study published by Meijer et al. [11].
Of the conventional chondrosarcoma patients, four had atypical cartilaginous tumors/chondrosarcoma grade 1 at time of diagnosis. Three had biopsy‐proven progression to grade 2 at disease recurrence/progression; for the fourth patient, no new biopsy was performed to establish progression to a higher‐grade tumor. Thus, except for this one patient, all patients in the analysis had a high‐grade chondrosarcoma at time of unresectability.
Treatment
The specific treatment regimens that patients received were compared using a swimmer plot for each chondrosarcoma subtype (Fig. 1). The numbers of different treatment regimens were too small for a statistical analysis, but trends can be observed.
Figure 1.
Swimmers plot for the different regimens used (PFS in months). Swimmer plot of the different treatment regimens used after unresectability comparing the PFS for conventional (A), dedifferentiated (B), mesenchymal (C), and clear cell (D) subtype.Abbreviations: VAC/IE, vincristine, doxorubicin, cyclofosfamide/ifosfamide, etoposide; VDC/VID, vincristine, doxorubicin, cyclophosphamide/vincristine, doxorubicin, ifosfamide; VID, vincristine, ifosfamide, doxorubicin; VIDE, vincristine, ifosfamide, doxorubicin, etoposide; VID/IE, vincristine, ifosfamide, doxorubicin/ifosfamide, etoposide.
For the conventional chondrosarcoma, the patients treated with doxorubicin monotherapy (n = 2) had a mean PFS on first treatment line of 2.5 months (Fig. 1A). Patients treated with a combination of doxorubicin with either cisplatin or ifosfamide (n = 10) had a mean PFS of 3.6 months. The combination of gemcitabine and docetaxel has a mean PFS of 2 months (n = 3). Seven patients, six males and one female, treated with antihormonal therapy, aromatase inhibitors, and antiestrogen drugs, had a mean PFS of 6.7 months. Six of these were also included in the study published by Meijer et al. [11]. Pazopanib and the combination of pazopanib with trametinib had a mean PFS of 3.7 months (n = 7), and dasatinib treatment had a mean PFS of 2.2 months (n = 4); these patients were treated in clinical trials. Patients treated with the combination of vorinostat and hydroxychloroquine (n = 4) had a mean PFS of 5 months. Hedgehog inhibitors (saridegib) and isocitrate dehydrogenase 1 (IDH1) inhibitors had a mean PFS of 3 months (n = 5).
For dedifferentiated chondrosarcoma, six patients treated with doxorubicin monotherapy had a mean PFS of 5.5 months (Fig. 1B). The combination of doxorubicin with cisplatin and doxorubicin with cisplatin and methotrexate had a mean PFS of 2.9 months (n = 13).
The 25 patients diagnosed with mesenchymal chondrosarcoma were all treated with chemotherapy‐based combination regimens (Fig. 1C). The mean PFS for all chemotherapy regimens is 6.7 months. Patients treated with the combination of ifosfamide and doxorubicin (n = 4) had a PFS of 3.7 months, and patients treated with the combination of cisplatin and doxorubicin (n = 4) had a PFS of 7.7 months (p = .04).
The three patients diagnosed with clear cell chondrosarcoma were either treated with sunitinib (n = 2) or the combination of pazopanib and denosumab (n = 1), and, on average, their PFS is the same (Fig. 1D).
Response
No complete responses according to RECIST criteria were seen after the first treatment line. Seven patients had a partial response—one patient diagnosed with conventional CS, four with mesenchymal CS, and two with dedifferentiated CS. The patient diagnosed with conventional CS was treated with the combination of doxorubicin and cisplatin. Of the four mesenchymal CS patients, three were treated with VAC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) and one with VID (vincristine, doxorubicin, ifosfamide). The two dedifferentiated CS patients were treated with doxorubicin monotherapy and doxorubicin in combination with cisplatin, respectively.
Survival
The mean PFS as calculated using the Kaplan‐Meier method for the first systemic treatment line after patients became unresectable was 11 months for patients diagnosed with conventional chondrosarcoma, 16 months for mesenchymal, 15 months for dedifferentiated, and 10 months for clear cell chondrosarcoma. The differences in outcome for PFS of first systemic treatment line between the histological subtypes were not significant (Fig. 2).
Figure 2.
Progression‐free survival for first treatment regimen after unresectability for patients divided in the different chondrosarcoma subtypes.
At the time of data collection, 35 (31%) of the 112 patients were still alive. The OS after unresectability was 87 months for conventional, 62 for mesenchymal, 32 for dedifferentiated, and 16 for clear cell chondrosarcoma patients (Fig. 3). The patients diagnosed with conventional chondrosarcoma or mesenchymal chondrosarcoma show a trend toward having a significant better OS than patients diagnosed with dedifferentiated chondrosarcoma (p = .53 and p = .26, respectively).
Figure 3.
Overall survival after unresectability for all patients subdivided in chondrosarcoma subtypes.
Prognostic Markers
Different prognostic markers were tested for significance for PFS after unresectability. For dedifferentiated chondrosarcoma, male patients had a significant better PFS (p = .042). For the other subtypes, no difference in PFS between genders was found. Age (≤50 vs. >50 years) and tumor localization showed no significant difference (data not shown). There is no difference in PFS between the different treatment centers (p = .443).
Discussion
Patients with unresectable chondrosarcoma still have a very poor prognosis, with an overall 2‐year survival around 24%–37% [8], [10]. The conventional, mesenchymal, dedifferentiated, and clear cell subtypes should not be considered the same disease and should not be treated equally. Even within the different subtypes, there is a wide range of clinical and biological heterogeneity. But to make clinical research feasible for this rare disease, patients with the same subtype are considered to have comparable disease.
Conventional chondrosarcoma is the most common form, and the low‐grade form (now called atypical cartilaginous tumor) infrequently develops metastases. Dedifferentiated CS is a high‐grade chondrosarcoma with a worse prognosis. From previous studies, we know that the overall survival depends on the histological subtype of chondrosarcoma [10], [12]. In line with these previous studies, the patients in our study diagnosed with conventional or mesenchymal chondrosarcoma also seem to have a nonsignificant better OS than patients diagnosed with dedifferentiated chondrosarcoma (Fig. 3).
In our cohort, several conventional chondrosarcoma patients (n = 7) were treated with hormonal‐based therapies and had a mean PFS of 6.7 months compared with 3.1 months for the patients treated with chemotherapy. Six of these patients were included in a previously published study [11]. In previous preclinical work, the presence of the estrogen receptor alpha and activity of aromatase in chondrosarcoma cell lines was confirmed, providing rationale for inhibition of estrogen and aromatase as a treatment strategy for chondrosarcoma [13], [14]. However, a beneficial effect could not be convincingly and reproducibly shown in vitro, and an in vivo pilot study in six patients showed no clear therapeutic benefit for advanced conventional or dedifferentiated chondrosarcoma patients treated with an aromatase inhibitor [11]. It is interesting, however, that in the current study that includes six of these patients, antihormonal therapy gave the longest PFS, with a mean of 6.7 months among the different treatment regimens. So far, we cannot explain the benefit in PFS for the conventional CS patients treated with these treatment regimens. Further preclinical and clinical studies need to be conducted to clarify if antihormonal therapy is a possible therapeutic strategy for CS patients.
In our cohort, three patients diagnosed with conventional CS were treated with saridegib. The mean PFS for these three patients was 3.6 months. Preclinical studies suggest that hedgehog signaling plays an important role in the pathogenesis of chondrosarcoma. The hedgehog pathway regulates chondrocyte proliferation and differentiation during endochondral bone development. In chondrosarcoma, hedgehog signaling is dysregulated. In previous preclinical work, only one of six chondrosarcoma cell cultures was responsive to the Hh inhibitor cyclopamine [15]. However, in primary human chondrosarcoma tissue xenotransplanted in mice, treatment with the hedgehog inhibitor IPI‐926 results in downregulation of the hedgehog pathway and inhibition of tumor growth [16]. In addition, chondrosarcoma xenografts responded to the hedgehog inhibitor triparanol with a 60% decrease in tumor volume [17]. Preclinical evidence suggests that a small subset of chondrosarcoma patients could perhaps benefit from hedgehog inhibition, although there are currently no biomarkers to predict which patients will respond. In a phase II, randomized, placebo‐controlled trial, inoperable chondrosarcoma patients were treated with the hedgehog inhibitor saridegib. The results of the study showed no improvement in PFS when compared with placebo, and the study was stopped [18]. Future studies should be performed to investigate whether the subgroup of patients with mutations in hedgehog pathway genes may benefit from hedgehog inhibitors.
In our study, the median PFS for patients with conventional chondrosarcoma treated with dasatinib was 2.2 months. Using kinome profiling, the Src pathway was identified as a possible therapeutic target for chondrosarcoma [19]. Inhibition of the Src pathway with dasatinib, a tyrosine kinase inhibitor, resulted in a decrease of cell growth. Combination treatment of dasatinib with the chemotherapeutic agent doxorubicin results in a synergistic effect on inhibition of cell viability and inducing apoptosis in chondrosarcoma cell lines [20]. This may suggest that blocking the Src pathway may overcome chemo resistance in chondrosarcoma. A recent phase II study with the tyrosine kinase inhibitor dasatinib included patients diagnosed with chondrosarcoma, who were incurable with conventional therapy. The median PFS for the patients in the study, enrolling all different chondrosarcoma subtypes, was 5.5 months [21].
Three conventional CS patients in the current study were treated with inhibitors of mutant IDH. In ∼50% of the conventional and the dedifferentiated chondrosarcomas, driver mutations are found in the IDH1 or the IDH2 gene [22], [23], providing a strong rationale to treat chondrosarcomas with inhibitors of the mutant enzyme. Promising results have been obtained in other IDH mutant tumors, including glioma and leukemia [24]. Preclinical data have shown that although IDH mutations are important for the development of the benign precursor lesion enchondroma [25], [26], after progression to malignant chondrosarcoma, the cells do not depend on the IDH mutation anymore for survival [27], [28]. This would imply that chondrosarcoma patients will not benefit from these inhibitors as single‐agent therapy, which is in line with the poor PFS in the three patients in the current study. Several clinical trials are currently investigating the effect of IDH inhibition for patients with solid tumors with an IDH1 or IDH2 mutation (ClinicalTrials.gov Identifier: NCT02746081, NCT02481154, NCT02073994, NCT02273739).
All patients diagnosed with mesenchymal chondrosarcoma were treated with chemotherapy. The combination of doxorubicin with cisplatin (n = 4) seems to have a better PFS than the regimens that contain three or more different chemotherapy agents (n = 13). Although numbers are small, one may—with reservation—conclude that the need for regimens with multiple different chemotherapy agents is doubtful.
The fusion gene HEY1‐NCOA2 is considered a diagnostic molecular marker [29]. Data on HEY1‐NCOA2 translocations, described in 73% of mesenchymal chondrosarcomas, and for IDH1 or ‐2 mutations, described in ∼50% of conventional and dedifferentiated chondrosarcoma, were not available for our patients. However, the IDH1 or ‐2 molecular alterations have no known prognostic value [30]; for HEY‐NCOA2 translocation, it is still unclear.
Patients diagnosed with dedifferentiated chondrosarcoma had a wide range of PFS when comparing the outcome with the same treatment regimens. Doxorubicin monotherapy seems to have a better outcome than treatment with the different combination regimens of doxorubicin. This difference in PFS is notable but nonsignificant (p = .275) and thus far unexplained. No difference in toxicity as a reason for discontinuing the treatment was seen: 16.6% in the monotherapy group versus 12.5% for the combination regimens.
From this database, we observed that there was a wide variation in effect of the same treatment between patients with the same subtype of CS. This may be related to the low number of patients per subgroup. This makes it hard to draw firm conclusions and propagate one treatment over the other. On the other hand, this is still one of the largest series of systemic treatment outcome in chondrosarcoma and the only study taking into account both line of systemic therapy and CS subtype.
Conclusion
Currently, there are no uniform treatment guidelines for advanced chondrosarcoma patients, which results in very diverse treatment regimens being used. In this study, we collected the data of 112 patients, but the numbers were still too small to do a statistical analysis on the different systemic treatments. Within the limitations of this study, with low numbers and a retrospective nature causing a selection bias, we can conclude that some treatment regimens seem to have a better PFS as compared with others, and that these results differ between the chondrosarcoma subtypes. Because of the retrospective nature of this study, we were not able to do a central pathological review of all the tumors, and this may have affected the results. However, all diagnoses were established in a multidisciplinary setting in a center of expertise. Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the histological subtype to improve their survival.
See http://www.TheOncologist.com for supplemental material available online.
Acknowledgments
The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007‐2013) under grant agreement 278742 (Eurosarc).
Author Contributions
Conception/design: Annemiek van Maldegem, Hans Gelderblom
Provision of study material or patients: Anthony P. Conley, Piotr Rutkowski, Shreyaskumar R. Patel, Ingrid M.E. Desar, Hans Gelderblom
Collection and/or assembly of data: Annemiek van Maldegem, Anthony P. Conley, Iwona Lugowska, Ingrid M.E. Desar
Data analysis and interpretation: Annemiek van Maldegem
Manuscript writing: Annemiek van Maldegem, Anthony P. Conley, Piotr Rutkowski, Iwona Lugowska, Ingrid M.E. Desar, Judith V.M.G. Bovée, Hans Gelderblom
Final approval of manuscript: Annemiek van Maldegem, Anthony P. Conley, Piotr Rutkowski, Shreyaskumar R. Patel, Iwona Lugowska, Ingrid M.E. Desar, Judith V.M.G. Bovée, Hans Gelderblom
Disclosures
Judith Bovée: Servier (RF), Elsevier, Wolters Kluwer, Nanobiotix (H). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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