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Annals of Oncology 21 (Supplement 7): vii270–vii276, 2010 Histology-driven chemotherapy of soft-tissue sarcoma Department of Oncology, Lund University and Ska˚nes University Hospital, Lund, Sweden Soft-tissue sarcomas are rare diseases with >50 subtypes. Surgery is the most important treatment in localized disease, sometimes combined with radiotherapy. Chemotherapy is used as palliation in advanced disease, sometimes also with a potential to decrease tumour size and eradicate micro-metastases, making meaningful surgery possible.
The role of chemotherapy as adjuvant treatment in localized disease is not finally settled. Doxorubicin and ifosfamide are the two drugs with the best established response rates in soft-tissue sarcoma, and a combination of these drugs has been a ‘gold standard’ for several years. However, there is an emerging knowledge of the biology and sensitivity to treatment for different histological subtypes. New drugs such as gemcitabine, taxanes and trabectedin have been explored in several studies, showing promising results. Even if most studies have encompassed many different subtypes and were limited in size, knowledge related to specific treatment for different subtypes is emerging.
Examples are trabectedin in liposacoma and leiomyosarcoma, and taxanes in angiosarcoma.
Key words: chemotherapy, histological subtypes, soft-tissue sarcoma treatment. This has led to the observation of different sensitivities for different drugs or drug combinations between Soft-tissue sarcomas (STS) are rare diseases encompassing <1% the more common subtypes. Formal evidence to guide first- or of all malignancies. More than 50 different histological second-line treatment in different situations is, however, still subtypes of STS have been described, most of them very rare.
Knowledge of the biological differences between subtypes, such as their genetics and natural history, has gradually increasedover the years, and we also now understand more about the sensitivity to treatment of different subtypes. However, theheterogeneity of the subtypes has rarely been taken into account The most effective drugs, especially doxorubicin, have shown when performing clinical trials on treatment for STS. Our an ability to produce overall response (complete or partial) in present knowledge is therefore mainly based on uncontrolled advanced cases in the range of 20–30% [3], even if additional phase II studies or retrospective case series.
patients benefit minor responses or stable disease for a shorter Most STS are localized in the extremities, especially in the or longer time. With the addition of more drugs, e.g.
legs, or on the trunk, but there are also STS localized in ifosfamide, in combinations, the overall response seems to be non-orthopaedic sites, e.g. uterus, retroperitoneum, thorax or somewhat improved [4], but the effect on overall survival (OS) head and neck. The most important treatment for all localized STS is radical surgery whenever possible. For orthopaedic sites, In most cases the response is limited in time, but long-term pre- or postoperative radiotherapy is demonstrated to decrease survivors after only chemotherapy do exist, as shown in studies Chemotherapy has been widely used for decades in different Some histiotypes seem to be totally resistant, at least to the situations in STS: (i) as palliative treatment in advanced cases; chemotherapeutic drugs available today, even if immunoactive (ii) for down-staging, i.e. decreasing size to facilitate radical drugs such as interferon or modern targeted drugs may have surgery of the primary tumour, lung metastases or, an effect in some cases. There is no evidence for the use of occasionally, metastases in other sites; and (iii) as adjuvant or chemotherapy in, for example, gastrointestinal stromal tumours neoadjuvant treatment in high-grade localized disease in (GISTs) [6], extraskeletal myxoid chondrosarcoma [7, 8], clear combination with the local treatment of the primary tumour.
cell sarcoma [9, 10] or alveolar soft part sarcoma [11].
The most used chemotherapeutic drugs in all these Rather low sensitivity for chemotherapy is reported for, for situations, especially during later years, have been doxorubicin example, epithelioid cell sarcoma, adult fibrosarcoma, and ifosfamide, but especially in palliative situations many haemangiopericytoma, and malignant peripheral nerve sheet other drugs have been tested as second or further lines of tumour (MPNST), but that does not exclude that some patientswith these variants may show response. This probability mayincrease by using drugs or combinations other than *Correspondence to: Dr M. Eriksson, Department of Oncology, Lund University and Ska˚nes University Hospital, Lund, Sweden. E-mail: mikael.eriksson@med.lu.se ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org Intermediate sensitivity for chemotherapy seems to be that patients with leiomyosarcoma did not benefit from present for most of the more common types of STS, such as ifosfamide, with a decreased OS (P = 0.0247). A trend towards liposarcoma, leiomyosarcoma, synovial sarcoma, better survival was seen for patients with liver metastases undifferentiated pleomorphic sarcoma and angiosarcoma.
(P = 0.0712). Regarding response, a decrease was seen for both Some sarcomas more common in childhood and adolescence liposarcoma (significant) and leiomyosarcoma are in most cases clearly sensitive to multiagent combinations (non-significant), but an increase (non-significant) was of drugs. This is true for extraskeletal Ewing sarcoma, demonstrated for synovial sarcoma when ifosfamide was added.
rhabdomyosarcoma of embryonal and alveolar types, and High-dose ifosfamide (9–12 g/m2) as single treatment may desmoplastic small round cell tumour; the last of these has, be effective as second-line treatment, even in patients nevertheless, a very poor prognosis. This group of tumours will initially treated with doxorubicin and ifosfamide in lower doses not be discussed further in this review.
Adjuvant treatment with doxorubicin with or without ifosfamide has been explored in many randomized studies,most of them small, and the results have been conflicting. In Many chemotherapeutic drugs have been tested in STS with best brief, the largest studies, performed by the EORTC soft-tissue single-agent response of 20–30% demonstrated for and bone sarcoma group, have been negative [25, 26]. On the doxorubicin [3]. A dose–response relationship has been other hand, a large meta-analysis with the last published update demonstrated, with optimal response rates at dose levels between including 1953 patients from 18 adjuvant trials demonstrated 75 and 90 mg/m2 [12]. Epirubicin is an antracycline analogue of that the combination of doxorubicin and ifosfamide gave an doxorubicin, with supposed lower cardiotoxicity, but high-dose absolute risk reduction for death of 11% [27]. Furthermore, epirubicin has not been shown to be a useful alternative to another meta-analysis including one of the EORTC studies also standard dose doxorubicin in STS [13]. Another way to reduce showed a significant benefit for doxorubicin-containing the potential risk of cardiotoxicity using antracyclines may be adjuvant treatment for both 5-year disease-free survival (DFS) the use of pegylated doxorubicin, but since the effect of this and OS [28]. Thus, it is still unclear whether to treat or not in preparation seems to be inferior to that of standard doxorubicin the adjuvant setting. The answer may be to select patients with [14] this option may be reserved for patients with pre-existing identified increased risk for metastatic disease based on cardiac disease who are otherwise excluded from antracyclines or biological tumour-related criteria; an option currently being in specific situations as discussed below.
investigated by the Scandinavian Sarcoma Group.
The only other drug with single-agent activity at the same magnitude is ifosfamide at doses of 9–11 g/m2 [15]. Even ifcardiac toxicity is absent with this drug, it may pose other problems such as renal or central nervous system (CNS) toxicity.
Many studies have investigated combination therapies, Dacarbazine is an old alkylating agent approved for use in STS including doxorubicin and ifosfamide and/or other drugs, as in many countries. It has a modest activity as a single agent, reviewed recently [16]. In this review, three phase III studies with a response rate of 17% [29, 30], and has mostly been used were included comparing single-agent doxorubicin [17, 18], or in multidrug combinations as MAID (mesna, doxorubicin, doxorubicin + dacarbazin [19], with combinations including ifosfamide and dacarbazine) or CyVADIC (cyclofosfamide, ifosfamide [18, 19] or the related drug cyclofosfamide [17].
vincristine, doxorubicin and dacarbazine). Its role in this A meta-analysis of these three studies showed that the context is not proven, but when single-agent doxorubicin was combinations including ifosfamide/cyclofosfamide produced compared with CyVADIC an increased response for the a significantly increased tumour response rate of 50% combination was shown, where dacarbazine may have (P = 0.009), but there was no difference in OS after 1 year contributed [17]. Dacarbazine has also been used as second- or (P = 0.76). The toxicity was significantly increased in the further line therapy with some effect [31].
combination arm, however. In the choice between alkylating Temozoloamide is an oral analogue of dacarbazine, mainly agents, ifosfamide has been shown to be the more effective [20].
used in brain tumours, which also has been explored in STS Based on these findings, the combination of doxorubicin and with somewhat conflicting results. A study from EORTC did ifosfamide is recommended as standard therapy, especially when not find a meaningful effect as second-line treatment [32], a good response would increase the possibility of surgery with whereas other studies have shown some responses and disease curative intent, or when a good response is considered to benefit stabilization in leiomyosarcoma especially of uterine origin the individual patient, e.g. by decreasing disturbing symptoms.
[33–36]. Another possible use for this drug could be in In other cases, doxorubicin alone is preferred if no other combination with bevacizumab in haemangiopericytoma/ tumour-specific factors favour the combination. Such a factor could be the histological subtype as discussed further on.
To explore further factors identifying patients who may benefit from the addition of ifosfamide in first-line treatment, a retrospective analysis was recently performed on the large Gemcitabine is a pyrimidine antimetabolite characterized by patient series from EORTC-STBSG [21]. In this analysis, the a favourable toxicity profile and used for several malignancies, increased response rate but equal OS for regimens containing such as carcinoma in the pancreas and bladder. Its effect in STS ifosfamide was confirmed. Predictive factor analysis showed was initially investigated 10 years ago in several small phase II studies, showing only modest activity with partial remissions The potential specific sensitivity for gemcitabine in (PRs) in single patients, mostly those with leiomyosarcomas leiomyosarcomas has led to investigations limited to such [38–40]. A somewhat larger study from the M.D. Anderson tumours of uterine origin, and very promising results have been Cancer Center comprised 17 patients with gastrointestinal achieved both in first-line [66] and in second-line treatment (GI) leiomyosarcomas and 39 other STS patients [41]. In the [67]. Furthermore, an adjuvant phase II study with the same GI group no responses were found; these cases were probably combination indicated an improved 2-year PFS superior to all GISTs. In the other group, however, seven PRs were observed and, interestingly, among them there were four out of10 leiomyosarcomas. The three remaining PRs occurred in one angiosarcoma, one malignant fibrous histiocytoma (MFH) and This family of antimitotic drugs has also been explored in STS, vincristine as early as in the 1960s. As a single agent its activity Apart from the verified responses, disease stabilization for seems to be very limited, with a possible exception for a shorter period has also been demonstrated in some of these paediatric rhabdomyosarcoma [69]. Nevertheless, its use in studies, also confirmed by later reports [42, 43]. One study explored combinations as CyVADIC was established as a standard in gemcitabine as first-line therapy in advanced STS with rather the late 1970s following US studies with very promising disappointing results; 7% PR and 20% stable disease (SD) [44].
responses [70]. Later on, the efficacy of vincristine in adult The promising effect of gemcitabine in some studies, STS was questioned, and its use has been abandoned.
especially with regard to leiomyosarcomas, has prompted However, some studies indicate effects in some patients studies with combinations including this drug. This has led to treated with other Vinca alkaloids such as vindesine [71] or the development of the now very common combination of vinorelbine [72]. Vinorelbine in combination with gemcitabine and docetaxel described below.
gemcitabine has been associated with meaningful diseasecontrol, also including one patient with a high-grade pleomorphic sarcoma achieving a complete remission lasting Paclitaxel has shown a convincing activity in human immunodeficiency virus (HIV)-associated Kaposi’s sarcoma[45, 46]. Several reports have also demonstrated that classical Kaposi’s sarcoma responds to the taxanes docetaxel [47] or Binding of the DNA minor groove is the mechanism of action for the marine-derived drug trabectedin, making it the first A high response rate for paclitaxel in angiosarcoma of the compound in a new class of chemotherapeutic drugs.
scalp or face [51] has shown this treatment to be a reasonable Intensively explored in many malignant diseases, it was initially first-line option, and a later study showed that a similar effect is considered of specific interest in STS based on promising achieved by docetaxel [52]. Other angiosarcomas also respond results in phase II studies in pre-treated patients showing rather well to paclitaxel [53] or docetaxel [54, 55]. Radiation-induced low response rates, but stabilization of disease in several angiosarcomas most often occur in the breast, and in advanced patients and an OS of 1 year [74–76]. Since a somewhat cases good treatment options seem to be offered by docetaxel superior efficacy was indicated for liposarcomas and leiomyosarcomas in these studies, a randomized multicentre Paclitaxel has also been explored for other STS with some phase II study including these histiotypes was performed activity demonstrated in first-line treatment [58], but without comparing two dose schedules: 1.5 mg/m2 in 24 h every third a clear effect in pre-treated patients [59, 60]. In previously week and 0.58 mg/m2 in 3 h every week for three weeks out of treated leiomyosarcoma of the uterus a moderate efficacy has four. A statistically significant benefit was demonstrated for the schedule with 24 h infusion every third week, with a mediantime to progression of 3.7 versus 2.3 months, and a median PFS at 6 months of 35.5% versus 27.5% [77]. Based on these The combination of gemcitabine and docetaxel, both with results, trabectedin was approved in Europe as second-line modest activity in STS, has been investigated in different STS, and promising effects have been found, especially for Tumour response has been noted in several different leiomyosarcoma, but to a certain extent also for other histological subtypes, but the most marked sensitivity has been seen in liposarcoma and leiomyosarcoma, followed by synovial A randomized trial compared single-agent gemcitabine in sarcoma. Myxoid liposarcoma seems to be especially sensitive fixed dose with a lower fixed dose gemcitabine combined with to trabectedin, which recently was verified in a single- docetaxel [65]. The combination produced better progression- institution series from Milan with a response rate of 50% and free survival (PFS) and OS compared with gemcitabine alone.
In the combination arm, response or disease stabilization for at The combination of trabectedin and doxorubicin has been least 24 weeks was observed in eight out of 29 patients with explored in a dose-finding phase I study in 41 patients [79].
leiomyosarcoma, in seven out of 11 patients with a high-grade Five patients (12%) achieved a PR (two myxoid liposarcoma, pleomorphic sarcoma and in two out of 3 patients with one other liposarcoma, one leiomyosarcoma and one with pleomorphic liposarcoma, whereas other histiotypes responded sarcomatoid carcinoma) and 37% maintained stable disease for >6 months. Median PFS was 9.2 months.
hampered by the rarity of all these variants, and the The topoisomerase II inhibitor etoposide in short-duration following recommendations must therefore be interpreted with infusions has not shown convincing activity in studies in STS, caution. However, in spite of lacking randomized trials for either as a single drug [80] or in combination with ifosfamide most situations, there is now good reason for not always [81, 82]. However, a randomized study in small cell lung cancer using ‘the golden standard’ of doxorubicin 6 ifosfamide has shown a dramatic schedule dependency of this drug, favouring long-duration continuous infusions [83]. Based on Certainly, issues other than histology also influence our that observation, the Scandinavian Sarcoma Group has treated choice of treatment. Age, co-morbidity and expected tolerance advanced STS with 600 mg/m2 given continuously for of side effects may all be of importance, with less toxic 72 h followed by ifosfamide 1.5 g/m2 per day for 3 days, regimens to be preferred for more vulnerable patients. The supported by granulocyte colony-stimulating factor (G-CSF); purpose of the treatment is also of importance, and in patients both drugs were dose escalated if haematological toxicity so where surgery with curative intent may be possible later, the permitted [84]. In spite of a relatively low dose of ifosfamide, an regimen with best possible response should be used.
overall response of 42% (11% CR, 31% PR) was noted in this Furthermore, for some patients, options other than group of untreated patients with metastatic or locally advanced conventional chemotherapy may be available. Such options disease. A marked dose–response association was observed.
may be chemotherapy with hyperthermia, showing impressive The combination of etoposide with carboplatin induced results in a randomized study [93], isolated limb perfusion remissions in one study of MPNST refractory against first-line [94, 95] or targeted drug therapy. In the following treatment [85]. Pre-clinical data indicate elevated levels of recommendations, none of these factors has been taken topoisomerase IIa in MPNST, and it is possible that etoposide is especially useful in this histiotype.
The following recommendations only include specific This concept is further investigated in an ongoing trial of the options and advice for some of the more common histiotypes, US group SARC (Sarcoma Alliance for Research through and do not exclude the use of the other options mentioned Collaboration). Early results speak in favour of a possible effect of the combination of ifosfamide and etoposide in MPNST.
Etoposide has also been given in tablet form, but as a single drug at doses of 50 mg/m2 daily it has shown no or low efficacy non-uterine. No drug has been shown to be superior to [86, 87]. In per oral combinations, e.g. with trofosfamide, it doxorubicin in this common entity, but ifosfamide should may be more active, as discussed below.
probably be avoided as discussed above [21]. As second line,there are two good alternatives: (i) gemcitabine + docetaxel [62–65]; and (ii) trabectedin [77].
Trofosfamide is an oxazaphosphorine with ifosfamide as the uterine. Gemcitabine + docetaxel seems to be the most effective main metabolite, and with generally low toxicity. It is given as option in this entity [86, 87] and may be regarded as first-line tablets, continuously or over longer periods, so-called treatment. As further line treatments doxorubicin metronomic use, which is shown to sharply reduce endothelial and trabectedin may be used, and temozolomide may also be progenitor cells that may participate in tumour angiogenesis [88]. Some phase II studies have shown activity in heavilypre-treated patients with advanced STS, predominantly disease stabilization but also some formal responses [89–91]. Another Doxorubicin is regarded as first-line treatment. Whether to add trial used the drug as maintenance after partial remission or ifosfamide or not is an open question in the light of the disease stabilization and seemed to demonstrate a prolonged recent EORTC survey indicating a somewhat lower response PFS and OS compared with patients without maintenance [92].
rate for the combination [21]. Since the main reason to add An ongoing German randomized phase II trial is comparing ifosfamide in the treatment of STS in general is the oral trofosfamide with intravenous doxorubicin in metastatic possibility of achieving a better response, liposarcoma may be an entity favourably treated with doxorubicin only, as Furthermore, the German Cooperative STS study (CWS) described for leiomyosarcoma. Trabectedin seems to be recommended trofosfamide as maintenance therapy in a reasonable second-line choice [77]; in myxoid liposarcomas combination with oral etoposide and idarubicin after aggressive it may even be more effective than doxorubicin for many chemotherapy in children with STS. The combination of etoposide and trofosfamide has been used in Scandinavia aspalliation for patients failing single-agent trofosfamide. Results are often encouraging, but have not yet been published.
Doxorubicin + ifosfamide is strongly recommended for thisentity, which seems to be the histiotype which benefits most from ifosfamide [21]. The concept of using high-dose ifosfamide as a single drug even after resistance to the combination,which has been successful in several studies [22–24], may be The evidence-based knowledge of the optimal especially well suited for this entity. Some patients with synovial chemotherapeutic drugs to use in specific STS histiotypes is sarcoma also seem to benefit from trabectedin [76, 96].
STS, emerging knowledge indicates that other drugs may be Taxanes (paclitaxel or docetaxel) seem to be the drugs of defined as the first- or second-line choice for certain first-line choice [51–57], reserving doxorubicin + ifosfamide for histiotypes. The most important of these drugs seem to be trabectedin, gemcitabine and taxanes, but others, such asetoposide, dacarbazine and temozolomide, may play an important role. Collaborative efforts with preferablyrandomized trials are needed to increase our knowledge of the Doxorubicin + ifosfamide is the main alternative, assuming that best available treatment for these rare tumours.
the findings of the superiority of this combination for STS ingeneral is also true for this common entity. If the impressiveeffect of gemcitabine + docetaxel found in one study [65] is verified, this could be an alternative.
The author has received honoraria from Novartis, SwedishOrphan, GSK, MSD and Pfizer.
Doxorubicin + ifosfamide is regarded as the standard option even if this histiotype probably has a rather low sensitivity forthis combination. Ongoing and further studies will define the 1. Yang JC, Chang AE, Baker AR et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of theextremity. J Clin Oncol 1998; 16: 197–203.
2. Pisters PW, O’Sullivan B, Maki RG. Evidence-based recommendations for local haemangiopericytoma/solitary fibrous tumour therapy for soft tissue sarcomas. J Clin Oncol 2007; 25: 1003–1008.
This entity seems to respond poorly to chemotherapy in 3. Scurr M, Judson I. Neoadjuvant and adjuvant therapy for extremity soft tissue general. A promising effect, however, has been noted for the sarcomas. Hematol Oncol Clin North Am 2005; 19: 489–500.
combination of temozolamide and bevacizumab [37].
4. Casali PG, Jost L, Sleijfer S et al. Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 5. Blay JY, Van Glabbeke M, Verweij J et al. Advanced soft-tissue sarcoma: Taxanes and pegylated doxorubicin have both shown a disease that is potentially curable for a subset of patients treated with remarkable effects in HIV-associated and classical Kaposi’s chemotherapy. Eur J Cancer 2003; 39: 64–69.
sarcoma, and should be used as first- and second-line 6. Edmonson JH, Marks RS, Buckner JC et al. Contrast of response to dacarbazin, treatments when systemic therapy is needed.
mitomycin, doxorubicin and cisplatin (DMAP) plus GM-CSF between patients withadvanced malignant gastrointestinal stromal tumors and patients with otheradvanced leiomyosarcomas. Cancer Invest 2002; 20: 605–612.
7. Patel SR, Burgess M, Andrew M et al. Extraskeletal myxoid chondrosarcoma Infrequent or no responses to chemotherapy are reported for long-term experience with chemotherapy. Am J Clin Oncol 1995; 18: 161–163.
several rare histiotypes, e.g. alveolar soft part sarcomas [11], 8. Drilon AD, Popat S, Bhuchar G et al. Extraskeletal myxoid chondrosarcoma: extraskeletal myxoid chondrosarcoma [7, 8] and clear cell a retrospective review from 2 referral centers emphasizing long-term outcomes sarcoma [9, 10], even if divergent good results have been with surgery and chemotherapy. Cancer 2008; 113: 3364–3371.
reported in rare case reports [97]. Other variants not specifically 9. Ferrari A, Casanova M, Bisogno G et al. Clear cell sarcoma of tendons and mentioned here, e.g., fibrosarcoma, myxofibrosarcoma, and aponeuroses in pediatric patients: a report from the Italian and German softtissue sarcoma cooperative group. Cancer 2002; 94: 3269–3276.
pleomorphic rhabdomyosarcoma, may be sensitive to 10. Jacobs IA, Chang CK, Guzman G et al. Clear cell sarcoma: an institutional review.
chemotherapy, and no drugs have been demonstrated superior to doxorubicin + ifosfamide for these entities.
11. Reichardt P, Lindner T, Pink D et al. Chemotherapy in alveolar soft part sarcomas: what do we know? Eur J Cancer 2003; 39: 1511–1516.
12. Patel SR, Vadhan-Raj S, Burgess MA et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with More controlled randomized trials are needed to tailor therapy sarcomas. Am J Clin Oncol 1998; 21: 317–321.
for patients with different STS subtypes in the future. In 13. Nielsen OS, Dombernowsky P, Mouridsen H et al. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue parallel, we may well obtain tools other than the histiotype, sarcomas. A study by the EORTC soft tissue and bone sarcoma group.
such as molecular markers or other biological or patient-related predictors, to lead us in this tailoring. Furthermore, new drugs, 14. Judson I, Radford JA, Harris M et al. Randomized phase II trial of pegylated new combinations and new dose schedules must be explored to liposomal doxorubicin in the treatment of advanced or metastatic soft tissue optimize therapy and, of course, this is a process without an sarcoma: a study by the EORTC soft tissue and bone sarcoma group.
end. One interesting field where very little has been done so far is the option of combining classical chemotherapeutic drugs 15. Tascilar M, Loos WJ, Seynaeve C et al. The pharmacological basis of ifosfamide use in adult patients with advanced soft tissue sarcomas. Oncologist 2007; 12:1351–1360.
16. Verma S, Younus J, Stys-Norman D et al. Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma. Cancer Treat Rev2008; 34: 339–347.
Even if doxorubicin, with or without ifosfamide, still must be 17. Santoro A, Tursz T, Mouridsen H et al. Doxorubicin versus CyVADIC versus regarded as the main chemotherapeutic drug in most cases of doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcoma: a randomized study of the EORTC soft tissue and bone sarcoma group.
37. Park MS, Patel SR, Ludwig JA et al. Combination therapy with temozolomide and bevacizumab in the treatment of hemangiopericytoma/solitary fibrous tumor.
18. Edmonson JH, Ryan LM, Blum RH et al. Randomized comparison of doxorubicin J Clin Oncol 2008; 26 (15 Suppl): abstract 10512.
alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and 38. Amodio A, Carpano S, Manfredi C et al. Gemcitabine in advanced stage soft cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993; 11: tissue sarcoma: a phase II study. Clin Ter 1999; 150: 17–20.
39. Okuno S, Edmonson J, Mahoney M et al. Phase II trial of gemcitabine in 19. Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized advanced sarcoma. Cancer 2002; 94: 3225–3229.
study of doxorubicin and dacarbazin with or without ifosfamide and mesna 40. Sˇvanca´rova´ L, Blay JY, Judson IR et al. Gemcitabine in advanced adult soft- in advanced soft tissue and bone sarcomas. J Clin Oncol 1993; 11: tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002; 38: 556–559.
20. Bramwell VH, Mouridsen TH, Santoro A et al. Cyclophosphamide versus 41. Patel SR, Gandhi V, Jenkins J et al. Phase II clinical investigation of gemcitabine ifosfamide: final report of a randomized phase II trial in adult soft tissue in advanced soft tissue sarcomas and window evaluation of dose rate on sarcomas. Eur J Cancer Clin Oncol 1987; 23: 311–321.
gemcitabine triphosphate accumulation. J Clin Oncol 2001; 19: 3483–3489.
21. Sleijfer S, Ouali M, Van Glabbeke M et al. Prognostic and predictive factors 42. Hartmann J, Oechsle K, Huober J et al. An open label, non-comparative phase II for outcome to first-line ifosfamide-containing chemotherapy for adult study of gemcitabine as salvage treatment for patients with pretreated adult type patients with advanced soft tissue sarcomas. An exploratory, retrospective soft tissue sarcoma. Invest New Drugs 2006; 24: 249–253.
analysis on large series from the European Organization for Research and 43. Ferraresi V, Ciccarese M, Cercato MC et al. Gemcitabine at fixed dose-rate in Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG).
patients with advanced csoft tissue sarcomas: a mono-institutional phase II study. Cancer Chemother Pharmacol 2008; 63: 149–155.
22. Le Cesne A, Antoine E, Le Chevalier T et al. High-dose ifosfamide: circumvention 44. Von Burton G, Rankin C, Zalupski MM et al. Phase II trial of gemcitabine as first of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.
line chemotherapy in patients with metastatic or unresectable soft tissue sarcoma. Am J Clin Oncol 2006; 29: 59–61.
23. Palumbo R, Palmeri S, Antimi M et al. Phase II study of continuous-infusion 45. Saville MW, Lietzau J, Pluda JM et al. Treatment of HIV-associated Kaposi´s high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcoma with paclitaxel. Lancet 1995; 346: 26–28.
sarcomas. Ann Oncol 1997; 8: 1159–1162.
46. Stebbing J, Wildfire A, Portsmouth S et al. Paclitaxel for antracycline-resistant 24. Patel S, Vadhan-Raj S, Papadopoulos N et al. High-dose ifosfamide in bone and AIDS-related Kaposi’s sarcoma: clinical and angiogenic correlations. Ann Oncol soft tissue sarcomas: Results of phase II and pilot studies—dose response and schedule dependence. J Clin Oncol 1997; 15: 2378–2384.
47. Stoebner PE, Nocera T, Meynadier J et al. Efficacy of docetaxel in disseminated 25. Woll PJ, Van Glabbekke M, Hohenberger P et al. Adjuvant chemotherapy with classical Kaposi’s sarcoma. Br J Dermatol 2000; 143: 1319–1320.
doxorubicin and ifosfamide in soft tissue sarcoma: interim analysis of 48. Chao SC, Lee JY, Tsao CJ. Treatment of classical type Kaposi’s sarcoma with a randomized phase III trial. J Clin Oncol 2007; 25 (18 Suppl): abstract 10008.
paclitaxel. Anticancer Res 2001; 21: 571–573.
26. Le Cesne A, Van Glabbekke M, Woll PJ et al. The end of adjuvant chemotherapy 49. Engin H, Celik I. Treatment of classic Kaposi’s sarcoma with visceral involvement (adCT) era with doxorubicin-based regimens in resected high grade soft by weekly paclitaxel. Clin Oncol 2002; 14: 178.
tissue sarcoma (STS): pooled analysis of the two STBSG-EORTC phase II clinical 50. Osawa R, Kato N, Yanagi T et al. Clearance of recurrent classical Kaposi’s trials. J Clin Oncol 2008; (26 Suppl): abstract 10525.
sarcoma using multiple paclitaxel treatments. Acta Derm Venerol 2007; 87: 27. Pervaiz N, Colterjohn N, Farrokhyar F et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable 51. Fata F, O’Reilly E, Ilson D et al. Paclitaxel in the treatment of patients with soft-tissue sarcoma. Cancer 2008; 113: 573–581.
angiosarcoma of the scalp or face. Cancer 1999; 86: 2034–2037.
28. O’Connor JM, Chacon M, Petracci FE et al. Adjuvant chemotherapy in soft tissue 52. Nagano T, Yamada Y, Ikeda T et al. Docetaxel: a therapeutic option in the sarcoma (STS): a meta-analysis of published data. J Clin Oncol 2008; 26 (Suppl): treatment of cutaneous angiosarcoma. Cancer 2007; 110: 648–651.
53. Skubitz KM, Haddad PA. Paclitaxel and pegylated-liposomal doxorubicin are both 29. Gottlieb JA, Benjamin RS, Baker LH et al. Role of DTIC (NSC-45388) in the active in angiosarcoma. Cancer 2005; 104: 361–366.
chemotherapy of sarcomas. Cancer Treat Rep 1976; 60: 199–203.
54. Isogai R, Kawada A, Aragane Y et al. Successful treatment of pulmonary 30. Buesa JM, Mouridsen HT, van Oosterom AT et al. High-dose DTIC in advanced metastasis and local recurrence of angiosarcoma with docetaxel. J Dermatol soft-tissue sarcomas in the adult. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 1991; 2: 307–309.
55. Yamada M, Hatta N, Mizuno M et al. Weekly low-dose docetaxel in the treatment 31. Zucali PA, Bertuzzi A, Parra HJS et al. The ‘old drug’ dacarbazine as a second/ of lung metastases from angiosarcoma of the head. Br J Dermatol 2005; 152: third line chemotherapy in advanced soft tissue sarcomas. Invest New Drugs 56. Mano MS, Fraser G, Kerr J et al. Radiation-induced angiosarcoma of the breast 32. Woll PJ, Judson I, Lee SM et al. Temozolomide in adult patients with advanced shows major response to docetaxel after failure of anthracyclin-based soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone chemotherapy. Breast 2006; 15: 117–118.
Sarcoma Group. Eur J Cancer 1999; 35: 410–412.
57. Perez-Ruiz E, Ribelles N, Sanchez-Mun˜oz A et al. Response to paclitaxel in 33. Talbot SM, Keohan ML, Hesdorffer M et al. A phase II trial of temozolomide a radiotherapy-induced breast angiosarcoma. Acta Oncol 2009; 48: in patients with unresectable or metastatic soft tissue sarcoma. Cancer 2003; 58. Balcerzak SP, Benedetti J, Weiss GR et al. A phase II trial of paclitaxel in patients 34. Garcia del Muro X, Lopez-Pousa A, Martin J et al. A phase II trial of with advanced soft tissue sarcomas. A Southwest Oncology Group Study. Cancer temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas.
59. Gian VG, Johnson TJ, Marsh RW et al. A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue sarcoma and bone sarcoma.
35. Anderson S, Aghajanian C. Temozolomide in uterine leiomyosarcomas. Gynecol J Exp Ther Oncol 1996; 1: 186–190.
60. Patel SR, Linke KA, Burgess MA et al. Phase II study of paclitaxel in patients with 36. Ferriss JS, Atkins KA, Lachance JA et al. Temozolomide in advanced and soft tissue sarcomas. Sarcoma 1997; 1: 95–97.
recurrent uterine leiomyosarcoma and correlation with O6-methylguanine DNA 61. Gallup DG, Blessing JA, Andersen W et al. Evaluation of paclitaxel in previously methyltransferase expression: a case series. Int J Gynecol Cancer 2010; 20: treated leiomyosarcoma of the uterus: a Gynecologic Oncology Group study.
62. Hensley ML, Maki R, Venkatraman E et al. Gemcitabine and docetaxel in patients 79. Blay JY, von Mehren M, Samuels BL et al. Phase I combination study of with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002; trabectedin and doxorubicin in patients with soft-tissue sarcoma. Clin Cancer 63. Leu KM, Ostruszka LJ, Shewach D et al. Laboratory and clinical evidence of 80. Welt S, Magill GB, Sordillo PP et al. Phase II trial of VP-16-213 in adults with synergistic cytotoxicity of sequential treatment with gemcitabine followed advanced soft tissue sarcomas. Proc Am Soc Clin Oncol 1983; 3: 234.
by docetaxel in the treatment of sarcoma. J Clin Oncol 2004; 22: 81. Blair SC, Zalupski M, Baker LH et al. Ifosfamide and etoposide in the treatment of advanced soft tissue sarcomas. Am J Clin Oncol 1994; 17: 480–484.
64. Bay JO, Ray-Coquard I, Fayette J et al. Docetaxel and gemcitabine combination 82. Kawai A, Chuman H, Makimoto A et al. Ifosfamide–etoposide chemotherapy in in 133 advanced soft-tissue sarcomas: a retrospective analysis. Int J Cancer patients with advanced adult soft tissue sarcomas. J Clin Oncol 2004; 22 65. Maki RG, Wathen K, Patel SR et al. Randomized phase II study of gemcitabine 83. Slevin ML, Clark PI, Joel SP et al. A randomized trial to evaluate the effect of and docetaxel compared with gemcitabine alone in patients with metastatic soft schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol tissue sarcomas: Results of Sarcoma Alliance for Research Through Collaboration study 002. J Clin Oncol 2007; 25: 2755–2763.
84. Sæter G, Alvega˚rd TA, Monge OR et al. Ifosfamide and continuous infusion 66. Hensley ML, Blessing J, Mannel R et al. Fixed-dose rate gemcitabine plus etoposide in advanced adult soft tissue sarcoma. A Scandinavian Sarcoma Group docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: phase II study. Eur J Cancer 1997; 33: 1551–1558.
a Gynecologic Oncology Group phase II trial. Gynecol Oncol 2008; 109: 85. Steins MB, Serve H, Zu¨hlsdorf M et al. Carboplatin/etoposide induces remission of metastasised malignant peripheral nerve tumours (malignant schwannoma) 67. Hensley ML, Blessing J, DeGeest K et al. Fixed-dose rate gemcitabine plus refractory to first-line therapy. Oncol Rep 2002; 9: 627–630.
docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: 86. Licht JD, Mazanet R, Loehrer PJ et al. Phase IV trial of daily oral etoposide in a Gynecologic Oncology Group phase II study. Gynecol Oncol 2008; 109: the treatment of advanced soft-tissue sarcoma. Cancer Chemother Pharm 1994; 68. Hensley ML, Ishill N, Soslow R et al. Adjuvant gemcitabine plus docetaxel for 87. Keizer HJ, Crowther D, Steen Nielsen O et al. EORTC group phase II study of oral completely resected stages I–IV high grade uterine leiomyosarcoma: results of etoposide for pretreated soft tissue sarcoma. Sarcoma 1997; 1: 99–101.
a prospective study. Gynecol Oncol 2009; 112: 563–567.
88. Stoelting S, Trefzer T, Kisro J et al. Low-dose oral metronomic chemotherapy 69. Sutow WW, Berry DH, Huddy TB et al. Vincristine sulphate therapy in children prevents mobilization of endothelial progenitor cells into the blood of cancer with metastatic soft tissue sarcoma. Pediatrics 1966; 38: 465–472.
patients. In Vivo 2008; 22: 831–836.
70. Gottlieb JA, Baker LH, O´Bryan RM et al. Adriamycin (NSC-123127) used alone 89. Blomqvist C, Wiklund T, Pajunen M et al. Oral trofosfamide: an active drug in the and in combination for soft tissue and bone sarcomas. Cancer Chem Rep 1975; treatment of soft-tissue sarcoma. Cancer Chemother Pharmacol 1995; 36: 71. Sordillo PP, Magill GB, Gralla RJ. Phase II evaluation of vindesine sulfate in 90. Kollmannsberger C, Brugger W, Hartmann JT et al. Phase II study of oral patients with advanced sarcomas. Cancer Treat Rep 1981; 65: 515–516.
trofosfamide as palliative therapy in pretreated patients with metastatic soft- 72. Fidias P, Demetri GD, Harmon D. Navelbine shows activity in previously treated tissue sarcoma. Anticancer Drugs 1999; 10: 453–456.
sarcoma patients: phase II results from MGH/DANA Farber/partner’s cancercare 91. Hartmann JT, Oechsle K, Mayer F et al. Phase II trial of trofosfamide in patients study. Proc Am Soc Clin Oncol 1998; 17: 513a.
with advanced pretreated soft tissue sarcomas. Anticancer Res 2003; 23: 73. Dileo P, Morgan JA, Zahrieh D et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas. Cancer 2007; 92. Reichardt P, Pink D, Tilgner J et al. Oral trofosfamide: an active and well- tolerated maintenance therapy for adult patients with advanced bone and soft 74. Garcia-Carbonero R, Supko JG, Manola J et al. Phase II and pharmacokinetic tissue sarcomas. Results of a retrospective analysis. Onkologie 2002; 25: study of ecteinascidin 743 in patients with progressive sarcomas of the soft tissues refractory to chemotherapy. J Clin Oncol 2004; 22: 1480–1490.
93. Issels R, Lindner LH, Wendtner CM et al. Impact of regional hyperthermia (RHT) 75. Yovine A, Riofrio M, Blay JY et al. Phase II study of ecteinascidin-743 in on response to neo-adjuvant chemotherapy and survival of patients with high- advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22: risk soft-tissue sarcoma (HR-STS): results of the randomized EORTC-ESHO intergroup trial (NCI-00003052). Eur J Cancer Suppl 2009; 7: 2 (abstract 1LBA).
76. Le Cesne A, Blay JY, Judson I et al. Phase II study of ET-743 in advanced soft 94. Bonvalot S, Rimareix F, Causeret S et al. Hyperthermic isolated limb perfusion in tissue sarcomas: a European Organisation for the Research and Treatment of locally advanced soft tissue sarcoma and progressive desmoid-type fibromatosis Cancer (EORTC) Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol 2005; with TNF 1 mg and melphalan (T1-M HILP) is safe and efficient. Ann Surg Oncol 77. Demetri GD, Chawla SP, von Mehren M et al. Efficacy and safety of 95. Gru¨nhagen DJ, de Wilt JHW, Van Geel AN et al. Isolated limb perfusion with trabectedin in patients with advanced or metastatic liposarcoma or TNF-a and melphalan in locally advanced soft tissue sarcomas of the leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of extremities. Recent Results Cancer Res 2009; 179: 257–270.
a randomized phase II study of two different schedules. J Clin Oncol 2009; 27: 96. Garcia-Carbonero R, Supko JG, Maki RG et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter 78. Grosso F, Sanfilippo R, Virdis E et al. Trabectedin in myxoid liposarcomas (MLS): phase II and pharmacokinetic study. J Clin Oncol 2005; 23: 5484–5492.
a long-term analysis of a single-institution series. Ann Oncol 2009; 20: 97. Fujimoto M, Hiraga M, Kiyosawa T et al. Complete remission of metastatic clear cell sarcoma with DAV chemotherapy. Clin Exp Dermatol 2003; 28: 22–24.

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