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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: [email protected] 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: [email protected] 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.
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