Stefan Sleijfer, Caroline Seynaeve, Jaap Verweij

Transcription

1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Sarcomas Using Single-Agent Therapy in Adult Patients with Advanced Soft Tissue Sarcoma Can Still Be Considered Standard Care Stefan Sleijfer, Caroline Seynaeve, Jaap Verweij Learning Objectives Department of Medical Oncology, Daniel den Hoed Cancer Centre, Erasmus University Medical Centre, Rotterdam, The Netherlands After completing this course, the reader will be able to: Key Words. Soft tissue sarcoma Adults Chemotherapy 1. Discuss the current status of the chemotherapeutic treatment of advanced soft tissue sarcomas in adult patients. 2. Explain the pitfalls in trial design when reading published papers on performed clinical studies. 3. Discuss the importance of identifying the several subtypes comprising the group of soft tissue sarcomas. 4. Describe new strategies to improve future research in adult soft tissue sarcomas. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract The group of soft tissue sarcomas in adult patients is a heterogeneous group with more than 40 different subtypes. While local treatment remains the mainstay for localized disease, systemic chemotherapy can importantly contribute in the treatment of advanced soft tissue sarcoma. For patients with metastatic disease, chemotherapy is a palliative treatment in the vast majority of the cases. In this setting, toxicity should not outweigh the potential benefits resulting from chemotherapy. In patients with locally advanced disease too extensive for local treatment, systemic chemotherapy can contribute to cure, provided that tumor shrinkage renders subsequent optimal local treatment possible. In these cases, chemotherapeutic regimens yielding the highest response rates achievable should be used. In the last decades, several randomized studies have aimed to determine whether combination regimens yield benefit over single-agent treatment in terms of response rate and overall survival. This review addresses the current available data on chemotherapy for adult patients with soft tissue sarcoma, excluding gastrointestinal stromal tumor, the Ewing-like sarcomas, and other small blue round cell tumors. In addition, it is increasingly recognized that future research in soft tissue sarcoma should focus on the identification of tumor factors that can serve as targets for treatment and that the diverse tumor subtypes should be analyzed separately for their sensitivity to systemic treatment. This review also focuses on these and other strategies that will hopefully lead to better outcomes in this disease entity in the near future. The Oncologist 2005;10: Correspondence: Stefan Sleijfer, M.D., Ph.D., Department of Medical Oncology, Daniel den Hoed Cancer Centre, Erasmus University Medical Centre, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands. Telephone: 31-(0) ; Fax: 31-(0) ; s.sleijfer@erasmusmc.nl Received August 18, 2005; accepted for publication September 26, AlphaMed Press /2005/$12.00/0 The Oncologist 2005;10:

2 834 Combination Chemotherapy for Advanced Soft Tissue Sarcoma in Adults Introduction Adult soft tissue sarcomas are tumors arising from mesenchymal tissue. They can develop at any site in the body but occur predominantly at the extremities in approximately 50% of the cases, the trunk and retroperitoneal space (40%), or head and neck region (10%). With an annual incidence of two to three per 100,000 persons, these are rare tumors accounting for fewer than 1% of all solid malignancies. The group of adult soft tissue sarcomas consists of a very heterogeneous group of tumors, including more than 40 subtypes. All these subtypes differ in terms of genetic alterations, clinical behavior and aggressiveness, dissemination pattern, predominant age of occurrence, and frequently their sensitivity to antitumor agents. Despite these differences, all soft tissue sarcoma subtypes occurring in adults are similarly treated, with the exception of advanced gastrointestinal stromal tumors (GISTs), the Ewing-like sarcomas, and other small blue round cell tumors. For patients with local disease, optimal local treatment consisting of surgical resection followed by radiotherapy is regarded as standard. However, despite considerable improvements in local control rates over the last decades, many patients still develop metastatic disease in due time. Until now, chemotherapy administered as adjuvant treatment has been demonstrated to improve the time to local and distant recurrence but failed to improve overall survival [1]. Systemic chemotherapy should be considered for patients presenting with metastatic disease or with locally advanced disease inaccessible to adequate local treatment. In such locally advanced cases, cure may still be possible if chemotherapy is able to induce tumor shrinkage, rendering the tumor amenable for subsequent optimal local treatment. In these circumstances, chemotherapeutic regimens yielding the highest response rates achievable should be applied. For patients with overt metastatic disease, chemotherapy should be regarded as palliative although in a small subset of patients, long-term survival is achieved [2]. Yet, given that the primary aim is palliation, it is of utmost importance that the toxicity accompanying chemotherapy be in balance with the limited chance of potential benefit of chemotherapy, which should be translated into a period of no (or only a few) disease-related symptoms. This review addresses the chemotherapeutic treatment of adult patients with locally advanced and/or metastatic soft tissue sarcomas, except GIST, the Ewing-like sarcomas, and other small blue round tumors. It focuses, in particular, on the value of multidrug chemotherapeutic combinations compared with single-drug chemotherapy. In addition, strategies aiming to improve the outcome of systemic treatment in this tumor entity will be highlighted. Single-Agent Treatment The anthracycline doxorubicin is one of the few drugs that clearly have antitumor activity against soft tissue sarcoma. As a single agent given in metastatic disease, it induces response rates of approximately 16% 27%, with median overall survival ranging from 7.7 to 12.0 months [3 10]. Although the few studies examining whether there is a dose-response relation of doxorubicin suffer from several methodological flaws, it is generally assumed that such a relation does exist [11]. It is, therefore, commonly recommended to administer doxorubicin at doses above 70 mg/ m 2 in 3-week intervals. In view of the consistent activity of this drug and the acceptable toxicity profile found in several studies, doxorubicin has served as control treatment in most randomized studies performed until now. The use of doxorubicin is mainly limited by myelosuppression and cardiomyopathy, the latter being cumulative, more frequently occurring at total doses exceeding 450 mg/ m 2 and rendering this drug undesirable for application at very high cumulative doses. Strategies have been explored to circumvent or attenuate these toxicities of doxorubicin, which would enable administration of higher doses. One such approach is through administering doxorubicin encapsulated in liposomes with a polyethylene glycol group. In a randomized phase II study, pegylated liposomal doxorubicin had equivalent activity compared with doxorubicin, with less myelotoxicity but at the expense of more skin toxicity [12]. Due to the latter, the application of high doses is also undesirable with this formulation. Another way to attenuate doxorubicin-related side effects is by using epirubicin, a compound very closely related to doxorubicin but considered to possess a more favorable toxicity profile. In a randomized study, two different high-dose epirubicin schedules were compared with doxorubicin but failed to yield any additional benefit and were characterized by greater myelotoxicity [13]. Besides doxorubicin, the drug that consistently shows activity against advanced soft tissue sarcoma is ifosfamide. Like doxorubicin, ifosfamide yields response rates of approximately 25% and a median overall survival of 1 year in metastatic disease [14]. Also for this drug there seems to be a dose-response relationship. Using higher doses of ifosfamide, higher response rates are seen, although these are not translated into better survival while more toxicity is encountered [14 15]. Based on these studies, doses of at least 9 10 g/m 2 per cycle given at 3-week intervals are recommended for single-agent ifosfamide. An even higher dose of 12 g/m 2 leads to unacceptable toxicity [15], whereas above this dose, even when split over 3 4 days, ifosfamide has saturable pharmacokinetics. This means that there is no further formation of the The Oncologist

3 Sleijfer, Seynaeve, Verweij 835 active metabolite, resulting in increased toxicity without an enhancement of the antitumor activity. Unfortunately, there are no randomized studies comparing doxorubicin and ifosfamide when given as a single agent. Nevertheless, given the apparent equivalent activity, ifosfamide given at adequate doses (at least 9 10 g/m 2 per cycle given at 3- week intervals) seems to be a valid alternative in patients for whom doxorubicin is contraindicated. The third agent with modest activity in soft tissue sarcoma yielding a response rate exceeding 10% is dacarbazine. It should be noted, however, that this agent has not been thoroughly evaluated. Dacarbazine applied in high doses of 1.2 g/m 2 as second line yields a response rate of approximately 20%, but with the very short response duration of only 8 weeks [16]. Many other chemotherapeutic drugs have been assessed as first- or second-line treatment in this disease. Only two of these, docetaxel [17] and cyclophosphamide [18], have been directly compared with doxorubicin or ifosfamide, respectively, but both exhibited inferior antitumor activity. Drugs tested in a single-arm study design include gemcitabine [19, 20], paclitaxel [21, 22], temozolomide [23], mitoxantrone [24], methotrexate [25], topotecan [26], and etoposide [25], but all were judged to lack substantial antitumor activity. Anthracycline-Based Combination Chemotherapy Compared with Anthracycline Monotherapy Numerous drug combinations have been explored for their efficacy and activity in advanced soft tissue sarcoma. As combinations containing at least one active compound can always be anticipated to show some activity, such combinations should be explored in a randomized setting to avoid patients selection bias [27]. Unfortunately, because most of the combinations tested have not been randomly assessed, it is very difficult to draw conclusions about their exact efficacy. Until now, eight randomized studies comparing doxorubicin-based combinations with a doxorubicin control arm have been published as full papers (Table 1). Two of these studies were limited to patients with uterine sarcomas [6, 7]. Therefore, the results of these two studies are not completely applicable to the whole group of soft tissue sarcomas, given their heterogeneity. In the eight randomized studies, there was no superiority in terms of response rate and median overall survival over doxorubicin alone for the combinations of doxorubicin and streptozocin [3]; doxorubicin, vincristine, and cyclophosphamide [4]; doxorubicin and cyclophosphamide [7]; doxorucin and vindesine [8]; doxorubicin, mitomycin, and cisplatin [9]; or doxorubicin, vincristine, cyclophosphamide, and dacarbazine [10]. In addition, the application of these combinations was at the expense of more toxicity, in particular more bone marrow suppression. One reason for the nonsuperiority of these combinations is that many of the agents used in the combinations are actually inactive, which became clear later on. Moreover, the doses of doxorubicin, the most active compound, had to be reduced in most combinations to accommodate the overlapping toxicities with the other drugs used. Furthermore, some of these studies were conducted in relatively small numbers of patients. Two combinations were shown to yield a statistically significant advantage in response rates over doxorubicin monotherapy. These higher responses, however, were not translated into increased survival, whereas toxicity with the combination regimen was more pronounced. The first combination consisted of doxorubicin (60 mg/m 2 ) and dacarbazine (250 mg/m 2 days 1 5) and was compared with doxorubicin given at a dose of 70 mg/m 2 [5]. In this study, the combination yielded a response rate of 30%, whereas doxorubicin alone achieved a response in 18% of the patients. However, the response rate in the patients allocated to receive doxorubicin alone was somewhat lower than usually seen with this drug. Furthermore, in another study assessing the same combination at similar doses, but in patients with uterine sarcomas, no benefit was seen over doxorubicin alone, which was given at a lower dose of 60 mg/m 2 [6]. The other combination resulting in a better response rate than doxorubicin alone was doxorubicin with ifosfamide [9]. This study was a random comparison of doxorubicin (80 mg/m 2 ) versus doxorubicin (60 mg/m 2 ) in combination with ifosfamide (3.75 g/m 2 per day for 2 days). The response rates significantly differed between the doxorubicin-alone and the combination arms (20% and 34%, respectively). However, also in this study, no difference in overall survival was reached whereas toxicity was clearly increased in the combination. Again, the better response rate of this combination over doxorubicin alone was not confirmed in another randomized study of larger size, although in this latter study lower doses were used (doxorubicin 50 mg/m 2 and ifosfamide 5 g/m 2 ) [10]. In view of the dose-response relations of both doxorubicin and ifosfamide that only recently were recognized, doubts have been raised whether optimal doses of these two drugs were used in these studies. Therefore, the European Organization of Research and Treatment of Cancer (EORTC) has initiated a large study randomly assigning patients to either doxorubicin (75 mg/ m 2 ) or doxorubicin (75 mg/m 2 ) combined with ifosfamide (10 g/m 2 per cycle). This study is still in progress. Recently, a meta-analysis from the Cochcrane group of the eight studies comparing doxorubicin monotherapy with doxorubicin-based combinations was published [28]. In the pooled analysis, a slightly higher response rate in favor of combination chemotherapy was revealed, but that rate

4 836 Combination Chemotherapy for Advanced Soft Tissue Sarcoma in Adults Table 1. Randomized trials comparing anthracycline-based combinations versus anthracyline alone Reference Regimens [3] Dox Dox/Strept [4] Dox Dox/VCR/ Cyclo [5] Dox Dox/DTIC [6] Dox Dox/DTIC [7] Dox Dox/Cyclo [8] Dox Dox/VDN [9] Dox Dox/Ifos Dox/MITC/ cddp [10] Dox Dox/VCR/ Cyclo/DTIC Dox/Ifos [29] Epi Epi/cDDP Dose (mg/m 2 ) per cycle 60 60/2, /1.4/ /1, /1, / / /7,500 40/8/ /1.5/500/750 50/ /120 No. of patients did not reach statistical significance (odds ratio [OR] 1.26; 95% confidence interval [CI], ; p =.10). Also, the overall survival at 1 and 2 years did not differ between doxorubicin and the assessed multidrug combinations, with ORs of 0.87 (95% CI, ; p =.14) and 0.84 (95% CI, ; p =.13), respectively. Although high-dose epirubicin did not exhibit an increased antitumor activity as compared with doxorubicin [13], single-agent high-dose epirubicin (180 mg/m 2 per cycle) served as the control arm in a study assessing the efficacy of the combination of epirubicin and cisplatin (180 mg/m 2 and 120 mg/m 2 per cycle, respectively) [29]. In this study, the combination showed superiority in terms of response rate (29% versus 54%) and overall survival (1-year survival approximately 10% versus 30%). The outcomes of this study are remarkable because cisplatin is not considered a very active agent in soft tissue sarcomas, suggesting that these agents interact synergistically. In addition, the 1-year overall survival in the epirubicin-alone group is rather low compared with other studies, which may account for the statistical difference in overall survival. Furthermore, it should be noted that selection bias may play a role in the favorable Response rate (%) Median overall survival (months) a a a a 7 10 a Remarks Only patients with sarcoma of the uterus Only patients with sarcoma of the uterus CYVADIC arm prematurely closed after interim analysis Median overall survival not reported for whole group a Statistically significant difference compared with control arm (p <.05) Abbreviations: cddp, cisplatin; Cyclo, cyclophosphamide; CYVADIC, cyclophosphamide, vincristine, adriamycin, and dacarbazine; Dox, doxorubicin; DTIC, dacarbazine; Epi, epirubicin; Ifos, ifosfamide; MITC, mitomycin-c; Strept, streptozocin; VCR, vincristine; VDN, vindesine. outcomes of this study. The high doses of epirubicin applied in both arms were deemed tolerable, which is in contrast with another study in which unacceptable toxicity was encountered using epirubicin doses above 150 mg/m 2 per cycle [13]. With the exception of the latter study, which should be confirmed by others before this regimen can be recommended, no combination regimen has shown a clear benefit in overall survival over doxorubicin alone in light of the current available data. Therefore, doxorubicin monotherapy can still be considered the standard palliative therapy for adult patients with metastatic soft tissue sarcoma. Randomized Trials Comparing Anthracycline- Containing Combination Treatments Several trials compared polychemotherapeutic regimens with each other despite the fact that no combination has yet been convincingly shown to be superior to doxorubicin alone (Table 2). Antman et al. [30] reported on the comparison of doxorubicin and dacarbazine (AD) versus the same combination with the addition of ifosfamide and mesna (MAID). Initially, a dose of 7.5 g/m 2 ifosfamide was used, which was adjusted to 6 g/m 2 later because of unac- The Oncologist

5 Sleijfer, Seynaeve, Verweij 837 Table 2. Randomized studies comparing combination regimens with each other Reference Regimens [30] Dox/DTIC Dox/DTIC/Ifos [31] Dox/DTIC Dox/DTIC/Cyclo Dox/DTIC/Dact [32] Dox/VCR/Cyclo/DTIC Dox/DTIC + Cyclo/ VCR [33] Dox/Ifos Dox/Ifos [34] Dox/Ifos Dox/Ifos Dose (mg/m 2 ) per cycle 60/1,000 60/750/1,000 60/1,250 60/1,250/500 60/1,250/1.2 50/1.5/500/1,250 50/1, /1.5 50/5,000 75/5,000 60/6,000 60/12,000 ceptable bone marrow suppression. Response rate (17% versus 32%) and time to progression (4 versus 6 months) both favored MAID. The overall survival, however, was (in statistically significant terms) better for the two-drug regimen (median 11.9 versus 13.3 months), though these survival figures are in the same range as those reported for single-agent doxorubicin. Another three-arm study compared doxorubicin plus dacarbazine with the same two drugs with either cyclophosphamide or actinomycin-d [31]. No differences in response rate or overall survival were seen between the three arms, consistent with the notion that cyclophosphamide and actinomycin-d are inactive agents in soft tissue sarcomas. In a study examining the scheduling of combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dacarbazine, patients were randomized to receive these drugs simultaneously every 4 weeks or in pairs (doxorubicin and dacarbazine alternated with cyclophosphamide and vincristine) [32]. The latter regimen yielded a poorer response rate, which in retrospect is not surprising given the lack of activity of cyclophosphamide and vincristine as is currently known. Through the alternating scheduling, the dose density and intensity of the active drugs in this combination (doxorubicin and dacarbazine) were very low, thereby compromising activity. There were no differences in toxicity or overall survival. As previously mentioned, one of the most important reasons underlying the failure of combinations to show superiority over doxorubicin alone is thought to lie in the No. of patients Response rate (%) Median overall survival (months) a 11.9 a a /7 preoperative 3/13 metastatic 3/17 preoperative 3/12 metastatic NR NR Remarks Dox/DTIC + Cyclo/ VCR was alternately given Both metastatic and localized disease. Localized (52 pts, 25 adjuvant, 27 pts preoperative), metastatic (27 pts) a Statistically significant difference compared with other arm (p <.05) Abbreviations: Cyclo, cyclophosphamide; Dact, actinomycin-d; Dox, doxorubicin; DTIC, dacarbazine; Ifos, ifosfamide; NR, not reached; pts, patients; VCR, vincristine. fact that doxorubicin and ifosfamide had to be given in lower doses when combined because of overlapping toxicity, in particular bone marrow depression. The occurrence of neutropenic events, which is generally considered the most severe sequelae of myelosuppression, can be attenuated to a large extent by the use of hematopoietic growth factors. Therefore, the EORTC Soft Tissue and Bone Sarcoma Group conducted a trial comparing doxorubicin (50 mg/m 2 ) and ifosfamide (5 g/m 2 ) with a higher dose of doxorubicin (75 mg/m 2 ) with the same dose of ifosfamide supported by granulocyte-macrophage colony-stimulating factor (GM-CSF) [33]. Response rate was equivalent in both arms. Progression-free survival was better for the intensified regimen, but this was not reflected in an enhanced overall survival. Another study assessed the value of increasing the ifosfamide dose [34]. In this study, doxorubicin (60 mg/m 2 ) with ifosfamide at 6 g/m 2 per cycle was randomly compared with doxorubicin in the same dose combined with high-dose ifosfamide at 12 g/m 2 per cycle. A heterogeneous group of patients was allocated to this study, receiving chemotherapy preoperatively, as adjuvant treatment or as palliative treatment in case of metastatic disease. The number of allocated patients was rather small, being stratified for localized or metastatic disease. In those patients in whom a response could be established, there was no difference in response rates between both arms. Also, the overall survival did not differ between treatment arms. Due to the small number of patients, no firm conclusions can be made.

6 838 Combination Chemotherapy for Advanced Soft Tissue Sarcoma in Adults However, in view of the available data, increasing the doses of doxorubicin and ifosfamide above the levels considered optimal does not seem to augment the efficacy when given in combination. This applies also for the response rate. Collectively, these studies do not lend support for the application of combination regimens for this tumor entity, either in the metastatic or in the preoperative setting. Factors Affecting Outcome of Chemotherapeutic Treatment Several studies have examined whether specific factors have an influence on the outcome of chemotherapy in adult patients with soft tissue sarcomas. The largest report was an analysis of 2,185 patients participating in EORTC studies [35]. In multivariate analysis, absence of liver metastases, young age, and a high histopathological grade were identified as favorable factors for response to chemotherapy. In the same cohort, good performance status, young age, no liver involvement, a low histopathological grade, and a long time period between primary diagnosis and initiation of chemotherapy were independently associated with a better overall survival [35]. The phenomenon that a high tumor grade is associated with a better response but with a shorter overall survival was confirmed in other series [30]. This strongly suggests that tumors with a higher proliferation rate are initially more sensitive to chemotherapy but that these responses are short-lived and are followed by rapid progression as a consequence of which the overall survival is short. The EORTC also analyzed the characteristics of longterm survivors after initial chemotherapeutic treatment of advanced disease, roughly in the same group as used for the identification of prognostic factors associated with response and overall survival. A survival lasting longer than 5 years in this cohort was observed in 66 out of 1,888 patients (8%) [2]. Using multivariate analysis, a good performance, female gender, low-grade tumors, and complete response after first-line treatment were identified as predictive for 5-year survival. The Oncologist Histological Subtypes Despite great differences among the diverse subtypes comprising the group of soft tissue sarcomas, tumor subtype has not been revealed as an important independent determinant for the outcome of chemotherapy [35]. However, most, if not all, sarcoma experts are strongly convinced that tumor subtypes differ in their susceptibility to chemotherapy and that treatment strategies should therefore be tailored according to subtype. There are several indications to support this notion. For instance, the progression-free rates (PFRs) after first-line chemotherapeutic treatment differ considerably between the distinct subtypes with synovial sarcomas and GIST as positive and negative outliers, with a PFR at 3 months after first-line chemotherapeutic treatment of 77% and 44%, respectively [36]. Furthermore, synovial sarcoma is considered by experts to be sensitive to ifosfamide, in particular, although published data supporting this expert-based opinion are lacking. Paclitaxel, which has been shown to be inactive for the whole group of soft tissue sarcomas [21, 22], yielded a promising, high response rate in patients with angiosarcoma of the scalp [37]. A similar situation holds true for the combination of gemcitabine and docetaxel. Both are regarded as inactive as single agents [17, 19, 20] but demonstrated an impressive response rate when combined in patients with metastatic leiomyosarcoma [38]. It should be emphasized, however, that none of these treatments has been tested in a randomized fashion yet. A study by the Sarcoma Alliance for Research Through Collaboration that randomly allocated patients to single-agent gemcitabine or to the combination of gemcitabine and docetaxel was recently completed, and results are expected shortly. The most convincing evidence that subtypes should be treated separately is based on the successes obtained in GIST with imatinib (Glivec Novartis International AG, Basel, Switzerland, novartis.com). Advances in molecular biology revealed that GIST depends for its malignant behavior on activating mutations in the genes encoding CD117 or platelet-derived growth factor receptor-α (PDGFRA). Through these activating mutations, these proteins that use tyrosine kinase activity for signal transduction are constitutively activated. Imatinib inhibits the tyrosine kinase activity and thereby the function of several proteins, including CD117 and PDGFRA. Because of the dependency of GIST on activated CD117 or PDGFRA, imatinib results in an impressive response rate exceeding 50%, whereas stable disease is achieved in many of the remaining patients. This translates into more than 50% of the patients being alive at 2 years after treatment initiation, a major improvement in comparison with the 10% 2-year survival rate obtained with single-agent doxorubicin [39]. Furthermore, it has been found that imatinib also exerts antitumor activity in dermatofibrosarcoma protuberans (DFSP), a tumor type that depends on activating mutations in the PDG- FRB gene [40]. In sarcomas other than GIST or DFSP, imatinib failed to exert antitumor activity [41]. This is very likely due to the fact that these tumor subtypes are not driven by one or more factors sensitive to inhibition by imatinib. All together, these findings indicate that the subtypes comprising the group of soft tissue sarcomas differ strongly in their sensitivity to the different drugs. Consequently, these subtypes should be separately tested in clinical trials. Although at first glance the rarity of soft tissue sarcomas may hinder such separate assessment of the different sub-

7 Sleijfer, Seynaeve, Verweij 839 types, the short time period elapsed between the appearance of the first case report [42] and the publication of a large phase III study with imatinib in advanced GIST [39] shows that this can be achieved in a relatively short time, provided that patients with advanced sarcomas are referred for systemic treatment to specialized centers. The increasing trend of considering worldwide trials for these disease entities, stimulated by institutions such as the Connective Tissue Oncology Society, will further support this aim. Future Directions The above-mentioned data obviously underscore the importance of future research focusing primarily on the diverse subtypes and their different susceptibility to antitumor treatments. Additionally, we should pursue better characterization and identification of factors driving the different subtypes, which is very likely to offer possibilities for new treatment modalities. Potential examples of the latter include drugs targeting the epidermal growth factor-1 (EGFR1) in synovial sarcomas, given the frequent overexpression of EGFR1 in this tumor type [43], or drugs such as Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) agonistic antibodies in liposarcomas overexpressing the TRAIL-receptor 1 [44]. Another potential target for therapy is the process of angiogenesis, a prerequisite for the development and dissemination of all tumor types, including soft tissue sarcomas. The value of several anti-angiogenic agents is currently being evaluated in advanced soft tissue sarcomas. Furthermore, a promising approach aiming to enhance the efficacy of systemic therapy may lie in the combinations of conventional chemotherapeutic drugs and novel compounds. In breast cancer, for example, the addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2)/Neu, enhances the efficacy of taxanes in HER2/Neu-overexpressing tumors. Likewise, bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), increases the activity of fluoropyrimidine-based chemotherapy in advanced colorectal carcinoma. The synergism of this combination is thought to be partially through a bevacizumab-mediated decrease of the interstitial fluid pressure in the tumor, thereby facilitating the penetration of chemotherapeutic drugs into the tumor. It can be anticipated that similar mechanisms will also hold true when applied in soft tissue sarcomas. Other important points of attention for future trials in soft tissue sarcomas are the establishment of new end points and the application of new study designs. For instance, despite the fact that imatinib yields a high response rate in advanced GIST, tyrosine kinase inhibitors are regarded as cytostatic rather than cytotoxic. Therefore, response rates according to the standard criteria (e.g., the World Health Organization and RECIST [Response Evaluation Criteria in Solid Tumors]) are likely to underestimate the actual antitumor activity of these agents. In addition, the discrepancy between better response rates and poorer survival rates in high-grade soft tissue sarcomas underlines that response rate is not a suitable end point for the assessment of palliative therapy in this disease. New end points, such as progression arrest [45], the ratio between the time to progression before and after treatment [46], or PFRs at certain points of time, might be more relevant [36]. PFRs at 3 and 6 months have already been proposed as a reference standard enabling discrimination between active and inactive regimens [36]. Based on this new end point, a novel compound called ET-743(Ecteinascidin 743), a DNA minor groove binder, showed promising antitumor activity in soft tissue sarcomas. Although a response rate of only 8% was seen, 45% of the patients achieved relatively long lasting stable disease, with 29% of the patients being progression-free at 6 months [47]. New study designs may also facilitate the more rapid assessment of novel agents or regimens with respect to antitumor activity (Table 3). Examples are randomized phase II studies with early stopping rules or hierarchical Bayesian approaches [48]. Especially for agents thought to yield clinical benefit by inducing long-lasting stable disease, the socalled randomized discontinuation design looks attractive [49]. In this design, patients achieving stable disease at a predefined point of time after treatment initiation are randomized to either continuation or cessation of the drug to assess whether it is really the drug and not the natural course of the disease that underlies the progression-free period. However, Table 3. Suggested means for improving future clinical trials in adults soft tissue sarcomas Tumor-related Drug-related New end points New study designs Focusing on the diverse specific subtypes Identification of tumor targets Novel compounds directed toward specific tumor targets Combinations of conventional chemotherapy and new compounds Progression arrest Time to progression before and after treatment Progression-free rate Randomized phase II trials with early stopping rules Hierarchical Bayesian approaches Randomized discontinuation design

8 840 Combination Chemotherapy for Advanced Soft Tissue Sarcoma in Adults it should be noted that this design may be prone to false-positivity when testing kinase-targeted inhibitors because there are indications that tumor growth acceleration occurs after stopping treatment with drugs such as imatinib [50]. References 1 [No authors listed.] Adjuvant chemotherapy for localized resectable softtissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta- Analysis Collaboration. Lancet 1997;350: Blay J-Y, van Glabbeke M, Verweij J et al. Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy. Eur J Cancer 2003;39: Chang P, Wiernik PH. Combination chemotherapy with doxorubicin and streptozocin. I. Clinical results in patients with advanced sarcoma. Clin Pharmacol Ther 1976;20: Schoenfeld DA, Rosenbaum C, Horon J et al. A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycine-d and cyclophosphamide for advanced sarcoma. Cancer 1982;50: Borden EC, Amato DA, Rosenbaum C et al. Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcoma. J Clin Oncol 1987;5: Omura GA, Major FJ, Blessing JA et al. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcoma. Cancer 1983;52: Muss HB, Bundy B, DiSaia J et al. Treatment of recurrent or advanced uterine sarcoma: A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 1985;55: Borden EC, Amato DA, Edmonson JH et al. Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft tissue sarcomas. Cancer 1990;66: Edmonson JH, Ryan LM, Blum RH et al. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993;11: Conclusions In the past 30 years, many studies have aimed at identifying more active chemotherapeutic regimens. Despite these efforts, there is no regimen with improved efficacy in terms of overall survival other than monotherapy doxorubicin given at appropriate doses. In view of the latter and the increased toxicity accompanying combination regimens, patients with metastatic disease should not be treated with combination chemotherapy outside the context of a clinical trial. Also with regard to response rate, which is of particular importance for patients with locally advanced disease to whom chemotherapy is given with the aim of tumor shrinkage and facilitating optimal local treatment afterward, it has not been convincingly proven that combination chemotherapy yields a better outcome. This also applies for the combination of doxorubicin and ifosfamide, theoretically the most promising combination given the single-agent activity of both agents. Even when the doses of both agents are increased to levels above those considered optimal, there is no available evidence that this combination yields better efficacy. It can be anticipated that the final results of the ongoing EORTC study comparing single-agent doxorubicin versus doxorubicin and ifosfamide, all drugs applied in doses regarded as optimal, will definitely answer the question of whether this combination regimen yields better outcomes. For the future, it is evident that research should focus more on the specific subtypes as it is increasingly recognized that systemic treatment should be tailored according to the exact tumor subtype. Furthermore, it is envisioned that improved understanding of the mechanisms underlying the malignant behavior of the diverse subtypes will help identify factors that can serve as targets for novel treatments. The importance of such approaches is underscored by the successes obtained in GIST. Hopefully, similar breakthroughs will be achieved shortly in other soft tissue sarcoma subtypes. Disclosure of Potential Conflicts of Interest The authors indicate no potential conflicts of interest. 10 Santoro A, Tursz T, Mouridsen HT et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcoma: a randomized study of the European Organization of Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995;13: OʼBryan RM, Baker LH, Gottlieb JE et al. Dose-response evaluation of adriamycin in human neoplasia. Cancer 1977;39: Judson I, Radford JA, Harris M et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL /CAELYX ) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001;37: Nielsen OS, Dombernowsky P, Mouridsen HT et al. High-dose epirubicin is not an alternative of standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Br J Cancer 1998;78: van Oosterom AT, Mouridsen HT, Nielsen OS et al. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first-and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 2002;38: Nielsen OS, Judson I, van Hoesel Q et al. Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2000;36: Buesa JM, Mouridsen HT, van Oosterom AT et al. High-dose DTIC in advanced sarcomas in the adult. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 1991;2: Verweij J, Lee SM, Ruka W et al. Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the European Organization of Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 2000;18: The Oncologist

9 Sleijfer, Seynaeve, Verweij Bramwell VH, Mouridsen HT, Santoro A et al. Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization of Research and Treatment Cancer (EORTC), Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 1993;31(suppl 2):S180 S Okuno S, Ryan LM, Edmonson JH et al. Phase II trial of gemcitabine in patients with advanced sarcomas (E1797). Cancer 2003;97: Švancárová L, Blay JY, Judson IR et al. Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002;38: Balcerzak SP, Benedetti J, Weiss GR et al. A phase II trial of paclitaxel in patients with advanced soft tissue sarcomas: a Southwest Oncology Group study. Cancer 1995;76: Gian VG, Johnson TJ, Marsch RW et al. A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue or bone sarcomas. J Exp Ther Oncol 1996;1: Woll PJ, Judson I, Lee SM et al. Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 1999;35: Muss HB, Bundy BN, Adcock L et al. Mitoxantrone in the treatment of advanced uterine sarcoma. A phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol 1990;13: Brennan MF, Alektiar KM, Maki RG. Soft tissue sarcoma. In: DeVita Jr VT, Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology, 6th Ed. Philadelphia: Lippincott Williams & Wilkins 2001: Budd GT, Rankin C, Hutchins LF et al. Phase II trial of topotecan by continuous infusion in patients with advanced soft tissue sarcomas, a SWOG study. Invest New Drugs 2002;20: van Glabbeke M, Steward W, Armand JP. Non-randomised phase II trials of drug combinations: often meaningless, sometimes misleading. Are there alternative strategies? Eur J Cancer 2002;38: Bramwell VHC, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adults with locally advanced or metastatic soft tissue sarcoma. The Cochcrane Database of Systematic Reviews 2001;4. 29 Jelic S, Kovcin V, Milanovic N et al. Randomized study of high-dose epirubicin versus high-dose epirubicin and cisplatin chemotherapy for advanced soft tissue sarcoma. Eur J Cancer 1997;33: Antman K, Crowley J, Balcerzak SP et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11: Baker LH, Frank J, Fine G et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin-d for advanced soft tissue sarcomas: a randomized comparative trial. A phase III Southwest Oncology Group Study (7613). J Clin Oncol 1987;5: Pinedo HM, Bramwell VH, Mouridsen HT et al. Cyvadic in advanced soft tissue sarcoma: a randomized study comparing two schedules. A study of the EORTC Soft Tissue and Bone Sarcoma Group. Cancer 1984;53: Le Cesne A, Judson I, Crowther D et al. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a trial of the European Organization of Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol 2000;18: Worden FP, Taylor JMG, Biermann JS et al. Randomized phase II evaluation of 6 g/m 2 of ifosfamide plus doxorubicin and granulocyte colonystimulating factor (G-CSF) compared with 12 g/m 2 of ifosfamide plus doxorubicin and G-CSF in the treatment of poor-prognosis soft tissue sarcoma. J Clin Oncol 2005;23: van Glabbeke M, van Oosterom AT, Oosterhuis JW et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens -- A European Organization of Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1999;17: van Glabbeke M, Verweij J, Judson J et al. Progression-free rate as the principal end point for phase II trials in soft tissue sarcomas. Eur J Cancer 2002;38: Fata F, OʼReilly E, Ilson D et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 1999;86: Hensley ML, Maki R, Venkatraman E et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002;20: Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: a randomised trial. Lancet 2004;364: McArthur GA, Demetri GD, van Oosterom AT et al. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: imatinib target exploration consortium study B2225. J Clin Oncol 2005;23: Verweij J, van Oosterom A, Blay J-Y et al. Imatinib mesylate (STI-571, Glivec, Gleevec ) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target: results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39: Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344: Nielsen OS, West RB, Linn SC et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet 2002;359: Tomek S, Koestler W, Horak P et al. Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines. Eur J Cancer 2003;39: van Oosterom AT. Phase II new drug trials in soft tissue sarcomas. In: Pinedo H and Verweij J, eds. Clinical Management of Soft Tissue Sarcomas. Boston: Martinus Nijhoff Publishers, 1986: Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for noncytotoxic anticancer agents for which time to disease progression is the primary end-point. Control Clin Trials 2000;21: Le Cesne A, Blay JY, Judson I et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organization of Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group trial. J Clin Oncol 2005;23: Thall PF, Wathen JK, Bekele N et al. Hierarchical bayesian approaches to phase II trials in diseases with multiple subtypes. Stat Med 2003;2003: Rosner GL, Stadler W, Ratkin MJ. Randomized discontinuation design: application to cytostatic antineoplastic agents. J Clin Oncol 2002;20: van den Abbeele AD, Badawi RD, Manola J et al. Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning. Proc Annual Meeting Am Soc Clin Oncol 2004;3012a.