Chemotherapy for Soft Tissue Sarcoma

Chemotherapy for Soft Tissue Sarcoma Ravin Ratan, MD; and Shreyaskumar R. Patel, MD Soft tissue sarcoma is a term used to describe a heterogeneous group of many rare tumors. Since the initial description of activity of doxorubicin, several additional agents have been brought to bear in the treatment of these diseases. Despite 2 recent drug approvals, doxorubicin and ifosfamide remain the most effective chemotherapy drugs available for the treatment of majority of these tumors. Optimal dosing and administration influence outcomes because of the steep dose-response curves associated with these agents. The debate endures regarding whether patients who have advanced disease should routinely receive single agents sequentially or in combination. Adjuvant therapy remains similarly controversial, although meta-analyses do support its use. Contemporary treatment of soft tissue sarcoma routinely incorporates additional lines of treatment that have become available over the last 15 years. Fixed-doserate gemcitabine with or without docetaxel is a standard second-line treatment. In keeping with the paradigm shift favoring subsetspecific therapy, several recent approvals are linked with specific sarcoma subtypes. Eribulin has recently been approved on the basis of improved overall survival for patients with adipocytic sarcomas, and trabectedin is now approved in the United States for patients with leiomyosarcoma and liposarcoma. Within the spectrum of targeted therapies, pazopanib is approved for all nonadipocytic sarcomas, and imatinib is approved for dermatofibrosarcoma protuberans. Each of these drugs represents incremental rather than radical progress, although they constitute important and much needed treatment options for patients with these diseases. Cancer 2016;122:2952-60. VC 2016 American Cancer Society. KEYWORDS: chemotherapy, adjuvant, doxorubicin, drug therapy, ifosfamide, sarcoma. INTRODUCTION Soft tissue sarcoma is a term used to describe over 50 recognized entities according to the World Health Organization (WHO) classification. Despite the variety of tumor types, these cancers represent less than 1% of incident cancers in the United States, with an estimated 11,930 diagnoses and 4870 deaths in 2015. 1 Given their relative rarity, there is limited experience caring for patients with soft tissue sarcoma outside of specialty centers. This review is intended to serve as an overview of the approved and commonly used therapies to treat soft tissue sarcomas, with guidance regarding the appropriate choice and dosing of these agents, particularly cytotoxic chemotherapies. Like in many rare diseases, there is disagreement on some aspects of management that is borne out of the limitations of small sample size, heterogeneity of the patient population, and variable treatment regimens. We have attempted to highlight these areas while also explaining the approach taken by our center. DOXORUBICIN Before the introduction of doxorubicin in the 1970s, most sarcomas were treated with regimens incorporating vincristine, actinomycin-d, and cyclophosphamide (VAC). 2 Clinical responses with these older regimens reportedly were as high as 23.5%, but many of those were in pediatric rhabdomyosarcoma, a particularly sensitive subtype for which VAC remains in use today. Among other unselected sarcomas, the clinical response rate was much lower. 2 Doxorubicin, an antitumor antibiotic, was initially introduced in the 1970s 3,4 and remains one of the most efficacious agents routinely used in the treatment of soft tissue sarcomas. O Bryan and colleagues were the first to describe the steep dose-response curve observed with this agent. In a study examining increasing doses of doxorubicin given to patients with several different malignancies, response rates in soft tissue sarcoma were 0% at 25 mg/m 2, 11% at 50 mg/m 2, 20% at 60 mg/m 2, and 37% at 75 mg/m 2. 3 The dose-response curve in that study was not as pronounced in other malignancies, including breast cancers and lymphomas. In a recent frontline study, the response rate to single-agent doxorubicin in soft tissue sarcoma was approximately 14%. 5 The lower rate likely reflects the use of more stringent computed tomographybased criteria in the evaluation of tumor response in modern clinical trials. Corresponding author: Shreyaskumar R. Patel, MD, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0345, Houston, TX 77005; Fax: (713) 794-1934; spatel@mdanderson.org Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas DOI: 10.1002/cncr.30191, Received: April 11, 2016; Accepted: April 14, 2016, Published online July 19, 2016 in Wiley Online Library (wileyonlinelibrary.com) 2952 Cancer October 1, 2016

Chemotherapy for Soft Tissue Sarcoma/Ratan and Patel The importance of giving optimal doses of doxorubicin is often overlooked by clinicians who have less experience treating sarcomas. In our practice, and in modern studies of dose-intensive chemotherapy, 75 mg/m 2 of doxorubicin has been targeted as an appropriate dose in otherwise fit patients, both as a single agent and in combination with other therapies. 5,6 Regimens incorporating higher doses than this have been described, but data on the efficacy of doses in excess of 75 mg/m 2 have been equivocal. 7 Given the increased risk of toxicity and lack of demonstrated benefit, higher doses are rarely used. DACARBAZINE Dacarbazine is an alkylating agent that was initially introduced into the treatment of sarcomas in the early 1970s. 4 In the initial studies, as summarized by Gottlieb et al, the clinical response rate for single-agent dacarbazine was approximately 17%. 8 Randomized trials of modern agents in patients with relapsed sarcomas using computed tomography-based staging criteria have demonstrated single-agent response rates in the range from 5% to 8% in pretreated patients. 9,10 At our institution, dacarbazine is often used in combination with doxorubicin, particularly in patients who, because of age or comorbidities, may not tolerate ifosfamidebased chemotherapy regimens. In the initial studies, the combination of doxorubicin and dacarbazine was noted to have a clinical response rate of 41%. 4 More recent randomized trials using cross-sectional imaging-based criteria have demonstrated response rates in the range from 16% to 30%. 11-13 Despite evidence in at least 1 study of a significantly improved response rate, no randomized study has demonstrated significantly improved overall survival for the combination over single-agent doxorubicin. IFOSFAMIDE Before the introduction of doxorubicin, cyclophosphamide was often incorporated into sarcoma regimens as part of VAC, although it appears to have been most effective in pediatric rhabdomyosarcomas. Ifosfamide, which initially was introduced in the late 1970s, was noted to have single-agent activity in sarcoma, although it was not vigorously investigated because of the prohibitive incidence of hemorrhagic cystitis and renal dysfunction. The introduction of mesna, a compound that detoxifies the acrolein metabolite of ifosfamide and prevents bladder toxicity, allowed for additional study and subsequent widespread use of the drug. 14 A phase 2 study performed by investigators at the Royal Marsden Hospital looked at ifosfamide at doses from 5 to 8 g/m 2 given as a 24-hour infusion every 3 weeks with mesna in patients with metastatic soft tissue sarcoma. The overall response rate in that study based on WHO criteria was 38%. 15 Subsequently, a randomized study comparing single-agent ifosfamide 5 g/m 2 with single-agent cyclophosphamide 1.5 g/m 2 was conducted. Also using WHO criteria, the single-agent response rate to cyclophosphamide was 9%, compared with 18% for ifosfamide. This was statistically significant, and the incidence of bladder and renal complications was minimal. 14 Going forward, ifosfamide was studied extensively as the preferred alkylating agent in patients with soft tissue sarcoma. Like doxorubicin, it has been noted that ifosfamide also has a steep dose-response curve. Sequential trials done at our institution have demonstrated a response rate of 10% at 6 g/m 2, which rose to 14% at 8 g/m 2, and to 21% at 10 g/m 2. 16 Moreover, it also has been noted that the dosing schedule has an impact on patients outcomes. Antman and colleagues noted that ifosfamide, delivered as a daily bolus of 2 to 2.5 g/m 2 for 4 days, was associated with a response rate of 26% versus 9% for the same dose delivered as a continuous infusion over 4 days, albeit with a higher incidence of dose-limiting myelosuppression. Similarly, we reported outcomes in patients who received high-dose ifosfamide either as a continuous infusion or as a bolus, with a total dose of 14 g/m 2 in each cycle. The response rate for patients with soft tissue sarcomas treated on the continuous infusion schedule was 19% versus 45% for those treated on the daily bolus schedule. 17 Thus, the appropriate dose per cycle and proper administration are important considerations when using ifosfamide to treat patients. Going forward in the discussion of doxorubicincontaining and ifosfamide-containing regimens, attention to these parameters is critical when using these agents. ANTHRACYCLINE AND IFOSFAMIDE- BASED COMBINATIONS Descriptions of the activity of doxorubicin and dacarbazine in soft tissue sarcoma led to the logical addition of these drugs to the agents that had been used as a part of the VAC regimen. The addition of vincristine to doxorubicin and dacarbazine (VADIC) did not seem to improve activity. Adding cyclophosphamide resulted in the socalled CYVADIC regimen (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dacarbazine). In the initial report, Yap and colleagues included both bone and soft tissue sarcomas and reported a clinical response rate of 47%, with another 31% of patients achieving stable disease. Among patients with soft tissue sarcoma, the Cancer October 1, 2016 2953

clinical response rate was 50%. 18 Through the 1980s, CYVADIC was considered the most active combination regimen in soft tissue sarcoma, with vincristine omitted except in patients with rhabdomyosarcomas, Ewing sarcoma, or other small round blue-cell sarcomas. Given the growing data to support the single-agent activity of ifosfamide in soft tissue sarcomas in the salvage setting, Antman and colleagues at the Dana Farber Cancer Center attempted to augment the activity of CYVADIC by substituting ifosfamide for the less active cyclophosphamide and dropping the marginally active vincristine. The phase 2 study of the resulting maid regimen, done in previously untreated patients, used doses of 60 mg/m 2 doxorubicin, 7500 mg/m 2 ifosfamide, and 900 mg/m 2 dacarbazine, all delivered as a continuous infusion over 72 hours. The overall response rate was 47%, and 10% of patients achieved complete remission. 19 The subsequent multicenter phase 3 results were reported in 1993 and compared doxorubicin 60 mg/m 2 and dacarbazine 1000 mg/m 2 with or without ifosfamide 7.5 g/m 2 delivered by continuous infusion. The dose of ifosfamide was subsequently decreased to 6 g/m 2 because of unacceptable myelosuppression, and the dose density of doxorubicin in the 3-drug maid regimen also was lower than that in the doxorubicin and dacarbazine arm because of dose adjustments. The overall response rate for the maid arm was 32% compared with 17% for the doxorubicin and dacarbazine alone arm. This response rate came at the price of increased adverse events, with 8 deaths because of toxicity (1 encephalopathy and 7 sepsis) in the experimental arm. 13 The median overall survival was slightly in favor of the 2-drug regimen (12 vs 13 months), although the difference was not statistically significant in multivariate analysis. Given the improved response rate over doxorubicin and dacarbazine, the maid regimen became the standard for fit patients through much of the 1990s. The next significant development in combination chemotherapy for sarcoma was the dose intensification of doxorubicin and ifosfamide, drugs for which the doseresponse curve had been firmly established. This was done in the context of 3 randomized studies comparing doxorubicin-based regimens with or without ifosfamide. The first was the previously discussed Intergroup study evaluating the maid regimen versus doxorubicin and dacarbazine. That study, as discussed above, had demonstrated an improved response rate but no change in survival with the addition of ifosfamide. A second study by the Eastern Cooperative Oncology Group compared doxorubicin 80 mg/m 2 with doxorubicin 60 mg/m 2 plus ifosfamide 7.5 g/m 2 (administered as a daily bolus for 2 days) or doxorubicin 40 mg/m 2 with mitomycin C 8 mg/m 2 plus cisplatin 60 mg/m 2. The doxorubicin and ifosfamide regimen produced a response in 34% of patients compared with 20% of patients in the doxorubicin alone arm (a statistically significant result), although with considerably more myelosuppression and no improvement in overall survival. 20 A third study, conducted by the European Organization for Research and Treatment of Cancer (EORTC) compared 3 arms: doxorubicin 75 mg/m 2, doxorubicin 50 mg/m 2 and ifosfamide 5 g/m 2 delivered as a continuous infusion, and the CYVA- DIC regimen. No differences were observed in response rate or overall survival among any of the 3 arms. 21 All 3 of the studies discussed above were done before the widespread availability of hematopoietic growth factors; and, as these agents became readily available, attention turned to maximizing the doses of the 2 most active agents studied in previous combinations (doxorubicin and ifosfamide). Patel and colleagues reported our institution s experience using dose-intensive doxorubicin and ifosfamide at doses of 75 mg/m 2 and 10 g/m 2, respectively, as well as 90 mg/m 2 and 10 g/m 2, respectively. The overall response rate reported in the combined study was 66% at all dose levels (59% with doxorubicin 90 mg/m 2 and 69% with doxorubicin 75 mg/m 2 ). The lower response rate with the higher dose of doxorubicin was not expected and may have been explained by a preponderance of less sensitive histologies in that cohort. 7 Given the lack of data to indicate improved survival with doxorubicin-based combination therapy, many centers around the world have advocated for the use of singleagent doxorubicin as the standard of care for patients with metastatic soft tissue sarcoma. At our center, doxorubicin 75 mg/m 2 and ifosfamide 10 g/m 2 (bolus administration) has been the standard first-line regimen in appropriately selected patients. In an attempt to settle this debate, the EORTC conducted a large randomized study of doxorubicin 75 mg/m 2 compared with doxorubicin 75 mg/m 2 and ifosfamide 10 g/m 2 in the frontline treatment of metastatic or unresectable soft tissue sarcoma. The response rate was 26% in the combination therapy arm and 14% in the single-agent doxorubicin arm. These response rates were lower than those in previously reported trials, likely because of the use of Response Evaluation Criteria in Solid Tumors to define responses. Progression-free survival (PFS) was improved significantly in the combination therapy arm (7.4 vs 4.6 months); and, although overall survival trended toward an improvement in the combination arm (12.8 vs 14.3 months), it fell short of being statistically significant (P 5.076). 2954 Cancer October 1, 2016

Chemotherapy for Soft Tissue Sarcoma/Ratan and Patel That study, a rigorous and well run therapeutic trial in the frontline treatment of metastatic sarcoma, has been cited both against and in support of the use of singleagent doxorubicin over combination therapy. Supporters of single-agent treatment point to the clearly decreased toxicity and absence of statistically improved overall survival. Those in favor of combination therapy point to the improved PFS and response rate. With respect to median overall survival, the study required a 10% difference in 1- year survival to meet criteria for significance. The study demonstrated a 9% improvement, with 51% of patients in the single-agent arm and 60% in the combination arm alive at 1 year. Moreover, overall survival is a composite endpoint and is perhaps not the ideal measure of efficacy in a situation in which patients receive extensive treatment after they come off study. 22 Therefore, the decision to use doublet versus singleagent therapy in the first line is one that must be tailored according to patient factors. For those who require a tumor response to make the palliation of symptoms or a resection possible, it is clear that combination therapy provides the most robust response rates and possibly improved overall survival. For patients who value minimization of toxicity, have significant comorbidities, or have marginal performance status, single-agent doxorubicin (or doxorubicin and dacarbazine) can be considered a reasonable first-line treatment. GEMCITABINE AND DOCETAXEL Although doxorubicin and ifosfamide-based treatments continue to be the most effective and widely used regimens in the treatment of soft tissue sarcoma, they are admittedly noncurative and of limited benefit. Therefore, several additional treatments have taken on an increasingly important role over the last 20 years, especially in specific subsets. In the late 1990s, the nucleoside analog gemcitabine was approved by the US Food and Drug Administration (FDA) for the treatment of pancreas cancer. The drug requires intracellular modification to its triphosphorylated form to become active. This mechanism is saturated when the drug is administered as a bolus, and studies have demonstrated that slower fixed-dose-rate administration of 10 mg/m 2 /minute results in an improved rate of active triphosphate formation. 23 Several phase 2 studies (using both bolus and fixed-dose-rate administration) demonstrated mild efficacy of single-agent gemcitabine in soft tissue sarcomas, with response rates ranging from 3% to 18% and disease stabilization for 12 to 27 weeks. 23,24 Similarly, the availability of docetaxel in the middle to late 1990s led to multiple phase 2 studies illustrating minor single-agent activity, with response rates ranging from 0% to 22%. 25-28 Given the relatively nonoverlapping toxicities, the 2 drugs were subsequently studied together. Phase 2 studies of the combination demonstrated overall response rates as high as 53% in uterine leiomyosarcomas 29 and from 14% to 53% in studies that enrolled patients with other soft tissue sarcoma types. Complete responses were uncommon, occurring in 2% to 8% of patients. 30-32 Two randomized trials have explored whether the improved effect observed in combination studies was because of fixed-dose-rate administration of gemcitabine or the addition of docetaxel. The first, conducted by the Sarcoma Alliance for Research through Collaboration (SARC), was reported in 2007. The study was conceived as a phase 3 trial that used a Bayesian adaptive randomization design to randomize 122 patients with soft tissue sarcoma to receive fixed-dose-rate gemcitabine at 1200 mg/ m 2 on days 1 and 8 of a 21-day cycle versus fixed-doserate gemcitabine at 900 mg/m 2 on days 1 and 8 plus docetaxel 100 mg/m 2 on day 8 with growth factor support. That study demonstrated a response rate of 16% in the 2- drug arm and 8% in the gemcitabine-alone arm for uterine leiomyosarcomas. Overall survival also improved significantly, with a median overall survival of 12.9 months in the combination arm and 11.5 months in the gemcitabine arm. 31 The second trial, conducted by the French Sarcoma Group using a more traditional statistical design, specifically studied patients with leiomyosarcoma who had previously received doxorubicin treatment. Patients were stratified by uterine and nonuterine origin of their tumors and received either gemcitabine 1000 mg/m 2 at a fixed dose rate of 10 mg/m 2 /minute on days 1, 8, and 15 of a 21-day cycle or fixed-dose-rate gemcitabine 900 mg/m 2 on days 1 and 8 of a 15-day cycle plus docetaxel 100 mg/ m 2 on day 8 with growth factor support. Contrary to the SARC study, there was no evidence of superior outcomes in the combination arm relative to single-agent gemcitabine, with a response rate of 24% in the combination arm and 19% in the gemcitabine-alone arm. Similarly, in patients with nonuterine leiomyosarcomas, the response rate was 14% in the gemcitabine-only arm and 5% in the gemcitabine and docetaxel arm. None of these differences reached statistical significance. The median PFS was also unchanged, at 5.5 months for gemcitabine alone and 4.7 months for the combination in uterine leiomyosarcoma group and 6.3 and 3.4 months, respectively, in the nonuterine leiomyosarcoma group. Cancer October 1, 2016 2955

The recently reported GeDDiS trial randomized patients to receive gemcitabine and docetaxel or singleagent doxorubicin. The investigators determined that the PFS rate was similar (46% vs 46.1%, respectively, at 24 weeks), but the toxicity of gemcitabine and docetaxel was worse, with more treatment delays and discontinuations because of toxicity. 33 Given these findings, our general approach remains to use doxorubicin-based treatment in the first line and combined gemcitabine plus docetaxel after disease progression or discontinuation of first-line treatment. We acknowledge that there are conflicting data with respect to the value of adding docetaxel to optimally administered gemcitabine; and, when adjustments are needed in combination therapy doses because of toxicity, we favor dose reducing or discontinuing docetaxel. TRABECTEDIN Trabectedin is a novel antineoplastic agent that was initially isolated from the marine tunicate Ecteinascidia turbinata, although it is now produced synthetically. 34 The drug s major mechanism of action seems to be related to binding of the minor groove of the DNA strand and interference of late S-phase and G2-phase of the cell cycle. It also may also work to disrupt microtubule networks, inhibit transcription, and modify the tumor microenvironment. 35 On the basis of the responses observed in patients with sarcoma in phase 1 studies, several phase 2 studies were conducted investigating trabectedin in soft tissue sarcoma. The largest of these was a multicenter effort in which patients were randomized to receive either trabectedin 1.5 mg/m 2 as a 24-hour infusion every 3 weeks or trabectedin 0.58 mg/m 2 as a weekly 3-hour infusion. On the basis of a pooled analysis of previous studies that demonstrated the most pronounced efficacy in leiomyosarcomas and liposarcomas, only patients with these subsets were enrolled. It was observed that the 24-hour infusion arm was the most efficacious, with a PFS of 3.3 months and an overall survival of 13.9 months. 36 In 2007, the results from those studies led to the approval of trabectedin for use in Europe in patients who had progressed on doxorubicin or ifosfamide. 37 The subsequent phase 3 study randomized patients with leiomyosarcoma or liposarcoma to receive either trabectedin at the now standard 1.5 mg/m 2 24-hour infusion dose or dacarbazine at a dose of 1 g/m 2. That study demonstrated a statistically significant improvement in the median PFS (4.2 vs 1.5 months, respectively), with the largest benefit observed in patients with myxoid liposarcomas, who had a PFS of 5.6 months in the trabectedin group and 1.5 months in the dacarbazine group. However, the trial did not meet its primary endpoint of improved median overall survival (12.4 vs 12.9 months, respectively). Several reasons have been postulated for this result, including the receipt of more subsequent therapy in the dacarbazine control arm. 37 Trabectedin was approved for use in liposarcomas and leiomyosarcomas after anthracycline containing therapy in 2015. ERIBULIN Eribulin is a synthetic analog of halichondrin B, a compound produced by marine sponges. Its anticancer activity stems from its interference with microtubule assembly. The drug was approved for the treatment of breast cancer in 2010. On the basis of preclinical activity observed in fibrosarcoma and leiomyosarcoma, the EORTC conducted a phase 2 study investigating the activity of eribulin in patients with synovial sarcoma, leiomyosarcoma, adipocytic sarcomas, and other sarcomas. The primary endpoint of the study was the 12-week PFS rate. In total, 115 patients were analyzed and received treatment with eribulin 1.4 mg/m 2 on days 1 and 8 of a 21-day cycle. The 12- week PFS rate was 31.6% in patients with leiomyosarcoma, 46.9% in those with adipocytic sarcoma, 21.1% in those with synovial sarcoma and 19.2% in patients with other sarcomas. The median PFS was 2.6 months in patients with adipocytic sarcomas and 2.9 months both for patients with leiomyosarcoma and for those with synovial sarcoma. The tumors that that met the prespecified endpoint of a 12-week PFS rate >30%, adipocytic and leiomyosarcomas, were included in the subsequent confirmatory study. 38 That phase 3 study randomized patients with adipocytic sarcomas and leiomyosarcomas to receive treatment with eribulin or dacarbazine. The trial was powered to detect a 2.5-month improvement in overall survival, with the assumption that the dacarbazine control group would have a median overall survival of 6 months. In fact, the control group outperformed this expectation, with a median overall survival of 11.5 months. Still, the eribulin cohort fared significantly better, with an overall survival of 13.5 months. It is noteworthy that no difference in PFS was observed: both eribulin and dacarbazine produced a median PFS of 2.6 months. The 12-week PFS rate also was unchanged. In subgroup analyses, the survival benefit was most pronounced in patients with liposarcoma. 39 No added benefit was observed in the leiomyosarcoma cohort, although, notably, the study was not powered to detect differences at the level of tumor-specific subgroup analyses. Given these findings, the FDA elected to approve 2956 Cancer October 1, 2016

Chemotherapy for Soft Tissue Sarcoma/Ratan and Patel eribulin for the treatment of liposarcomas, but not for leiomyosarcomas. TARGETED THERAPY IN SARCOMA In the 2000s, as multitargeted tyrosine kinase inhibitors became available for other disease indications, several were empirically studied in soft tissue sarcomas. 40 Of these, pazopanib was eventually brought to a randomized, placebo-controlled phase 3 study. On the basis of a 12- week PFS rate that did not meet prespecified criteria during phase 2, adipocytic sarcomas were excluded from the study. Investigators demonstrated a statistically significant improvement in PFS (4.6 months vs 1.6 months) but did not demonstrate an improvement in overall survival. The response rate for pazopanib was minimal at 6% versus 0% for placebo. 41 Although a survival benefit was not demonstrated, pazopanib was approved by the FDA for the treatment of nonadipocytic soft tissue sarcomas. Additional targeted therapies are also used in the treatment of specific sarcoma subtypes. A detailed discussion of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors is beyond the scope of this review, but imatinib and related drugs have revolutionized the treatment of that disease. Imatinib is also active and is used in patients with locally advanced or metastatic dermatofibrosarcoma protuberans harboring t(17;22) translocation. 42 Inflammatory myofibroblastic tumors occur primarily in young patients and at various sites. They rarely metastasize but can be locally aggressive and recurrent. Approximately 50% of these tumors harbor anaplastic lymphoma kinase (ALK) rearrangements, and the ALK inhibitor crizotinib, which has been approved in ALK-rearranged lung cancer, has demonstrated activity. 43 Clear cell sarcoma has a characteristic Ewing sarcoma-activating transcription factor 1 (EWS-ATF1) translocation, which results in the up-regulation of c-met (hepatocyte growth factor receptor). 44 Met inhibitors are currently under investigation in that disease. Alveolar soft parts sarcoma, a slow-growing tumor that is typically widely metastatic at diagnosis, reportedly responds to multitargeted tyrosine kinase inhibitors, including cediranib 45 and sunitinib. 46 ADJUVANT TREATMENT Since the late 1970s, several small studies have suggested a benefit from adjuvant chemotherapy for soft tissue sarcoma, whereas other reports have been negative or equivocal. 47 The data from those studies were pooled in a metaanalysis published by the Sarcoma Meta-Analysis Collaboration in 1997, which demonstrated improvements in both local and distant recurrence rates as well as recurrence-free survival. Although a trend was noted toward improved overall survival with the administration of doxorubicin-based chemotherapy, this did not meet the criteria for statistical significance. 48 Possible factors that may have diluted this result include the inclusion of lower risk sarcoma subtypes and small tumors. Patients also received various doses of doxorubicin and did not receive concurrent ifosfamide. 47 That analysis was updated in 2008 to include 4 studies done after the Sarcoma Meta-Analysis Collaboration analysis was published. Each of the new studies used anthracycline and ifosfamide-containing regimens. The pooled analysis indicated a statistically significant decrease in local recurrence when patients from all analyzed trials were considered. In all doxorubicin-based studies, the risk of distant recurrence was also decreased. Most notably, survival was improved with a hazard ratio of 0.56 for patients who received doxorubicin and ifosfamidecontaining adjuvant therapy. The absolute risk reduction for death in that category was 11%. 49 The most recent randomized adjuvant chemotherapy study was reported by the EORTC in 2012 and enrolled patients who had intermediate-grade and highgrade sarcomas of any size. The chemotherapy regimen was 5 cycles of doxorubicin 75 mg/m 2 and ifosfamide 5 g/ m 2. The investigators did not observe any improvement in overall survival or relapse-free survival with adjuvant chemotherapy. The trial was powered to detect a 15% difference in 5-year overall survival, which, based on data from the meta-analyses described above, may have been an overestimate of the magnitude of the benefit. Moreover, the enrollment of patients with small tumors (as small as 0.3 cm) also may have interfered with the ability to detect a difference in the studied groups as a whole. Adjuvant treatment for patients with resectable soft tissue sarcoma remains a controversial topic. The data for such an approach are mixed, and interpretation is confounded by issues like the identification of a suitably highrisk population, the appropriate chemotherapy regimen, and heterogeneity with respect to chemosensitivity of the enrolled tumor types. Also, the rarity of soft tissue sarcoma makes it difficult to generate high-quality evidence. It has been suggested that a study that is adequately powered to detect a 10% difference in overall survival would require about 900 patients, and even more patients would be required to detect a smaller difference. 47 Still, in adequately high-risk patients who can receive appropriately dose-intensive chemotherapy with doxorubicin-based regimens, preferably in combination with ifosfamide, we Cancer October 1, 2016 2957

TABLE 1. Standard Therapy for Soft Tissue Sarcoma Experimental Arm vs Control Arm Trial No. Experimental Arm Control Arm Tumor Types Line of Therapy Response Rate, % SD Rate, % Median PFS, mo Median OS, mo NCT00061984 Doxorubicin 75 mg/m 2, ifosfamide 10 g/m 2 Doxorubicin High-grade soft 75 mg/m 2 tissue sarcoma First 14 vs 26 46 vs 50 4.6 vs 7.4 a 12.8 vs 14.3 NCT00142571 Gemcitabine 900 mg/m 2, docetaxel 100 mg/m 2 Gemcitabine Soft tissue 1200 mg/m 2 sarcoma Fourth or earlier 8 vs 16 53 vs 53 3.0 vs 6.2 a 11.5 vs 17.9 a NCT00227669 Gemcitabine 900 mg/m 2, docetaxel 100 mg/m 2 Gemcitabine Leiomyosarcoma Second (after 1000 mg/m 2 anthracycline) Uterine, 19 vs 24; nonuterine, 14 vs 5 Uterine, 43 vs 48; nonuterine, 54 vs 58 Uterine, 5.5 vs 4.7; nonuterine, 6.3 vs 3.4 Uterine, 20 vs 23; nonuterine, 15 vs 13 NCT00753688 Pazopanib 800 mg/m 2 tissue sarcoma Placebo Nonadipocytic soft NCT101343277 Trabectedin 1.5 Dacarbazine Adipocytic mg/m 2 1000 mg/m 2 sarcoma and leiomyosarcoma NCT01327885 Eribulin mesylate Dacarbazine 1.4 mg/m 2 850-1200 mg/m 2 Adipocytic sarcoma and leiomyosarcoma Second or later (after anthracycline) Second or later (after anthracycline) Third or later (after anthracycline) 0 vs 6 38 vs 67 1.6 vs 4.6 a 10.7 vs 12.5 6.9 vs 9.9 35 vs 51 1.5 vs 4.2 a 12.9 vs 12.4 4 vs 5 48 vs 52 2.6 vs 2.6 1.5 vs 13.5 a Abbreviations: OS, overall survival; NCT, National Clinical Trial no. (www.clinicaltrials.gov); PFS, progression-free survival; SD, stable disease. a This value is statistically significant. 2958 Cancer October 1, 2016

Chemotherapy for Soft Tissue Sarcoma/Ratan and Patel believe there is sufficient evidence to support adjuvant chemo therapy. CONCLUSION To date, despite recent drug approvals for common sarcoma subtypes, doxorubicin and ifosfamide remain the cornerstones of treatment for soft tissue sarcoma, as they have been for decades. Lessons learned in using these drugs are that dose intensity and optimal administration are key to optimizing patient outcomes. There are data to suggest inferior results when patients with these tumors are treated in less specialized settings, 47 and part of the explanation for this may be the tendency of more experienced centers to start with and subsequently maintain appropriate doses in the right patient population. Adjuvant therapy, although controversial, is also reasonable; and, in that setting, dose intensity is likely to be even more critical to success. The conflicted state of level 1 evidence pertaining to adjuvant therapyislikelycompoundedbythesmallsizeofindividual trials, and we believe that well conducted meta-analyses provide sufficient evidence to support its use. The sequencing of second-line, third-line, and fourthline therapies, particularly with 2 new drug approvals in the last year in the United States, remains open to debate (see Table 1). A trend with these new approvals, which we hope will continue, is the identification of differential responses based on the sarcoma subtype, allowing us to better tailor our treatments to patients specific histologies. Still, caution must be exercised in over-interpreting data from small subgroups of patients when studies are not adequately powered to do so.finally,with immunotherapy becoming a reality in many other tumor types, the role of these therapies in sarcoma has yet to be adequately investigated. FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES Shreyaskumar R. Patel reports personal fees from Janssen, Johnson & Johnson, CytRx, Bayer, Eli Lilly, and EMD-Serono and research funding from Johnson & Johnson, Eisai, and Morphotek outside the submitted work. Ravin Ratan made no disclosures. AUTHOR CONTRIBUTIONS Ravin Ratan: Writing original draft and writing review and editing. Shreyaskumar R. Patel: Writing original draft and writing review and editing. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5 29. 2. Jacobs EM. Combination chemotherapy of metastatic testicular germinal cell tumors and soft part sarcomas. Cancer. 1970;25:324 332. 3. O Bryan RM, Baker LH, Gottlieb JE, et al. Dose response evaluation of Adriamycin in human neoplasia. Cancer. 1977;39:1940 1948. 4. Gottlieb JA, Baker LH, Quagliana JM, et al. Chemotherapy of sarcomas with a combination of Adriamycin and dimethyl triazeno imidazole carboxamide. Cancer. 1972;30:1632 1638. 5. 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