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Systemic Therapy for Advanced Soft Tissue Sarcoma

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Systemic Therapy for Advanced Soft Tissue Sarcoma Systemic Therapy for Advanced Soft Tissue Sarcoma a, b Jennifer Y. Sheng, MD *, Sujana Movva, MD KEYWORDS Advanced soft tissue sarcoma Chemotherapy Novel therapies KEY POINTS Survival for advanced soft tissue sarcomas has improved significantly over the last 20 years because of advancements in histologic classification, improved treatment ap- proaches, and novel agents. An important factor guiding choice of therapy is soft tissue sarcoma subtype, as drugs such as eribulin and trabectedin may have particular activity in leiomyosarcoma and liposarcoma. Focus on angiogenesis inhibition has led to the approval of pazopanib for soft tissue sar- coma, and the pathway continues to be investigated in this disease. Toxicity is an important area of investigation in soft tissue sarcoma, and new agents, such as aldoxorubicin, may be alternatives with better safety profiles. Future studies on treatment of advanced soft tissue sarcoma will continue to focus on identification of novel drug targets, personalization of therapy, and combination immunotherapies. BACKGROUND Sarcomas are rare tumors that arise from or are differentiated from tissues of meso- dermal origin. They comprise less than 1% of all adult malignancies.1 In 2015 there were approximately 14, 900 new cases diagnosed, with 6360 deaths in the United States. Sarcomas are grouped into 2 general categories: soft tissues sarcomas and primary bone sarcomas, which have different staging and treatment approaches. This article includes a discussion of chemotherapy in advanced or refractory soft tis- sue sarcoma. Patients with metastatic disease are usually best managed with chemo- therapy. Distant metastasis occurs in up to 10% of patients, with the lung being the most common site in 83% of cases.2 Systemic therapy can involve cytotoxic a Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Uni- versity School of Medicine, Baltimore, MD, USA; b Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA * Corresponding author. E-mail address: [email protected] Surg Clin N Am 96 (2016) 1141–1156 http://dx.doi.org/10.1016/j.suc.2016.06.006 surgical.theclinics.com 0039-6109/16/$ – see front matter Published by Elsevier Inc. 1142 Sheng & Movva chemotherapy or targeted therapy with different toxicity profiles. In general, the response rates to doxorubicin and ifosfamide have ranged from 20% to 35%, while the response to other single-agent chemotherapy is low (10% or less).3 In addition, combination and dose-intense regimens have largely failed to improve survival.4 New therapies such as eribulin, olaratumab, and immunotherapy are promising and are under further investigation. DOXORUBICIN Doxorubicin is an anthracycline antibiotic isolated from Streptomyces peucetius, which intercalates in the DNA helix and prevents replication.5 It has been used since the 1970s, with initial studies demonstrating a complete remission in 6.7% and partial remission in 20% of patients with metastatic soft tissue sarcoma.6 More recent studies of doxorubicin 75 mg/m2 administered every 3 weeks have demonstrated objective response rates (ORRs) ranging from 18.8% to 25.6%.7,8 A 2001 EORTC (European Organization for Research and Treatment of Cancer) phase II trial compared Doxil (pegylated liposomal doxorubicin) 50 mg/m2 every 4 weeks with doxorubicin 75 mg/m2 every 3 weeks (Table 1). Response rates in the cohort of patients with soft tissue sarcoma excluding gastrointestinal stromal tumor were 14% and 12% for Doxil and doxorubicin, respectively. Incidents of hematologic toxicity, febrile neutropenia, and alopecia were higher in the doxorubicin arm. Howev- er, more patients had palmar–plantar erythrodysesthesia in the Doxil arm.9 Doxil has activity specifically in cutaneous angiosarcoma. A review of 8 cases in Germany demonstrated a complete response in 2 patients, partial response in 4 patients, and a response followed by progressive disease in 1 patient.10 Another retrospective anal- ysis of 119 patients with metastatic angiosarcoma showed that doxorubicin, Doxil, and taxanes resulted in similar response rates (30%) and median overall survival (OS) of 12.1 months.11 Response rates as high as 66% in patients receiving doxorubicin 75 to 90 mg/m2 in combination with ifosfamide have been noted.12 Combinations of Doxil and ifosfamide as first-line therapy for metastatic soft tissue sarcoma have demonstrated ORRs as high as 55.9%.13 However, a meta-analysis of 2281 patients showed that although the response rate was marginally higher for patients receiving doxorubicin and ifosfamide versus single-agent doxorubicin, pooled analysis using random effects showed no statistically significant difference. Additionally, a significant difference was not achieved with 1-year year or 2-year mortality rate.14 Some of these findings are supported by the multicenter phase III trial, EORTC 62012. Patients with locally advanced, unresectable, or metastatic high-grade soft tissue sarcomas were randomly assigned to receive doxorubicin (n 5 228) or doxorubicin and ifosfamide (n 5 227). Doxorubicin was given at 75 mg/m2 on day 1 bolus or 72-hour infusion at 25 mg/m2/d. In the combination arm, ifosfamide was given at 10 g/m2 over 4 days with mesna and pegfilgastrim. There was no significant difference in OS between the 2 groups (hazard ratio [HR] 0.83, 95.5% confidence interval [CI], 0.67–1.03; P 5 .076), as OS was 12.8 months in doxorubicin group (95.5% CI, 10.5–14.3) and 14.3 months in the combination group (95.5% CI, 12.5–16.5). However, the median progression-free survival (PFS) was significantly higher for combination chemotherapy at 7.4 months (95% CI, 6.6–8.3) versus doxoru- bicin at 4.6 months (95% CI, 2.9–5.6); (HR 0.74, 95.5% CI, 0.60–0.90; P 5 .003).15 IFOSFAMIDE Ifosfamide, a nitrogen mustard alkylating agent that crosslinks DNA, has demon- strated activity in soft tissue sarcoma at doses of 7.5 g/m2 to 10 g/m2. A phase III trial Table 1 Select phase II/III trials of active drugs in soft tissue sarcoma Previous OS, median (months)a Author, Year N Subtype Regimen Chemotherapy Response Ratea or PFSb Judson et al,9 2001 95 Soft tissue sarcoma Doxil 50 mg/m2 every 4 wk N Doxil: 14% Doxil: 10.7 excluding vs doxorubicin 75 mg/m2 Doxorubicin: 12% Doxorubicin: 8.2 gastrointestinal every 3 wk stromal tumor Judson et al,15 2014 455 Locally advanced, Doxorubicin 75 mg/m2 on N Doxorubicin: 14% Doxorubicin: 12.8 unresectable or day 1 bolus or 72-h Combination: 26% Combination: 14.3 metastatic high-grade infusion at 25 mg/m2/d vs (P 5 .0006) soft tissue sarcoma Combination arm with 2 ifosfamide 10 g/m over Systemic Therapy for Advanced Soft Tissue Sarcoma 4 d every 3 wk Lorigan et al,16 2007 326 Locally advanced or Doxorubicin 75 mg/m2 vs N Doxorubicin: 11.8% Doxorubicin: 12.0 metastatic soft tissue ifosfamide 9 g/m2 over Ifos 3h/d: 5.5% Ifos 3h/d: 10.9 sarcoma 3 d (continuous vs 3 h/d) Ifos 9: 8.4% Ifos 9: 10.9 every 3 wk Maki et al,24 2007 119 Soft tissue sarcoma Gemcitabine 1200 mg/m2 Both treated Gemcitabine: 8% Gemcitabine: 11.5 excluding on days 1 and 8 every and untreated Combination: 16% Combination: 17.9 gastrointestinal 3 wk vs gemcitabine Pr(bGD>0j data) 5 .97 stromal tumor and 900 mg/m2 on days 1 Kaposi sarcoma and 8 with docetaxel 100 mg/m2 on day 8 every 3 wk Pautier et al,25 2012 90 Uterine LMS and Gemcitabine 1,000 mg/m2 Y Uterine LMS: Uterine LMS: nonuterine LMS on days 1, 8, and 15 of a Gemcitabine: 19% Gemcitabine: 20 28 d cycle vs combination Combination: 24% Combination: 23 gemcitabine 900 mg/m2 Non-uterine LMS: Non-uterine LMS: on days 1 and 8 plus Gemcitabine: 14% Gemcitabine: 15 docetaxel at 100 mg/m2 Combination: 5% Combination: 13 on day 8 of a 21 d cycle (continued on next page) 1143 1144 Sheng & Movva Table 1 (continued) Previous OS, median (months)a Author, Year N Subtype Regimen Chemotherapy Response Ratea or PFSb Seddon,28 2015 257 Advanced soft tissue Doxorubicin 75 mg/m2 N Includes Stable Disease: Doxorubicin: 16.4 sarcoma every 3 wk vs Doxorubicin: 65.9% Combination: 14.5 gemcitabine 675 mg/m2 Combination: 58.6% days 1 and 8 and docetaxel 75 mg/m2 day 8 every 3 wk Buesa et al,29 1991 44 Advanced soft tissue Dacarbazine 1.2 g/m2 Y 18% NR sarcoma every 3 wk Penel et al,36 2008 30 Angiosarcoma Paclitaxel 80 mg/m2 on Both treated 19% at 6 mo 8 mo days 1, 8 and 15 of a 28 d and untreated cycle Sleijfer et al,38 2009 142 Advanced soft tissue Pazopanib 800 mg orally Y 6.3% Adipocytic: 6.6 sarcoma once daily LMS: 11.8 Synovial: 10.3 Other: 10.0 van der Graaf 369 Metastatic soft tissue Pazopanib 800 mg orally Y Pazopanib: 6% Pazopanib: 12.5 et al,39 2012 sarcoma once daily vs placebo Placebo: 0 Placebo: 10.7 Yovine et al,42 2004 54 Soft tissue sarcoma Trabectedin 1.5 mg/m2 over Y 3.7% 12.8 mo 24 h every 3 wk Garcia-Carbonera 36 Soft tissue sarcoma Trabectedin 1.5 mg/m2 over Y 8% 12.1 mo et al,43 2004 24 h every 3 wk Le Cesne et al,44 2005 104 Soft tissue sarcoma Trabectedin 1.5 mg/m2 over Y 8.1% 9.2 mo 24 h every 3 wk Demetri et al,45 2009 270 Liposarcoma, LMS Trabectedin 1.5 mg/m2 over Y q3 wk 24-h: 5.6% q3 wk 24-h: 13.9 24-h every 3 wk vs qweek 3-h: 1.6% qweek 3-h: 11.8 0.58 mg/m2 3-h infusion every week for 3 wk of a 4-wk cycle Monk et al,47 2012 20 Uterine LMS Trabectedin 1.5 mg/m2 over N 10% >26.1 mo (median not 24- h every 3 wk reached) Demetri et al,50 2015 518 Liposarcoma and LMS Trabectedin 1.5 mg/m2 Y Trabectedin: 9.9% Trabectedin: 12.4 over 24 h vs dacarbazine Dacarbazine: 6.9% Dacarbazine: 12.9 1 g/m2 every 3 wk Schoffski
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