Vol 14, No 6 (2018)
Review paper
Published online: 2019-03-15

open access

Page views 2065
Article views/downloads 843
Get Citation

Connect on Social Media

Connect on Social Media

Advances in systemic treatment of advanced soft tissue sarcomas

Monika Dudzisz-Śledź1, Paweł Rogala1
Oncol Clin Pract 2018;14(6):377-391.

Abstract

Systemic treatment in soft tissue sarcoma (STS) is an important element of therapy in a disease eligible for combined treatment with a radical intention and is the basis for the treatment of an unresectable or metastatic disease. The possibilities of treating STS are limited and for many years progress in this area was minor and the main drugs used in this indication were and still remain anthracyclines and alkylating agents. Clinical trials with new drugs are difficult for STS due to the heterogeneity of these tumours and due to their rare occurrence. Over the past two decades, there have been tested many substances in this indication, including molecularly targeted drugs. Great success was imatinib in the treatment of gastrointestinal stromal tumours (GIST). Other drugs in STS have been tested and approved for use, e.g. sunitinib and regorafenib in the treatment of GIST, pazopanib in the treatment of non-GIST STS, trabectedin and olaratumab in the treatment of STS. First reports on the effectiveness of immunotherapy in the treatment of rare subtypes of STS are also available.

Article available in PDF format

View PDF Download PDF file

References

  1. Rutkowski P. Mięsaki tkanek miękkich. Biblioteka Chirurga Onkologa. 2015; 3.
  2. Kohler N, Lipton A. Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res. 1974; 87(2): 297–301.
  3. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016; 388(10043): 488–497.
  4. Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res. 2009; 15(12): 4220–4227.
  5. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009; 27(19): 3126–3132.
  6. van der Graaf WTA, Blay JY, Chawla SP, et al. EORTC Soft Tissue and Bone Sarcoma Group, PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012; 379(9829): 1879–1886.
  7. Kollár A, Jones RL, Stacchiotti S, et al. Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis. Acta Oncol. 2017; 56(1): 88–92.
  8. Stacchiotti S, Negri T, Zaffaroni N, et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol. 2011; 22(7): 1682–1690.
  9. Jagodzińska-Mucha P, Świtaj T, Kozak K, et al. Long-term results of therapy with sunitinib in metastatic alveolar soft part sarcoma. Tumori. 2017; 103(3): 231–235.
  10. https://www.clinicaltrials.gov/ct2/show/NCT01391962?cond=NCT01391962&rank=1.
  11. Larsen AK, Galmarini CM, D'Incalci M, et al. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010; 9(8): 2157–2163.
  12. Yovine A, Riofrio M, Blay JY, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol. 2004; 22(5): 890–899.
  13. Garcia-Carbonero R, Supko JG, Manola J, et al. Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol. 2004; 22(8): 1480–1490.
  14. Le Cesne A, Blay JY, Judson I, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol. 2005; 23(3): 576–584.
  15. Garcia-Carbonero R, Supko JG, Maki RG, et al. Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol. 2005; 23(24): 5484–5492.
  16. Demetri GD, Chawla SP, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009; 27(25): 4188–4196.
  17. Le Cesne A, Blay JY, Domont J, et al. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol. 2015; 16(3): 312–319.
  18. Barone A, Chi DC, Theoret MR, et al. FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen. Clin Cancer Res. 2017; 23(24): 7448–7453.
  19. Cesne ALe, Blay JY, Cupissol D, et al. Results of a prospective randomized phase III T-SAR trial comparing trabectedin (T) vs best supportive care (BSC) in patients with pretreated advanced soft tissue sarcoma (ASTS): A French Sarcoma Group (FSG) trial. Journal of Clinical Oncology. 2018; 36(15_suppl): 11508–11508.
  20. Koseła-Paterczyk H, Kozak K, Klimczak A, et al. Skuteczność i bezpieczeństwo stosowania trabektedyny w leczeniu pacjentów, u których rozpoznano zaawansowane tłuszczakomięsaki i mięśniakomięsaki gładkokomórkowe (L-mięsaki). Nowotwory. Journal of Oncology. 2016; 65(6): 451–457.
  21. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res. 2015; 21(11): 2445–2452.
  22. Demetri GD, Schöffski P, Grignani G, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016; 387(10028): 1629–1637.
  23. Kummar S, Allen D, Monks A, et al. Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol. 2013; 31(18): 2296–2302.
  24. Blay JY, Toulmonde M, Penel N, et al. 1601ONatural history of sarcomas and impact of reference centers in the nationwide NETSARC study on 35,784 patients (pts) from 2010 to 2017. Annals of Oncology. 2018; 29(suppl_8).
  25. https://www.clinicaltrials.gov/ct2/show/NCT02601950?cond=NCT02601950&rank=1.
  26. Chi Y, Sun Y, Cai J, et al. Phase II study of anlotinib for treatment of advanced soft tissues sarcomas. Journal of Clinical Oncology. 2016; 34(15_suppl): 11005–11005.
  27. Chi Y, Yao Y, Wang S, et al. Anlotinib for metastasis soft tissue sarcoma: A randomized, double-blind, placebo-controlled and multi-centered clinical trial. Journal of Clinical Oncology. 2018; 36(15_suppl): 11503–11503.
  28. Crago AM, Dickson MA, Jung J, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013; 31(16): 2024–2028.
  29. Nakayama R, Zhang YX, Czaplinski JT, et al. Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma. Oncotarget. 2016; 7(13): 16581–16592.
  30. Gounder MM, Zer A, Tap WD, et al. Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma. J Clin Oncol. 2016; 34(26): 3166–3174.
  31. https://www.clinicaltrials.gov/ct2/show/NCT02606461?cond=NCT02606461&rank=1.
  32. Liu D, Offin M, Harnicar S, et al. Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALKfusion-positive solid tumors. Ther Clin Risk Manag. 2018; 14: 1247–1252.
  33. Kummar S, Lassen U. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Targeted Oncology. 2018; 13(5): 545–556.
  34. Demetri GD, Paz-Ares L, Farago AF, et al. LBA17Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) Tumors: Pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Annals of Oncology. 2018; 29(suppl_8).
  35. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018; 378(8): 731–739.
  36. Mossé YP, Voss SD, Lim MS, et al. Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study. J Clin Oncol. 2017; 35(28): 3215–3221.
  37. Schöffski P, Sufliarsky J, Gelderblom H, et al. Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial. Lancet Respir Med. 2018; 6(6): 431–441.
  38. Stacchiotti S, Negri T, Libertini M, et al. Sunitinib malate in solitary fibrous tumor (SFT). Ann Oncol. 2012; 23(12): 3171–3179.
  39. Martin RC, Osborne DL, Edwards MJ, et al. Giant cell tumor of tendon sheath, tenosynovial giant cell tumor, and pigmented villonodular synovitis: defining the presentation, surgical therapy and recurrence. Oncology Reports. 2000.
  40. Ravi V, Wang WL, Lewis VO. Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol. 2011; 23(4): 361–366.
  41. Cupp JS, Miller MA, Montgomery KD, et al. Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides. Am J Surg Pathol. 2007; 31(6): 970–976.
  42. Tap W, Gelderblom H, Stacchiotti S, et al. Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT). Journal of Clinical Oncology. 2018; 36(15_suppl): 11502–11502.
  43. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010; 28(5): 835–840.
  44. Klimczak A, Pękul M, Wiater K, et al. PEComa — grupa rzadkich nowotworów pochodzenia mezenchymalnego. Nowotwory. 2011; 61(1): 52–56.
  45. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008; 358(2): 140–151.
  46. Gounder MM, Lefkowitz RA, Keohan ML, et al. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin Cancer Res. 2011; 17(12): 4082–4090.
  47. Gounder M, Mahoney M, Tine BV, et al. Phase III, randomized, double blind, placebo-controlled trial of sorafenib in desmoid tumors (Alliance A091105). Journal of Clinical Oncology. 2018; 36(15_suppl): 11500–11500.
  48. Szucs Z, Messiou C, Wong HH, et al. Pazopanib, a promising option for the treatment of aggressive fibromatosis. Anticancer Drugs. 2017; 28(4): 421–426.
  49. Bulut G, Ozluk A, Erdogan AP, et al. Pazopanib: a novel treatment option for aggressive fibromatosis. Clin Sarcoma Res. 2016; 6: 22.
  50. Chugh R, Wathen JK, Patel SR, et al. Sarcoma Alliance for Research through Collaboration (SARC). Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res. 2010; 16(19): 4884–4891.
  51. Penel N, Le Cesne A, Bui BN, et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol. 2011; 22(2): 452–457.
  52. Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017; 76: 60–67.
  53. Constantinidou A, van der Graaf WTA. The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma. Eur J Cancer. 2017; 84: 257–261.
  54. Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017; 18(8): 1089–1103.
  55. Gong J, Yan J, Forscher C, et al. Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas. Drug Des Devel Ther. 2018; 12: 777–786.
  56. Mita MM, Natale RB, Wolin EM, et al. Pharmacokinetic study of aldoxorubicin in patients with solid tumors. Invest New Drugs. 2015; 33(2): 341–348.
  57. Chawla SP, Papai Z, Mukhametshina G, et al. First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial. JAMA Oncol. 2015; 1(9): 1272–1280.
  58. Chawla S, Ganjoo K, Schuetze S, et al. Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas. Journal of Clinical Oncology. 2017; 35(15_suppl): 11000–11000.
  59. https://www.clinicaltrials.gov/ct2/show/NCT02235701?cond=NCT02235701&rank=1.
  60. Salvatorelli E, Menna P, Gonzalez Paz O, et al. Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin. J Pharmacol Exp Ther. 2012; 341(2): 474–483.
  61. Gupta S, Gouw L, Wright J, et al. Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation. Invest New Drugs. 2016; 34(2): 243–252.
  62. Geroni C, Marchini S, Cozzi P, et al. Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione. Cancer Res. 2002; 62(8): 2332–2336.
  63. Gelderblom H, Blay JY, Seddon BM, et al. Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: an European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study. Eur J Cancer. 2014; 50(2): 388–396.
  64. Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol. 2016; 34(32): 3898–3905.
  65. Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017; 18(10): 1397–1410.
  66. Kim JR, Moon YJ, Kwon KS, et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013; 8(12): e82870.
  67. Kim C, Kim EK, Jung H, et al. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer. 2016; 16: 434.
  68. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017; 18(11): 1493–1501.
  69. Ben-Ami E, Barysauskas CM, Solomon S, et al. Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study. Cancer. 2017; 123(17): 3285–3290.
  70. D'Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018; 19(3): 416–426.
  71. Conley AP, Trinh VA, Zobniw CM, et al. Positive Tumor Response to Combined Checkpoint Inhibitors in a Patient With Refractory Alveolar Soft Part Sarcoma: A Case Report. J Glob Oncol. 2018(4): 1–6.
  72. Yen CC, Chen TWW. Next frontiers in systemic therapy for soft tissue sarcoma. Chin Clin Oncol. 2018; 7(4): 43.
  73. Pollack SM, Lu H, Gnjatic S, et al. First-in-Human Treatment With a Dendritic Cell-targeting Lentiviral Vector-expressing NY-ESO-1, LV305, Induces Deep, Durable Response in Refractory Metastatic Synovial Sarcoma Patient. J Immunother. 2017; 40(8): 302–306.
  74. Somaiah N, Chawla S, Block M, et al. Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS). Journal of Clinical Oncology. 2017; 35(15_suppl): 11006–11006.
  75. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011; 29(7): 917–924.
  76. Robbins PF, Kassim SH, Tran TLN, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res. 2015; 21(5): 1019–1027.