Soft tissue sarcoma, treatment

Doxorubicin is one of the most effective agents used in the treatment of carcinomas of the breast, ovary, endometrium, bladder, and thyroid and in oat cell cancer of the lung. It is included in several combination regimens for diffuse lymphomas and Hodgkin s disease. Doxorubicin can be used as an alternative to daunorubicin in acute leukemias and is useful in Ewing s sarcoma, osteogenic sarcoma, soft-tissue sarcomas, and neuroblastoma. Some activity has been reported in non-oat cell lung cancer, multiple myeloma, and adenocarcinomas of the stomach, prostate, and testis. 

While the exact mechanism of action remains unclear, dacarbazine appears to inhibit DNA, RNA, and protein synthesis. Dacarbazine disappears rapidly from the plasma, with a terminal half-life of about 40 minutes. Dacarbazine has shown clinical benefit in the treatment of melanoma, Hodgkin s lymphoma, and soft tissue sarcomas. Side effects include myelosuppression, severe nausea and vomiting, and a flulike syndrome that starts about 7 days after treatment and lasts 1 to 3 weeks. 

The DNA minor groove binder brostallicin (PNU-166196, 24), currently in Phase 2 clinical trials for the treatment of soft-tissue sarcoma, exhibited potent... 

Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) 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 37 870. 

Trabectedin is licensed for the treatment of advanced soft-tissue sarcoma when treatment with anthracyclines and ifosfamide has failed or is contraindicated. It is administered by intravenous infusion. Trabectedin may cause hepatobiliary disorders and for this reason hepatic function should be evaluated before starting treatment and during treatment. Dexamethasone is administered intravenously with trabectedin for its anti-emetic and hepatoprotective effects. As with other antineoplastic drugs, trabectedin causes nausea and vomiting and bone-marrow suppression as side-effects. 

Trabectedin (36 Yondelis, ecteinascidin-743, ET-743 Zelfia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced hy the ascidian Ecteinascidia turbinate,received approval for its sale in Europe, Russia and South Korea by Zelfia and Johnson and Johnson under the brand name YondelisT for the treatment of advanced soft tissue sarcoma (STS). Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. 

In September 2007, the EMEA approved the use of trabectidin against ovarian cancer (OC) and STS. In November 2009, Yondelis received its second marketing authorization from the European Commission for its administration in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer presently, trabectedin (36) is under Phase II trials for the treatment of paediatric sarcomas as well as breast and prostate cancers. The European Commission and the US Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft tissue sarcomas and... 

Leahy M, Ray-Coquard 1, Verweij J, Le Cesne A, Duffaud F, Hogendoom PC, Fowst C, de Balincourt C, di Paola ED, van Glabbeke M, Judson 1, Blay JY. (2007) European Organisation for research and treatment of cancer soft tissue and bone sarcoma group. Ear J Cancer 43 308-315. 

Sarcomas are tumors of mesenchymal origin, arising in skeletal tissues and extra-skeletal connective tissues including the nerves. They are very rare and mainly effect a younger population. Sarcomas of soft tissues are relatively insensitive to drug treatment and are therefore not discussed in detail in this chapter. A systematic review of fourteen trials of doxorubicin-based adjuvant chemotherapy for the treatment of soft tissue sarcomas involving 1568 patients concluded Doxorubicin-based adjuvant chemotherapy appears to significantly improve time to local and distant recurrence and overall recurrence-free survival in adults with localised resectable soft tissue sarcoma. There is some evidence of a trend towards improved overall survival (see Sarcoma Meta-analysis Collaboration, 1999). 

Therapeutic applications Dactinomycin is used in combination with surgery and vincristine (see p. 390) for the treatment of Wilm s tumor. With methotrexate (see p. 378) it is effective in the treatment of gestational choriocarcinoma. Some soft-tissue sarcomas also respond. 

Therapeutic applications Although vincristine and vinblastine are structurally very similar, their therapeutic indications are different. They are generally administered in combination with other drugs. Vincristine is used in the treatment of acute lymphoblastic leukemia in children, Wilm s tumor, Ewing s soft-tissue sarcoma, and Hodgkin s and non-Hodgkin s lymphomas, as well as some... 

Ombrabulin (AVE8062, AC-7700) 58 (Sanofi-Aventis) is being evaluated in Phase II/III trials as a treatment for advanced stage soft tissue sarcoma for patients who have failed previous anthracycline and ifosfamide treatments.124 Ombrabulin 58125 128 is a synthetic combretastatin analogue that was licensed by Sanofi-Aventis from Ajinomoto and is also a vascular disrupting agent. 

Several phase II evaluations of elliptinium (5) have been carried out in recent years, with mixed results. Elliptinium is typically given to patients intravenously at a concentration of 100 mg/m in a 5% dextrose solution for 1-2 hr. A clinical study of 5 in the treatment of lymphoma was slightly encouraging in that, of 16 evaluable patients, there were 1 partial response and 7 minor responses (278). However, in the treatment of metastatic soft tissue sarcoma, none of the 19 patients had remission of their tumors (279). An extensive phase II trial of advanced breast cancer patients (74) was very encouraging 19% had objective responses, and in those patients with soft tissue metastases the response rate was 30% (280). These responses lasted from 3 to 12 months, and mild to moderate nausea and mouth dryness were the most frequently encountered side effects. 

Stuart-Elarris RC, Elarper PJ, Parson CAand coll. Ellgh-dose alkylation therapy using Ifosfamide infusion with Mesna in the treatment of adult soft-tissue sarcoma. Cancer Chemother Pharmacol, 11 69-74,1983... 

The study of marine organisms as sources of anticancer agents only began in the late 1960s, and Yondelis , the first marine-derived clinical agent has recently been recommended for approval for treatment of soft tissue sarcoma by the EMEA. " This section will cover this compound and two additional marine-derived agents which are in advanced clinical trials. 

Stuart-Harris RC, Harper PG, Parsons CA, Kaye SB, Mooney CA, Gowing NF, Wiltshaw E. High-dose all lation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 1983 ... 

The most important clinical use of dactinomycin is in the treatment of rhabdomyosarcoma and Wilms tumor in children, where it is curative in combination with primary surgery, radiotherapy, and other drugs, particularly vincristine and cyclophosphamide. Antineoplastic activity has been noted in Ewing s tumor, Kaposi s sarcoma, and soft-tissue sarcomas. Dactinomycin can be effective in women with advanced cases of choriocarcinoma in combination with methotrexate. Dactinomycin also has been used as an immunosuppressant in renal transplants. 

Ecteinascidins, isolated mainly from the Caribbean ascidian Ecteinascidia turbinata, are probably the most usefiil anticancer agents found to date in a marine source. The lead compoimd, trabectedin (ET-743, 136), is regarded as a successful story of modem marine dmg research it is indeed the first representative of a marine natural product to receive marketing authorization for the treatment of patients with advanced or metastatic soft tissue sarcomas (STS) and relapsed platinum -sensitive ovarian cancer under the brand name Yondelis [116,117). 

In phase II of treatment hepatic failure, renal failure, pancytopenia, and rhabdomyolysis were eommon adverse effects. Pharmacokinetic and pharmacodynamic studies show that biliary function can be served as reference parameter to indicate whether patient receive full dose of trabectedin or not. It is also reported that alkaline phosphatase and bilirubin can be served as a high risk indicator in full dose treatment. Phase II clinical trials show that trabectedin has greater efficacy in patient who suffered from breast and ovarian cancer and refractory soft tissue sarcoma. A search in Pubmed shows that there are several studies reporting the results of clinical trials (phase I, II and III) on the efficacy of trabectedin against ovarian cancer. Ferrandina et al. [38] performed retrospective, multicenter study to determine the potential efficacy of trabectedin as single agent in 98 patients (67 platinum sensitive, and 31 platinum refractory/resistant) who suffered from heavily relapsed ovarian cancer. They found that trabectedin treatment can prolong the survival of patients (18 month for treatment vs. 14 month for SD). They also found that hepatotoxicity and rare cardiotoxicity were the most important adverse effects of trabectedin treatment [38]. 

Thornton, K.A. (2009). Trabectedin the evidence for its place in therapy in the treatment of soft tissue sarcoma. Core evid., 4,191-198. 

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