Agents For Soft Tissue Sarcoma Research Articles

Mapping the literature: Role of trabectedin as a new chemotherapy option in advanced pretreated soft tissue sarcoma

This bibliographic review evaluated phase II clinical trials aimed at the identification of antitumor activity of single agents in soft tissue sarcoma (STS) after failure of standard- of-care therapy including anthracyclines and ifosfamide. A total of 63 articles (on anthracyclines, ifosfamide, trabectedin and 27 investigational agents) were included (data from 1979 to 2008).Trabectedin is the most extensively studied agent in patients with STS after failure of anthracyclines and ifosfamide (457 patients), followed by ifosfamide (412), cisplatin (144), temozolomide (137), docetaxel (114), gemcitabine (112), etoposide (95) and doxorubicin (59). Dacarbazine and the remaining investigational agents have usually been tested in 50 or fewer patients, with vastly negative results not warranting further investigation. Methodological limitations are identified in the majority of the reviewed phase II studies, including small sample size, single-institution studies, lack of independent review of the antitumor responses and inadequate description of previous therapies/agents. However, all trabectedin studies fulfilled these methodological characteristics relevant for a phase II trial. A phase II randomized trial confirmed the results of 3 prior nonrandomized studies and, therefore, trabectedin is currently considered an important new option to control advanced sarcomas in patients with STS following failure of all conventional treatments.

Role of New Chemotherapy Agents in Soft Tissue Sarcoma

Medical management of soft tissue sarcomas (STS) has been restricted by the limited availability of active drugs. A plethora of new oncologic agents are now available, many of which have specific therapeutic targets. Gemcitabine and docetaxel is a combination of drugs that have limited single-agent activity. Yondelis, a novel chemotherapeutic that binds DNA and functions partially by inhibiting transcription, is being tested alone and in combination with doxorubicin. Inhibitors of mTOR, a serine/threonine kinase that regulates cell cycle activation and cell growth, are also being tested. Growth factor receptor inhibitors are being evaluated in a variety of sarcomas that have been found to express the targets. In addition, a variety of agents are being assessed in gastrointestinal stromal tumors (GIST). Single agents and agents combined with imatinib are being tested in imatinib-refractory and in metastatic GIST. The increased use of targeted agents underscores the need for understanding sarcoma biology.

Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells.

Doxorubicin (DOX) and ifosfamide (IFO) are the most active single agents in soft tissue sarcomas (STS). Tumour necrosis factor-alpha (TNF-alpha) is used for STS in the setting of isolated limb perfusions. Like TNF-alpha, TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis. In contrast to TNF-alpha preliminary studies suggest that TRAIL lacks systemic side effects. The effects of TRAIL alone and in combination with DOX or 4-hydroxy-IFO were evaluated in the TNF-alpha sensitive rhabdomyosarcoma cell line KYM-1, its 5-fold TNF-alpha sensitive subline KD4 and its >150-fold TNF-alpha resistant subline 37B8R. Membrane expression of TRAIL-receptors DR4 (death receptor 4), DR5 (pro-apoptotic), DcR1 (decoy receptor 1), DcR2 (anti-apoptotic) was assessed by flow cytometry. Cytotoxicity was determined by microculture tetrazolium assays. Apoptosis assays were performed with acridine orange. DOX (doxorubicin) and 4-OH-IFO decreased survival in all cell lines; a 2-fold resistance was observed for both drugs in 37B8R. All cell lines expressed DR4 and DR5, but hardly any DcR1 or DcR2. TRAIL was cytotoxic in KYM-1, even more in KD4 and induced massive apoptosis; 37B8R was >500-fold resistant to TRAIL and little apoptosis could be observed. TRAIL plus DOX showed synergistic cytotoxicity in KYM-1 and 37B8R. TRAIL plus 4-OH-IFO showed addition in all three cell lines. DOX plus TRAIL-induced more cytotoxicity and apoptosis in all cell lines compared to TRAIL alone. In 37B8R, DOX overcame resistance to TRAIL. In KYM-1, KD4 and 37B8R, sensitivity and resistance to TNF-alpha and TRAIL parallels. TRAIL-resistance was independent from expression of TRAIL-receptors. DOX with TRAIL could overcome TRAIL-resistance in 37B8R cells.

Wild type p53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression.

p53 mutations occur in almost half of all soft tissue sarcomas (STS) and may contribute to multidrug resistance (MDR) in patients with STS. Doxorubicin (Dox) is one of the most active single agents in STS but is less effective in STS with p53 mutations. The effect of reintroducing wild type (wt) p53 into STS cells harboring p53 mutations on the cytotoxicity of DOX in vitro and in vivo was studied. The following cell lines were used in this study: SKLMS-1 STS cells, which do not express wt p53; two wt p53 stable transfectant cells derived from SKLMS-1 cells; and SKLMS-1 transfectant cells from a p53 temperature-sensitive mutant that expresses wt p53 at 32 degrees C and mutant p53 at 38 degrees C. The cytotoxicity of Dox was examined by [3-(4,5-dimethylthiazzol-2-yl)-2,5-diphenltetrazolium] (MTT) and clonogenetic assay, and the effect of reintroducing wt p53 on tumor suppression by Dox was evaluated with a tumorigenicity assay. DNA fragmentation was used to detect apoptosis. MDR-1 P-glycoprotein (P-gp) expression was detected by Western blot and immunohistochemical analyses of protein levels and by Northern blot analysis of mRNA levels, respectively. The intracellular accumulation of Dox was detected by flow cytometric analysis. The 50% inhibitory concentration (IC(50)) of Dox for the SKLMS-1 wt p53 transfectants decreased 16-fold compared with SKLMS-1 parental cells expressing mutant p53. Colony formation of SKLMS-1 cells after Dox treatment also was inhibited by wt p53 reintroduction. The tumorigenicity of SKLMS-1 cells was inhibited by wt p53 reintroduction alone or by Dox treatment alone and was inhibited further when p53 introduction was combined with Dox treatment in severe combined immunodeficient mice. Although no difference in DNA fragmentation, Bax expression, or Bcl-2 expression was detected among wt p53 transfectants and parental SKLMS-1 cells after Dox treatment, MDR-1 P-gp expression was decreased in wt p53 transfectants compared with parental SKLMS-1 cells. Furthermore, higher intracellular accumulations of Dox were found in wt p53 transfectants than that in SKLMS-1 cells. Reintroduction of wt p53 into STS cells harboring p53 mutations can enhance their chemosensitivity to Dox through the inhibition of MDR-1 P-gp expression. Thus, the combination of p53 gene therapy and chemotherapy may increase the therapeutic efficacy in the treatment of patients with STS.

Docetaxel: an interesting new drug for the treatment of head and neck cancers and soft tissue sarcomas

Results are summarized for two phase II studies of docetaxel as first-line therapy for advanced squamous cell carcinoma of the head and neck (SCCHN) and one study of docetaxel as second-line therapy for advanced soft tissue sarcomas. In all three studies, docetaxel was administered at a dose of 100 mg/m2 by intravenous infusion over 1 h every 3 weeks. A total of 62 patients were enrolled in the SCCHN trials, of whom 57 were evaluable for response. The combined overall response rate in the SCCHN patients was 35%. Median duration of overall response was 6.5 months in the EORTC-ECTG study. In the DFCI study, median durations of complete and partial remission were 6.75 months and 4.45 months, respectively. These results are at least comparable to those achieved with other single-agent therapies in this setting. In the soft tissue sarcoma study, 29 of the 31 patients enrolled were evaluable for response. Five patients (17%) achieved a partial response to docetaxel as second-line therapy and a further nine (31%) had stable disease. Median duration of response in these patients with soft tissue sarcomas was 5 months. Again, these results are similar to those seen with the three most active single agents in soft tissue sarcomas when used as second-line therapy. Docetaxel may therefore represent a useful drug in both advanced SCCHN and soft tissue sarcomas.

Treatment of Adult Soft-Tissue Sarcomas with Dose-Intensified Chemotherapy and Haematopoietic Growth Factors

Only few cytostatic drugs are used for the treatment of adult soft-tissue sarcoma, with adriamycin and ifosfamide being the most active agents achieving response rates of 20-35%. In addition, for dacarbazine and cyclophosphamide responses have been reported in 10-20% of patients. A dose-response relationship for adriamycin has been suggested based on results from phase II and III studies. 70 mg/m2 single-agent adriamycin every 3 weeks is considered as standard anthracycline treatment for metastatic soft-tissue sarcomas; higher doses have been associated with cardiac and skin toxicity. Clinical studies have also indicated a dose-response relationship for ifosfamide. Tumour responses to high-dose ifosfamide regimens ( > 5 g/m2, given as continuous intravenous infusion) have been achieved in patients relapsing after or resistant to ifosfamide-based regimens at standard doses. Haematopoietic growth factors, particularly G-CSF and GM-CSF, seem to reduce the number of infectious episodes following standard-dose chemotherapy and may allow the application of full doses of chemotherapy cycles on schedule. However, only moderate dose escalations of chemotherapy regimens by factors 1.2-1.4 were possible with the use of G-CSF or GM-CSF due to severe mucositis and cumulative thrombocytopenia. Studies with ultra-high doses of melphalan, ifosfamide or ifosfamide and either carboplatin or adriamycin followed by autologous bone marrow rescue or peripheral blood progenitor cells and growth factors have demonstrated that instead of myelosuppression other toxicities will be dose-limiting. Most studies using escalated doses of active agents in soft-tissue sarcomas followed by haematopoietic support measures have consistently demonstrated response rates of 40-50% compared with 20-30% following standard-dose chemotherapy. However, only a small proportion of complete remissions was achieved, and the overall duration of responses was not longer than for standard therapy. Currently dose-intensified chemotherapy cannot be regarded as standard treatment for soft-tissue sarcomas, and its value must be studied in controlled clinical trials. With the availability of new methods for haematopoietic support, such as myeloid growth factors and peripheral blood progenitor cells, the hypothesis of a dose-response relationship in soft-tissue sarcoma can be clinically tested. Its potential implication for cure should be further studied in a neoadjuvant or adjuvant setting.

Chemotherapy of advanced soft-tissue sarcomas.

The most active single agents in soft-tissue sarcomas are doxorubicin (Adriamycin) and ifosfamide, with response rates of 20-35%. Dacarbazine (DTIC) has a response rate of 16%. A randomized trial of 5 g/m2 of ifosfamide versus 1.5 g/m2 of cyclophosphamide noted a higher response rate for ifosfamide with less myelosuppression. Both randomized studies of doxorubicin with or without DTIC documented an increased response rate for the combination. In contrast, three randomized trials of doxorubicin-based regimens with and without cyclophosphamide have failed to detect an advantage for the addition of cyclophosphamide. Thus, the most active combination for soft-tissue sarcomas is doxorubicin and DTIC. The role of the addition of ifosfamide is currently under evaluation.