Systemic management strategies for metastatic soft tissue sarcoma

Soft tissue sarcomas are rare tumours in adults and therefore require a multidisciplinary approach for optimal management. In the metastatic setting, chemotherapy is the primary modality of therapy. Doxorubicin alone or in combination with ifosfamide or dacarbazine has been the backbone of therapy since the 1970s. There is considerable activity for gemcitabine and docetaxel in leiomyosarcoma and for paclitaxel in angiosarcoma. Newer agents such as trabectedin and eribulin may have a role in certain sarcoma subtypes. Palifosfamide may offer a safer alternative to ifosfamide in the future. Many sarcomas have molecular aberrations that can be targeted. Agents that inhibit the insulin-like growth factor receptor-1, mammalian target of rapamycin and vascular endothelial growth factor are currently being investigated.     

Pazopanib,a new therapy for metastatic soft tissue sarcoma

Through a review of randomised, controlled trials, this article evaluates the efficacy and tolerability of quetiapine in the acute and maintenance phases of bipolar disorder. In trials involving mania patients, quetiapine was found to be effective as adjunctive therapy in combination with lithium or valproate, significantly superior to placebo, and equal to lithium or haloperidol as monotherapy. With regard to the prevention of relapses in bipolar disorder, quetiapine seems to differ from other atypical antipsychotics in its characteristics as a mood stabiliser, which are associated with a promising efficacy in the treatment of bipolar depressive episodes. However, further larger controlled long-term prospective studies are needed to confirm the efficacy of quetiapine for the prevention of relapses in bipolar disorder. Quetiapine seems to have a satisfactory safety and tolerability profile, with a low prevalence of extrapyramidal symptom-related adverse events, treatment-emergent depression and weight gain. Sedation is the main side effect of treatment with quetiapine.     

An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma

Background: The number of effective cytotoxic agents for the treatment of patients with metastatic soft tissue sarcoma (STS) is limited, especially when patients have failed anthracyline-based chemotherapy. Patients and methods: Between 1999 and 2000 a total of 16 patients with histologically proven STS progressing during or after first-line anthracycline-based chemotherapy were entered into this open-label, noncomparative study. Topotecan was administered as a 30-min infusion at a dosage of 1.5mg/m² on five consecutive days every 3 weeks. All patients had received an anthracycline- or ifosfamide-based first-line chemotherapy. Results: None of the 16 included patients achieved an objective response to topotecan. Six patients achieved stable disease (38%), lasting for at least 6 weeks in four patients (25%) and for less than 6 weeks in two patients (13%). Ten patients (62%) had progressive disease. The median time to progression was 79 days calculated from the start of topotecan therapy (range, 28–230). The treatment was well tolerated; however, both anemia and thrombopenia grade III/IV occurred in 25% of the patients as well as severe neutropenia in 69% of the patients. Nonhematologic toxicities grade III/IV such as diarrhea and severe bleeding occurred only in one patient each (6%). Discussion: Topotecan is well tolerated in anthracycline-resistant patients with metastatic STS, but no objective response has been observed in this trial.     

Clinical efficacy of eribulin mesylate for the treatment of metastatic soft tissue sarcoma

Introduction: Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12–18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma.

Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate’s mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas.

Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.     

A phase II clinical trial of echinomycin in metastatic soft tissue sarcoma

Summary Echinomycin, a cyclic peptide in the family of quinoxaline antibiotics, was evaluated in patients with metastatic, soft tissue sarcoma not previously treated for metastatic disease. The starting dose of echinomycin was 1,200 mcg/m² administered intravenously, once weekly × 4, followed by a two-week break. The protocol design called for dose escalation on subsequent cycles of therapy, but because of significant toxicity, dose escalation occurred in only 5 of 25 treatment cycles. Severe nausea and vomiting was the most common toxicity. No clinical responses were observed in the 12 evaluable patients. Echinomycin at this dose and schedule is inactive in metastatic soft tissue sarcoma.     

An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma

Summary Background: The number of effective cytotoxic agents for the treatment of patients with metastatic adult type soft tissue sarcoma (STS) is limited, when patients have failed anthracyline-based chemotherapy. The aim of this trial was to evaluate the efficacy of gemcitabine in this setting. Methods: Between August 2001 and March 2003 19 patients were eligible to enter. Gemcitabine was administered as a 30-minutes infusion at a dosage of 1 g/m² on day 1, 8 and 15 every 4 weeks. All patients had progressive disease during (n = 12) or shortly after an anthracycline-based regimen (n = 3). Results: Four of 19 patients did not start study treatment because of fulminant progression. Fifteen patients with a median age 47 years (32–72) were assessable. All patients had received at least one prior treatment regimen (range, 1–6) for metastatic disease containing anthracyclines (n = 15) and ifosfamide (n = 11). To date, a total of 72+ cycles have been applied (median; 3, 1–28+). Seven patients (47%) had progressive disease after completion of two cycles at the first response assessment. One patient (6%) attained a partial remission, and 7 patients (47%) achieved disease stabilisations. One patient is still on treatment after more than 2.5 years. The calculated progression-free rate at 3 and 6 months was 46.7% (CI_95%, 21.4–71.9) and 13.3% (CI_95%, (0–30.5). 95% of the cycles have been applied without any dose modification or treatment delay. Conclusions: Considering response and progression-free rate as the primary endpoints for phase II trials in pretreated STS, gemcitabine has moderate efficacy.     

Olaratumab for advanced soft tissue sarcoma

Introduction: Olaratumab is a humanized IgG1 monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα). Its antagonistic behavior inhibits the receptor’s tyrosine kinase activity, thereby, turning off the downstream signaling cascades responsible for soft tissue sarcoma tumorigenesis. In October 2016, olaratumab received Food and Drug Administration (FDA) approval for its use in combination with doxorubicin for treatment of advanced soft tissue sarcoma.

Areas covered: This drug profile takes a comprehensive look at the clinical studies leading to FDA approval of olaratumab as well as its safety and efficacy as a front-line treatment option for sarcoma patients. The literature search was primarily conducted using PubMed.

Expert commentary: The combination of olaratumab plus doxorubicin has provided a new front-line therapeutic option for soft tissue sarcoma patients. An open-label phase Ib and randomized phase II trial in patients with advanced soft tissue sarcoma demonstrated that the addition of olaratumab to doxorubicin prolonged progression-free survival by 2.5 months and overall survival by 11.8 months when compared to doxorubicin alone. Of importance, this clinically meaningful increase in overall survival did not come at the expense of a significantly greater number of toxicities. A phase III confirmatory trial (ClinicalTrials.gov Identifier NCT02451943) will be completed in 2020.     

Recent developments in treatment stratification for metastatic breast cancer

The modern approach to management of metastatic breast cancer (MBC) is centred on individualizing treatment to best suit the patient's breast cancer characteristics (molecular subtype, disease burden and prognostic markers), as well as the patient's clinical history (co-morbidities, prior therapies and social factors). The wealth of treatments available has heightened the complexity of tailored patient care that in turn allows better optimization of treatment efficacy and quality of life. There are promising developments in the management of estrogen receptor (ER)-positive breast cancer, particularly with respect to overcoming resistance with dual targeting of the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin and ER-signalling pathways. A central focus in the management of triple negative breast cancer has been through efforts to identify novel therapeutic targets in this disease subgroup. Next-generation sequencing approaches have begun to reveal how breast cancer somatic mutational heterogeneity between tumours with the same histopathological subtype is likely to impede efforts to identify novel common therapeutic targets. The most successful example of targeted therapy in MBC is the targeting of human epidermal growth factor receptor 2 (HER2) by trastuzumab. Dual and irreversible HER2/epidermal growth factor receptor targeting and attenuation of downstream resistance pathways also appear promising in HER2-positive trastuzumab-refractory breast cancer. Targeted therapy with antiangiogenic agents shows clinical activity, but the balance between efficacy, toxicity and cost remains a topic of debate, emphasizing the unmet need for a predictive biomarker of response to this class of drug. Poly(ADP ribose) polymerase(PARP) inhibitors appear to have clinically meaningful activity in BRCA germline mutant breast cancer. Activity of PARP inhibitors in other breast cancer subgroups is yet to be clearly defined. Novel chemotherapy agents show marginally superior efficacy, at a cost of a moderate increase in toxicity. Bone-modifying drugs expand supportive care options; again, better permitting individualization of treatment choice. The future management of MBC will increasingly focus on stratifying therapeutics based on individualized-tumour molecular aberrations.     

Recent developments in oral chemotherapy options for gastric carcinoma

The incidence of carcinoma of the stomach is low in the United States, Canada, and Australia but is a significant health problem in Asia, South America, Eastern Europe, and countries of the previous Soviet Union. For patients with advanced disease, chemotherapy remains palliative. With the increasing emphasis on patients' quality of life, convenience, and cost containment, oral chemotherapy has come into increasing focus. We review oral chemotherapy agents for use in patients with advanced gastric carcinoma. Etoposide, given intravenously, has modest activity in gastric carcinoma. We studied oral etoposide, which was administered to 28 patients at the starting dose of 50 mg/m2/day for 21 days followed by a 7-day rest period. Five patients achieved a partial response and 4 patients achieved a minor response. The drug was well tolerated. Common toxicities included myelosuppression, alopecia, and nausea. Oral etoposide thus shows evidence of modest activity against gastric carcinoma. In Japan, considerable advances have been made in the oral chemotherapy of gastric carcinoma. The second generation fluorouracil prodrug tegafur/uracil (UFT) has been extensively evaluated in Japan, Korea, and Spain. Data predominantly from Japan indicate that tegafur/uracil has a response rate of approximately 20% in treatment naive patients with advanced gastric carcinoma. When combined with other active agents, tegafur/uracil has a response rate of more than 30% in these patients. The available data also suggest that tegafur/uracil is well tolerated and that patient acceptance is high. In conclusion, future clinical research is likely to focus on the development of convenient outpatient regimens with efficacy equal to that of intravenous regimens.     

New therapies in soft tissue sarcoma

Importance of the field: Soft tissue sarcomas are rare mesenchymal tumors accounting for <?1% of all adult neoplasia. In the last decade, locally advanced and metastatic soft tissue sarcoma have been managed only through surgery, radiotherapy and standard chemotherapy (mainly based on anthracycline and ifosfamide). Despite the efforts, overall 5-year survival rate in patients with soft tissue sarcomas of all stages remains only 50 – 60%.

Areas covered in this review: In the present article, all the main new molecules under clinical evaluation for the treatment of soft tissue sarcoma are revised by describing the mechanism of action, the biological rationale of their use in sarcoma and by reporting the available data about safety and efficacy, up to 2009.

What the reader will gain: A brief summary of the standard treatments available at the moment and a complete analysis of the state of art about the development of new target therapies in the management of soft tissue sarcoma.

Take home message: The identification of new biological therapies that target soft tissue sarcoma tumorigenesis key points seems to offer a real opportunity of improving the prognosis of this often aggressive disease. In this sense, the best management for soft tissue sarcoma patients is in a clinical trial and participation in clinical trials should be encouraged.     

Recent developments in the chemotherapy of malaria

Malaria remains a major infectious disease and is worsening in some areas, partly because of the spread of resistance to established antimalarial drugs. New drugs are urgently needed to combat the protozoan parasite, Plasmodium. This review covers new developments, including artemisinin derivatives, synthetic peroxides, folate pathway inhibitors, primaquine analogs and proteinase inhibitors. However, few of these agents are in clinical trials and many are derived from chemical classes already used extensively against malaria. The emerging understanding of parasite biology and new technological developments in drug discovery offer hope of improvement, but this will require increased interest from the pharmaceutical industry.     

Emerging treatments for soft tissue sarcoma of adults

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. Patients can present with a localised tumour (primary or local recurrence) at different sites (e.g., extremity, abdomen) or metastatic disease, which may require different treatment strategies. Is the surgical resection of a localised sarcoma enough or is it better to give an additional treatment like adjuvant and/or preoperative radiotherapy and/or chemotherapy? Which chemotherapy should be selected in the first or second line situation? Do new treatment options exist, such as targeted therapies? This review provides answers to some of these questions. To decide on consecutive treatment steps, it is important to know as many relevant factors as possible at first presentation. Therefore, the first part of this review discusses the specific characteristics and prognostic factors of importance for treatment planning. A short summary of current therapy strategies and existing standards is then given. The main body of the review summarises information on new and emerging clinical compounds for patients with soft tissue sarcoma of adults, including recent developments of targeted therapy.     

Oral piritrexim — A phase II study in patients with advanced soft tissue sarcoma

The study was sponsored by Burroughs Wellcome Co. and monitored and audited by Synertron, Inc.     

Aldoxorubicin for the treatment of soft tissue sarcoma

Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS.

Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It covalently binds to albumin in the blood until reaching the acidic tumor environment, which dissolves the hydrazone linker, thus releasing doxorubicin into the tissue. In this review paper, we analyze the pharmacokinetics, current phase I, phase II, and phase III trials, as well as adverse effect profile of aldoxorubicin in patients with advanced STS.

Expert opinion: Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with leiomyosarcoma and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment.     

Recent developments in the chemotherapy of Chagas disease

Chagas disease remains an important health problem in the Americas. Advances are being made in parts of South America in blocking transmission from insect vectors or blood transfusion, but more effective chemotherapy is needed for the millions who are already infected. This is especially important since recent results have indicated that treatment is beneficial for the elimination of the chronic course of the disease. The rational development of new drugs depends on the identification of differences between human metabolism and that of the causative parasite, Trypanosoma cruzi. Recent developments in the study of the basic biochemistry of the parasite have allowed the identification of novel targets for chemotherapy, such as sterol metabolism, protein prenylation, proteases, and phospholipid metabolism, and these are the subject of this review.     

Recent developments in cancer chemotherapy oriented towards new targets

Malignant diseases are one of the major causes of death in the western world. Patients are treated by surgery, radiation and chemotherapy. Chemotherapeutic treatment is used to decrease the tumour burden and to eliminate malignant cells. However, in most cases, resistance against chemotherapy develops. Therefore, there is a permanent need for new additional treatment strategies and chemotherapeutic combination regimens. In the present review article, the authors try to highlight the most promising approaches and summarise a selection of potential targets and compounds which might become alternative treatment options against malignant diseases. Due to the high number of scientific articles and the rapid developments in the area of cancer research, the authors can only mention a few selected targets and treatment options; however, the review focuses on new and notably important targets and com-pounds.