Anna Maria Frezza

Early Skin Toxicity as a Predictive Factor for Tumor Control in Hepatocellular Carcinoma Patients Treated with Sorafenib

INTRODUCTION Sorafenib is an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases and has led to a longer median overall survival (OS) time and time to progression (TTP) in patients with advanced hepatocellular carcinoma (HCC). This study was conducted to assess the link between the antitumor efficacy of sorafenib and its early cutaneous side effects in advanced HCC patients. MATERIALS AND METHODS All patients received 800 mg daily of sorafenib until progression or unacceptable toxicities. We retrospectively analyzed the incidence of rash and hand-foot skin reactions (HFSR) during the first month of treatment, comparing tumor control (partial response plus stable disease) and TTP. RESULTS Sixty-five HCC patients treated with sorafenib were included in this analysis: 47 (73.3%) received sorafenib after failure of some local treatment, whereas 18 (27.7%) received it as first-line treatment. Twenty-nine patients developed at least grade 1 skin toxicity (rash, 13; HFSR, 16). In patients who developed skin toxicity, the tumor control rate was 48.3%, versus 19.4% in patients without cutaneous side effects. The median TTP was 8.1 months in the group of patients with skin toxicity versus 4.0 months in those without skin toxicity. This difference was also statistically significant on multivariate analysis. A borderline statistically significant difference was also observed in terms of OS in patients with early skin toxicity. CONCLUSIONS Skin toxicity should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy.

Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study.

BACKGROUND Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations. PATIENTS AND METHODS Specialist centres collaborated to report prognostic factors and outcome for 113 patients. RESULTS Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P=0.046; hazard ratio (HR)=0.482 95% CI: 0.213-0.996) and death (P=0.004; HR=0.445 95% CI: 0.256-0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P=0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P<0.0001). Data on radiotherapy indications, dose and fractionation were insufficiently complete, to allow comment of its impact on outcomes. Median OS for patients with metastases at presentation was 3 years (95% CI: 0-4.25). CONCLUSIONS Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease.

Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer

Fluoropyrimidines, oxaliplatin, irinotecan and biologic therapies (Bevacizumab, Panitumumab, and Cetuximab) represent the backbone of metastatic colorectal cancer (CRC) treatment. The improvement in survival for mCRC patient led to two main outstanding issues: 1) there is a significant number of patients progressing beyond the third or fourth line of treatment still suitable for further therapy when enrollment into clinical trial is not possible. In this situation, the role of any therapy rechallenge (either chemotherapy alone, chemotherapy and biologic therapy or biologic therapy alone) is still not clear, particularly in patients who had previously responded, and if treatment choice is based on traditional dogma of primary and secondary resistance, rechallenge does not seem to be justified. 2) Prolonged intensive treatment is burdened from the high risk of cumulative toxicity, worsening in quality of life and a not well defined possibility of early acquired resistance.Different hypothesis could justify the research of different strategy in treatment of mCRC:1) Epigenetic changes might drive resistance and treatment could induce these changes. Re-expression of silenced tumor suppressive genes might resensitize tumors to therapy. It is therefore possible that a drug holiday (intermittent treatment) could allow reversion to a previous epigenetic profile. Moreover an intermittent treatment could delay acquired resistance. 2) It is plausible that tumor grows as a polyclonal mass. If it responds but then becomes resistant to one or more treatments, retreatment might be successful if changing therapies allows to that clone of cells to re-emerge. On these basis, we focused this review on the actual evidences in management of mCRC patients in terms of chemotherapy or biological therapies rechallenge and intermittent treatment. Moreover, we will discuss the potential biological mechanisms of the observed results of early clinical trials.

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.

Wide-spectrum characterization of trabectedin: biology, clinical activity and future perspectives

Ecteinascidin-743 (trabectedin, Yondelis((R)); PharmaMar, Madrid, Spain), a 25-year-old antineoplastic alkylating agent, has recently shown unexpected and interesting mechanisms of action. Trabectedin causes perturbation in the transcription of inducible genes (e.g., the multidrug resistance gene MDR1) and interaction with DNA repair mechanisms (e.g., the nucleotide excision repair pathway) owing to drug-related DNA double strand breaks and adduct formation. Trabectedin was the first antineoplastic agent from a marine source (namely, the Caribbean tunicate Ecteinascidia turbinata) to receive marketing authorization. This article summarizes the mechanisms of action, the complex metabolism, the main toxicities, the preclinical and clinical evidences of its antineoplastic effects in different types of cancer and, finally, the future perspectives of this promising drug.

Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy

Osteosarcoma, the most common primary bone sarcoma, is a genetically complex disease with no widely accepted biomarker to allow stratification of patients for treatment. After a recent report of one osteosarcoma cell line and one tumor exhibiting fibroblastic growth factor receptor 1 (FGFR1) gene amplification, the aim of this work was to assess the frequency of FGFR1 amplification in a larger cohort of osteosarcoma and to determine if this biomarker could be used for stratification of patients for treatment. About 352 osteosarcoma samples from 288 patients were analyzed for FGFR1 amplification by interphase fluorescence in situ hybridization. FGFR1 amplification was detected in 18.5% of patients whose tumors revealed a poor response to chemotherapy, and no patients whose tumors responded well to therapy harbored this genetic alteration. FGFR1 amplification is present disproportionately in the rarer histological variants of osteosarcoma. This study provides a rationale for inclusion of patients with osteosarcoma in clinical trials using FGFR kinase inhibitors.

Sorafenib and dacarbazine in soft tissue sarcoma: a single institution experience

Background: To report on the anti-tumour activity and toxicity of sorafenib combined with dacarbazine in patients with pre-treated advanced soft tissue sarcoma (STSs). Methods: From November 2009 to December 2010, 17 patients affected by STSs who had failed two or more regimen of chemotherapy, with a performance status ≤ 2 and measurable disease were consecutively enrolled in the present case series. Sorafenib was administered at 400 mg b.i.d. continuous dosing in combination with dacarbazine, 300 mg/m2 for three consecutive days every 21 days until disease progression or intolerable toxicity. Results: Fourteen patients were evaluable for response. Three patients stopped treatment early and were not evaluable for response. One of them died for not disease-dependent reason, the other two went off-study due to rapid clinical worsening, without performing radiologic evaluation. No complete responses were registered. As by RECIST, partial responses (PR) were observed in three patients (21%), stable disease (SD) in six patients (43%) and progressive disease (PD) in five patients (36%), with a clinical benefit rate (RECIST PR+SD > 6 months) of 64%. The median time of progression was 20 weeks (range: 9 – 34 weeks) and the median overall survival was 43 weeks (range: 17 – 65 weeks). The main toxicities were neutropenia (36%), thrombocytopenia (36%), hypertension (36%), fatigue (50%) and skin reactions (57%). Five patients required dose reductions (both dacarbazine and sorafenib) for toxicity and three patients required only sorafenib reduction for dermatologic reactions. One patient was taken off-study because of severe sorafenib-related dermatologic toxicity. Conclusions: Sorafenib and dacarbazine combination seems to be an active and safety regimen in pre-treated STSs. A Phase II trial is ongoing in patient affected by selected sarcoma subtypes.

Long-term efficacy of methotrexate plus vinblastine/Vinorelbine in a large series of patients affected by desmoid-type fibromatosis

Purpose Today, surgery and radiation therapy have a limited role in desmoid-type fibromatosis. Different systemic treatments were shown to be effective. Herein, we report on our institutional experience with low-dose methotrexate (MTX) + vinca alkaloids in this disease over the last 25 years. Methods We retrospectively reviewed data from all adult patients with sporadic desmoid-type fibromatosis treated with MTX and vinca alkaloids at our institution between 1989 and 2014. Results We identified 75 patients treated with MTX + vinblastine (40%), MTX + vinorelbine (57%), and vinorelbine alone (3%). All patients had progressive disease before chemotherapy; 72%, 10%, and 48% of patients had received previous surgery, radiation therapy, and/or systemic treatments, respectively. Chemotherapy was administered for a median duration of 14 months and a median number of 37.5 cycles. Eight patients interrupted chemotherapy because of toxicity. According to RECIST (Response Evaluation Criteria in Solid Tumors) complete response, partial response, stable disease, and progressive disease were observed in 1%, 47%, 51%, and 1% of patients, respectively. Symptomatic relief was obtained in 80% of symptomatic cases. The median progression-free survival (PFS) was 75 months; it was 136 months in responding patients. Upon progression, after chemotherapy withdrawal, MTX plus vinblastine/vinorelbine was offered to 11 patients with partial response, stable disease, and progressive disease in 4, 6, and 1 cases, resulting in a median PFS of 53 months. Conclusions In this series, chemotherapy with MTX and vinca alkaloids is confirmed to be active and effective, with a remarkable PFS, higher in responding patients, and limited toxicity. Even progression can be successfully rechallenged.

Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new

For metastatic soft tissue sarcoma (STS) patients not eligible for surgery, systemic treatments, including standard chemotherapy and newer biological compounds, still play the most relevant role in the management of the disease. An anthracycline and alkylating agent combination has formed the cornerstone of chemotherapy in STS for more than 30 years, with its value over that of administration of anthracycline as a single agent still being debated. Efforts have been made to improve the activity and minimise the toxicity of the combination, as well as to explore the upfront efficacy of agents known to be active in sarcoma and to develop new biological compounds. Nevertheless, beyond the first line, evidence for medical treatment in STS is less robust and all the more driven by histology. Thus, the introduction of kinases and small molecule inhibitors in the treatment armamentarium for STS is a major achievement in this setting. Preliminary data on immunotherapy are also available and discussed in this review.

The role of S-adenosylmethionine in preventing oxaliplatin-induced liver toxicity: a retrospective analysis in metastatic colorectal cancer patients treated with bevacizumab plus oxaliplatin-based regimen

BackgroundHepatotoxicity represents a frequent chemotherapy-related side effect, often associated with course delays, discontinuations, and dose reductions. S-adenosylmethionine (AdoMet) administration is effective in the treatment of a variety of liver injuries, but it has never been evaluated in the prevention of chemotherapy-induced damage.Patients and methodsSeventy-eight patients affected by metastatic colorectal cancer were enrolled. Forty-two patients were treated with bevacizumab and XELOX without administering AdoMet, 32 were treated with the same regimen plus supplementation with AdoMet. Liver enzymes levels were assessed before starting the treatment, and then every therapy cycle, liver toxicity, chemotherapy course delays, discontinuations, and dose reductions due to liver toxicity were recorded.ResultsAspartate aminotransferase (P = 0.02), alanine transaminase (P < 0.001), lactate dehydrogenase (P = 0.008), total bilirubin (P = 0.03), and gamma-glutamyltransferase (P < 0.001) were found to be significantly lower in patients treated with AdoMet than in those who were not. Patients supplemented with AdoMet experimented a lower grade of liver toxicity (P = 0.009) and had a reduced need of course delay (P = 0.042) and dose reduction (P = 0.051).ConclusionsAdoMet supplementation in patients affected by metastatic colorectal cancer treated with oxaliplatin-based regimen seems to be effective in the prevention of chemotherapy-induced liver injury.