Case Report of Suspected Rhabdomyolysis during Treatment with Trabectedin in a Patient with Metastatic Leiomyosarcoma

Trabectedin has been reported to occasionally induce rhabdomyolysis. In the present case, continuation of trabectedin was maintained despite suspected rhabdomyolysis related to trabectedin. Creatinine kinase levels dropped to normal levels. We suggest that continuation of trabectedin despite suspected rhabdomyolysis was safe in this specific patient

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic option

Definitive radiotherapy and Single-Agent radiosensitizing Ifosfamide in Patients with localized, irresectable Soft Tissue Sarcoma: A retrospective analysis

<p>Abstract</p> <p>Background and Purpose</p> <p>Standard therapy for soft-tissue sarcomas remains complete resection. For primary radiotherapy local control rates of 30-45% have been reported. We analyzed retrospectively 11 cases of radiochemotherapy with single-agent ifosfamide in patients with macroscopic soft-tissue sarcomas.</p> <p>Patients and Methods</p> <p>The patients were treated in irresectable high risk situations. Radiation therapy was performed with median 60 Gy. During the first and fifth week the concomitant chemotherapy with ifosfamide was added. Two patients received trimodal therapy with additional regional hyperthermia.</p> <p>Results</p> <p>The therapy was completed in 73% of the patients. Average local control time was 91 months, median disease-free-survival/overall-survival was 8/26 months. Five-year rates for local control/disease free survival/overall survival were 70%/34%/34%. The limited prognosis is mainly caused by systemic treatment failure.</p> <p>Conclusions</p> <p>The data strongly suggest a better outcome of radiochemotherapy with ifosfamide compared to radiotherapy alone and radiotherapy in combination with other radiosensitizers.</p

A phase II trial of a biweekly combination of paclitaxel and gemcitabine in metastatic breast cancer

BACKGROUND: Many emerging new drugs have recently been trialled for treatment of early and advanced breast cancer. Among these new agents paclitaxel and gemcitabine play a crucial role, mostly in patients with relapsed and metastatic disease after failure of chemotherapy with antracyclines. METHODS: A phase II study was started in order to evaluate the activity and toxicity of a combination of paclitaxel and gemcitabine in a biweekly schedule on metastatic breast cancer patients previously treated with antracyclines. RESULTS: Twenty-five patients received paclitaxel (150 mg/mq) by 3-hours infusion, followed by gemcitabine (2000 mg/mq) given as a 60 min i.v. infusion (day 1–14) for a maximum of eight cycles. In all patients treatment was evaluated for toxicity and efficacy; four patients (16%) achieved a complete response, 12 (48%) a partial response giving an overall objective response rate of 64%. Stable disease was documented in 5 patients (20%) and progressive disease occurred in 4 patients (16%). CONCLUSION: The schedule of treatment was safe and tolerable from a haematological and non-haematological point of view. These data confirm that the combination of gemcitabine and paclitaxel on a biweekly basis is an effective and well-tolerated regimen in breast cancer patients with prior therapeutic exposure to antracyclines

European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Experience with Advanced/Metastatic Epithelioid Sarcoma Patients Treated in Prospective Trials: Clinical Profile and Response to Systemic Therapy.

Aims Epithelioid sarcoma is a soft tissue sarcoma associated with a high rate of local recurrence after wide resection and high incidence of distant metastasis. Little is known about the clinical course and response to systemic treatments in epithelioid sarcoma patients. We carried out a retrospective analysis of clinical data from epithelioid sarcoma patients to provide a reference for the design of future epithelioid sarcoma-specific studies. Patients and methods Data from patients with epithelioid sarcoma entered in prospective multi-sarcoma phase II/III trials were pooled: EORTC trial 62012 (doxorubicin versus doxorubicin/ifosfamide), 62043 (pazopanib), 62072 (pazopanib versus placebo) and 62091 (doxorubicin versus trabectedin). Patients had either a local or a centrally confirmed diagnosis of epithelioid sarcoma, had inoperable/metastatic disease at study entry and were eligible for the according trial. Response was assessed according to RECIST 1.1. Progression-free survival (PFS) and overall survival were calculated from date of entry. Results Among 976 patients with advanced sarcomas, 27 epithelioid sarcoma patients (2.8%) were eligible for the analysis (17 men, median age at diagnosis 50 years, range 19–72). Eighteen (66.7%) received chemotherapy as first-line treatment (five doxorubicin, eight doxorubicin/ifosfamide, two pazopanib, three trabectedin) and nine (33.3%) received pazopanib as second line or later. The primary tumour was located in the lower extremity (n = 8; 29.6%), upper extremity (n = 5; 18.5%), retro/intra-abdominal (n = 4; 14.8%) and in other locations (n = 10; 37.0%). At entry, metastases were mainly found in lung (n = 17; 63%), lymph nodes (n = 9; 33.3%), bone (n = 8; 29.6%) and soft tissue (n = 7; 25.9%). The best response for first-line patients was four partial responses (22.2%), 10 stable disease (55.6%) and four progressive disease (22.2%). In subsequent lines, pazopanib achieved one partial response (11.1%), four stable disease (44.4%) and four progressive disease (44.4%). All patients but one progressed on treatment. The median PFS and overall survival were 3.8 (95% confidence interval 2.2–4.8) and 10.8 months (95% confidence interval 8.1–21.3), respectively. Five patients were still alive at the time of the according trial analysis. Conclusion With all limitations of such a rare disease and small data set, objective response and survival outcomes are similar in epithelioid sarcoma to non-selected sarcoma populations. The clinical testing of novel systemic treatments for epithelioid sarcoma remains an unmet medical need and a high priority

Elevated reticulocyte count – a clue to the diagnosis of haemolytic-uraemic syndrome (HUS) associated with gemcitabine therapy for metastatic duodenal papillary carcinoma: a case report

In adults, the haemolytic-uraemic syndrome (HUS) is associated with probable causative factors in the minority of all cases. Cytotoxic drugs are one of these potential causative agents. Although metastatic cancer by itself is a recognized risk-factor for the development of HUS, therapy with mitomycin-C, with cis-platinum, and with bleomycin carries a significant, albeit extremely small, risk for the development of HUS, compared with all other cytotoxic drugs. Gemcitabine is a novel cytotoxic drug with promising activity against pancreatic adenocarcinoma. We are reporting on one patient with metastatic duodenal papillary carcinoma developing HUS while on weekly gemcitabine therapy. The presenting features in this patient were non-cardiac pulmonary oedema, renal failure, thrombocytopenia and haemolytic anaemia. The diagnosis of HUS was made on the day of admission of the patient to this institution. Upon aggressive therapy, including one single haemodialysis and five plasmaphereses, the patient recovered uneventfully, with modestly elevated creatinine-values as a remnant of the acute illness. Re-exposure to gemcitabine 6 months after the episode of HUS instituted for progressive carcinoma, thus far has not caused another episode of HUS. © 1999 Cancer Research Campaig

First-line therapy with gemcitabine and paclitaxel in locally, recurrent or metastatic breast cancer: A phase II study

BACKGROUND: This phase II study evaluated the efficacy and safety of gemcitabine (G) plus paclitaxel (T) as first-line therapy in recurrent or metastatic breast cancer. METHODS: Patients with locally, recurrent or metastatic breast cancer and no prior chemotherapy for metastatic disease received G 1200 mg/m(2 )on days 1 and 8, and T 175 mg/m(2 )on day 1 (before G) every 21 days for a maximum of 10 cycles. RESULTS: Forty patients, 39 metastatic breast cancer and 1 locally-advanced disease, were enrolled. Their median age was 61.5 years, and 85% had a World Health Organization performance status (PS) of 0 or 1. Poor prognostic factors at baseline included visceral involvement (87.5%) and ≥2 metastatic sites (70%). Also, 27 (67.5%) patients had prior adjuvant chemotherapy, 25 of which had prior anthracyclines. A total of 220 cycles (median 6; range, 1–10) were administered. Of the 40 enrolled patients, 2 had complete response and 12 partial response, for an overall response rate of 35.0% for intent-to-treat population. Among 35 patients evaluable for efficacy the response rate was 40%. Additional 14 patients had stable disease, and 7 had progressive disease. The median duration of response was 12 months; median time to progression, 7.2 months; median survival, 25.7 months. Common grade 3/4 toxicities were neutropenia in 17 (42.5%) patients each, grade 3 leukopenia in 19 (47.5%), and grade 3 alopecia in 30 (75.0%) patients; 1 (2.5%) patient had grade 4 thrombocytopenia. CONCLUSION: GT exhibited encouraging activity and tolerable toxicity as first-line therapy in metastatic breast cancer. Phase III trials for further evaluation are ongoing

Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure

This multicentre, randomised phase III study compared docetaxel with 5-fluorouracil+vinorelbine in patients with metastatic breast cancer after failure of neo/adjuvant or one line of palliative anthracycline-based chemotherapy. One hundred and seventy-six metastatic breast cancer patients were randomised to receive docetaxel (100 mg m−2) every 3 weeks or 5-fluorouracil+vinorelbine: 5-fluorouracil (750 mg m−2 per day continuous infusion) D1–5 plus vinorelbine (25 mg m−2) D1 and D5 of each 3-week cycle. Eighty-six patients received 516 cycles of docetaxel; 90 patients received 476 cycles of 5-fluorouracil+vinorelbine. Median time to progression (6.5 vs 5.1 months) and overall survival (16.0 vs 15.0 months) did not differ significantly between the docetaxel and 5-fluorouracil+vinorelbine arms, respectively. Six (7%) complete responses and 31 (36%) partial responses occurred with docetaxel (overall response rate 43%, 95% confidence interval: 32–53%), while 4 (4.4%) complete responses and 31 (34.4%) partial responses occurred with 5-fluorouracil+vinorelbine (overall response rate 38.8%, 95% confidence interval: 29–49%). Main grade 3–4 toxicities were (docetaxel vs 5-fluorouracil+vinorelbine): neutropenia 82% vs 67%; stomatitis 5% vs 40%; febrile neutropenia 13% vs 22%; and infection 2% vs 7%. There was one possible treatment-related death in the docetaxel arm and five with 5-fluorouracil+vinorelbine. In anthracycline-pretreated metastatic breast cancer patients, docetaxel showed comparable efficacy to 5-fluorouracil+vinorelbine, but was less toxic

Designing a HER2/neu promoter to drive α1,3galactosyltransferase expression for targeted anti-αGal antibody-mediated tumor cell killing

INTRODUCTION: Our goal was to specifically render tumor cells susceptible to natural cytolytic anti-αGal antibodies by using a murine α1,3galactosyltransferase (mαGalT) transgene driven by a designed form of HER2/neu promoter (pNeu), the transcription of which is frequently observed to be above basal in breast tumors. Indeed, the αGalT activity that promotes Galα1,3Galβ1,4GlcNAc-R (αGal) epitope expression has been mutationally disrupted during the course of evolution, starting from Old World primates, and this has led to the counter-production of large amounts of cytotoxic anti-αGal antibodies in recent primates, including man. METHOD: Expression of the endogenous c-erbB-2 gene was investigated in various cell lines by northern blotting. A mαGalT cDNA was constructed into pcDNA3 vector downstream of the original CMV promoter (pCMV/mαGalT) and various forms of pNeu were prepared by PCR amplification and inserted in the pCMV/mαGalT construct upstream of the mαGalT cDNA, in the place of the CMV promoter. These constructs were transferred into HEK-293 control and breast tumor cell lines. Stably transfected cells were analyzed by northern blotting for their expression of αGalT and c-erbB-2, and by flow cytometry for their binding with fluorescein isothiocyanate-conjugated Griffonia simplicifolia/isolectin B4. RESULTS: We show that expression of the mαGalT was up- or down-modulated according to the level of endogenous pNeu activity and the particular form of constructed pNeu. Among several constructs, two particular forms of the promoter, pNeu250 containing the CCAAT box and the PEA3 motif adjacent to the TATAA box, and pNeu664, which has three additional PEA3 motifs upstream of the CCAAT box, were found to promote differential αGalT expression. CONCLUSION: Our results strengthen current concepts about the crucial role played by the proximal PEA3 motif of pNeu, and may represent a novel therapeutic approach for the development of targeted transgene expression