Evaluation of circulating cell-free DNA as a molecular monitoring tool in patients with metastatic cancer.

The clinical decisions made when treating patients with metastatic cancer require knowledge of the current tumor extent and response to therapy. For the majority of solid tumors, a response assessment, which is based on imaging, is used to guide these decisions. However, measuring serum protein biomarkers (i.e. tumor markers) may be of additional use. Furthermore, tumor markers exhibit variable specificity and sensitivity and cannot therefore be solely relied upon when making decisions regarding cancer treatment. Therefore, there is a clinical requirement for the identification of specific, sensitive and quantitative biomarkers. In recent years, circulating cell-free DNA (cfDNA) and mutation-specific circulating cell-free tumor DNA (cftDNA) have been identified as novel potential biomarkers. In the current study, cfDNA and cftDNA were compared using imaging-based staging and current tumor markers in 15 patients with metastatic colorectal, pancreatic or breast cancer. These patients were treated at the Third Medical Department of Paracelsus Medical University Salzburg (Austria). The results of the current study demonstrated a statistically significant correlation between the concentration changes of cfDNA and cftDNA and response to treatment, which was assessed by imaging. A correlation was not indicated with current clinically used tumor markers, including carcinoembryonic antigen, carcinoma antigen 15-3 and carcinoma antigen 19-9. The present study also indicated a correlation between cfDNA and cftDNA and the tumor volume of metastatic lesions, which was not observed with the current clinically used tumor markers. In conclusion, cfDNA and cftDNA exhibit the potential to become novel biomarkers for the response assessment following cancer treatment, and may serve as a tool for the estimation of tumor volume. The current study further supports the increasingly important role of cfDNA and cftDNA as new monitoring tools for use during cancer therapy.

Liver toxicity during temozolomide chemotherapy caused by Chinese herbs.

BACKGROUND: Complementary and alternative medicine is often used by patients with malignant glioma. Although several interactions of various alternative agents with chemotherapy are known, none has been described for temozolomide so far. CASE PRESENTATION: We report the case of severe liver toxicity with jaundice during radiochemotherapy with temozolomide likely due to interaction with a popular Chinese herbal formula after surgery for glioblastoma. After cessation of the herbal formula as well as the chemotherapy liver enzymes slowly normalized. Due to tumor progression the patient was retreated with temozolomide for 5 cycles without toxicity. Because of further progression combination treatment of bevacizumab and irinotecan was started and again no liver toxicity was observed. CONCLUSIONS: We conclude that the observed toxicity with jaundice was probably caused by an interaction of this popular Chinese formula and temozolomide. This is the first report about a relevant interaction of temozolomide and any herbal formula.

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07).

BACKGROUND: Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. METHODS: This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. RESULTS: Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. CONCLUSION: Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

Efficacy of temsirolimus after previous treatment with sunitinib, sorafenib or everolimus in advanced renal cell cancer.

OBJECTIVE: Temsirolimus inhibits the mammalian target of rapamycin with demonstrated efficacy in patients with advanced renal cell cancer. PATIENTS AND METHODS: We present a retrospective analysis of our single-center experience with temsirolimus in patients pretreated with sunitinib, sorafenib or everolimus. Sixteen patients were treated within our center starting in December 2006 until September 2009. The majority of patients (14 of 16) had received a prior antiangiogenic pretreatment. We further analyzed the efficacy of subsequent treatment with temsirolimus in these patients. RESULTS: Stable disease could be achieved in 8 of 14 pretreated patients (57%). The duration of median progression-free survival was 10 weeks (range 1-43). Especially patients with a good response to previous antiangiogenic treatment, a good overall condition and a low Memorial Sloan Kettering Cancer Center (MSKCC) score benefited from subsequent treatment with temsirolimus. We did not see any complete or partial response meeting the World Health Organization criteria. Temsirolimus was well tolerated. CONCLUSION: Temsirolimus appears to be an effective and well-tolerated substance in the treatment of patients with a good performance status, low MSKCC score and stable disease under previous antiangiogenic treatment in advanced renal cell cancer. However, its use is highly questionable in pretreated patients with a poor performance score and a high MSKCC score.

Multicenter phase II study of pegylated liposomal doxorubicin in combination with vinorelbine as first-line treatment in elderly patients with metastatic breast cancer.

BACKGROUND: This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. PATIENTS AND METHODS: From August 2002 to August 2004, 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m(2) intravenously (i.v.) on day 1 and vinorelbine 30 mg/m(2) i.v. on days 1 and 15 every 4 weeks. RESULTS: The median age of the patients in this trial was 68 years (range 60-82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0-1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. CONCLUSION: The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment.

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme.

BACKGROUND: Fulvestrant (Faslodex) is an oestrogen receptor (ER) antagonist with demonstrated efficacy in patients with advanced and pretreated breast cancer. PATIENTS AND METHODS: We present a single-centre experience with fulvestrant administered under the compassionate use programme (CUP) to a total of 54 postmenopausal women with metastatic breast cancer progressing on multiple endocrine and cytotoxic therapies. Patients received 250 mg fulvestrant i.m. once monthly as second- (n = 8), third- (n = 30), fourth- (n = 14) and fifth-line (n = 2) hormonal treatment. The median number of previous endocrine therapies was 2 (range 1-4). Most of the patients also had multiple palliative chemotherapies with a median of 1.7 (range 0-6) prior therapies. The median duration of fulvestrant treatment was 6.3 months (range 1-39 months) and the median duration of follow-up was 19.4 months (range 1-63 months). RESULTS: Objective response was achieved by five patients (9.3%): one complete remission (CR) (1.9%) and four partial remissions (PR) (7.4%). Stable disease (SD) lasting > or =6 months was achieved by 16 patients (29.6%). Thus in all, fulvestrant conferred clinical benefit (CB) on 21 women (38.9%). The median time to progression (TTP) was 6.4 months. In all patients with CR and PR, tumour cells were positive for both ER and progesterone receptor (PgR), but lacked HER2/neu overexpression; one patient with PR had an unknown HER2/neu status. Overall, the drug was well tolerated. No grade 3/4 toxicities were reported. CONCLUSIONS: Fulvestrant appears to be an efficient and well-tolerated drug even in women with advanced breast cancer progressing after multiple endocrine and/or cytotoxic treatments.