Palliative treatment of colorectal cancer with secondary metastasis resection in Germany - impact of the multidisciplinary treatment approach on prognosis and cost: the Northern Bavaria IVOPAK I Project.

PURPOSE: The aim of this study was to evaluate the quality of care and interdisciplinary cooperation in the palliative treatment of colorectal cancer (CRC), including the associated costs. PATIENTS AND METHODS: 103 patients were enrolled from 13 institutions to reflect the existing clinical treatment reality and costs of palliative CRC treatment. We present the clinical outcome of the patients and compare the results obtained in the 3 centers with double-figure recruitment numbers (centers A, B, and C). RESULTS: First-line treatment with 5-fluorouracil monotherapy was applied in exceptional cases. The regular treatment method comprised either an irinotecan- (30%) or an oxaliplatin-based regimen (32%). Biological agents were added to the treatment of 33 patients (32%). The median overall survival (OS) of the total patient collective was 25 months. The OS differed significantly in 2 out of the 3 centers, ranging between 27 and 11 months. Secondary metastasis resections were performed in 26% of the total patient collective. The center with the most favorable outcome results also had the lowest costs for palliative treatment and care, including the lowest drug costs. CONCLUSION: A combined chemotherapy treatment was the rule. Concerning biological agents, a significant lack of their application in first-line treatment and the quality of interdisciplinary cooperation have to be addressed.

Phase II STUdy with 3rd- or 4th-line bendamustine (flat dose) therapy in patients with metastatic breast cancer.

BACKGROUND: Bendamustine is a drug with a favorable side effect spectrum and it offers a chance to overcome tumor resistance in pretreated patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Bendamustine was given as flat dose with 200 mg at days 1 + 2 in MBC patients pretreated with 2-3 different chemotherapies. Therapy was repeated at day 28 or fully recovered neutrophils. After 2 treatment cycles, a tumor response evaluation was performed. Toxicity was graded according to the National Cancer Institute common toxicity criteria (NCI-CTC) catalogue. RESULTS: 22 patients were evaluated for toxicity. 4 patients dropped out before the first tumor response evaluation; thus, 18 patients were evaluable for anticancer efficacy evaluation. 3/18 patients reached a partial remission (PR), 4 stable disease and 11 showed progression after 2 treatment cycles. The time to progression (TTP) was 5 months in patients with PR and 4 months in patients with no change (NC). In patients with progressive disease (PD), TTP was < 2 months. The main toxicities were nausea, weight loss and fatigue. CONCLUSIONS: Bendamustine can be given with a fixed flat dose, which simplifies the drug preparation. 2/5th of all treated patients responded to this therapy whereas bendamustine showed no anticancer effect in 3/5th of all patients. Bendamustine is definitely a drug with anticancer potential.

Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin.

PURPOSE: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity. EXPERIMENTAL DESIGN: A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents. RESULTS: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission. CONCLUSIONS: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2.

Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients--results of a phase II study.

BACKGROUND: Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects. MATERIAL AND METHODS: 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 x 500 mg oral capecitabine/ day and 2 x 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue. RESULTS: Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression. CONCLUSION: Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit.

A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors.

PURPOSE: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-ß, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0). RESULTS: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma). CONCLUSION: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors.

Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors.

PURPOSE: BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors. PATIENTS AND METHODS: This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines. RESULTS: The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events