Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial.

OBJECTIVE: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. METHODS: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. RESULTS: PFS at 16 weeks was 64% (95% CI 51-76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6-19.7), and median PFS was 7.2 months (95% CI 5.6-8.3). Grade 3-4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. CONCLUSIONS: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

beta(2)microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients.

Colorectal cancer (CRC) is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. One of the most important determinants of CRC survival is lymph node metastasis. To determine whether molecular markers might be prognostic for lymph node metastases, we measured by quantitative real-time RT-PCR the expression levels of 15 cancer-associated genes in formalin-fixed paraffin-embedded primary tissues derived from stage I-IV CRC patients with (n=20) and without (n=18) nodal metastases. Using the mean of the 15 genes as an internal reference control, we observed that low expression of beta(2)microglobulin (B2M) was a strong prognostic indicator of lymph node metastases (area under the curve (AUC)=0.85; 95% confidence interval (CI)=0.69-0.94). We also observed that the expression ratio of B2M/Spint2 had the highest prognostic accuracy (AUC=0.87; 95% CI=0.71-0.96) of all potential two-gene combinations. Expression values of Spint2 correlated with the mean of the entire gene set at an R(2) value of 0.97, providing evidence that Spint2 serves not as an independent prognostic gene, but rather as a reliable reference control gene. These studies are the first to demonstrate a prognostic role of B2M at the mRNA level and suggest that low B2M expression levels might be useful for identifying patients with lymph node metastasis and/or poor survival.

IL-12 conditioning improves retrovirally mediated transduction efficiency of CD8+ T cells.

The ability to genetically modify T cells is a critical component to many immunotherapeutic strategies and research studies. However, the success of these approaches is often limited by transduction efficiency. As retroviral vectors require cell division for integration, transduction efficiency is dependent on the appropriate activation and culture conditions for T cells. Naive CD8(+) T cells, which are quiescent, must be first activated to induce cell division to allow genetic modification. To optimize this process, we activated mouse T cells with a panel of different cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-12, IL-15 and IL-23, known to act on T cells. After activation, cytokines were removed, and activated T cells were retrovirally transduced. We found that IL-12 preconditioning of mouse T cells greatly enhanced transduction efficiency, while preserving function and expansion potential. We also observed a similar transduction-enhancing effect of IL-12 preconditioning on human T cells. These findings provide a simple method to improve the transduction efficiencies of CD8(+) T cells.

Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy.

Current dosing strategies for anticancer drugs result in wide interindividual pharmacokinetic variability. Here, we explored the influence of age, body size, concomitant drugs, dose, infusion duration, and sex on the clearance for doxorubicin and docetaxel in 243 individual patients. Patients received doxorubicin (n=110) or docetaxel (n=152) as monotherapy or in combination chemotherapy regimens. The mean (+/-S.D.) clearance was 63.6+/-22.7 L/h for doxorubicin and 42.8+/-14.9 L/h for docetaxel. Normalisation for body surface area (BSA) reduced the interindividual variability by only <1.7%. Doxorubicin clearance was significantly reduced when administered at doses >50 mg/m(2) or in combination with cyclophosphamide. Upper extremes of body size were associated with increased clearance for both drugs, whereas no consistent effect of age on clearance was discerned. Overall, these findings suggest that incorporation of variables in addition to BSA should be considered in routine dosing strategies for doxorubicin and docetaxel.

Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma.

Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization.

Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT.

Cyclosporine (CsA) and MTX are commonly used for GVHD prophylaxis in pediatric allo-SCT. Mucositis and hepatic toxicity frequently restrict the delivery of the fourth dose of MTX. Folinic acid (FA) may ameliorate MTX toxicity. We conducted a retrospective chart review of all pediatric patients who received CsA and MTX for GVHD prophylaxis from January 2000 to July 2010. Patients treated before July 2007 (N=29) did not receive FA and those treated from July 2007 onward did receive FA (N=18). Patients who received FA were significantly more likely to receive day +11 MTX (odds ratio (OR) 10.42, 95% confidence interval (CI): 1.21-262.27) but there was no significant difference in Grade III-IV GVHD between the two groups (OR 1.15, 95% CI: 0.08-18.14). FA did not impact relapse-free survival (RFS) (P=0.82). Increased likelihood of receiving day +11 MTX suggests that FA ameliorates MTX toxicity, such as severe mucositis. FA administration for MTX GVHD prophylaxis should be studied in a prospective, randomized fashion.

High-dose fractionated radiotherapy to 80 Gy for stage I-II medically inoperable non-small-cell lung cancer.

INTRODUCTION: Management of medically inoperable non-small-cell lung cancer (NSCLC) has been historically challenging, with poor rates of local control and disease-specific survival. Nearly all published series of standard fractionation radiotherapy have utilised doses <70 Gy. The present investigation describes disease control and survival outcomes for a large series of patients prescribed high-dose radiotherapy for early-stage NSCLC. METHODS: Retrospective analysis of disease control and survival outcomes for stages I-II NSCLC patients prescribed ≥70 Gy at 1.8-2.5 Gy per fraction. RESULTS: Between May 1997 and August 2008, 100 primary lung tumours in 98 patients (two metachronous) were eligible for analysis. The median age was 71 years (range 49-93), and 92 patients were considered medically inoperable. Nearly all cases were clinical stage cT1N0 (51 patients) or cT2N0 (35). The median radiotherapy dose prescribed was 80.5 Gy (range 70-90). At a median follow-up of 18 months, 72 patients died (44 of/with disease) and 50 experienced recurrence. The estimated 3-year in-field control, progression-free survival, disease-specific, and overall survival rates were 50, 29, 30 and 24%, respectively. Univariate analyses demonstrated an inverse association between local control and tumour size. Medical inoperability was associated with decreased disease-specific and overall survivals. Patient age and biologically equivalent dose were also associated with overall survival. CONCLUSIONS: Disease control and survival of fractionated radiotherapy for early-stage NSCLC remain suboptimal. Medical inoperability is associated with worse overall survival; however, local control remains a predominant pattern of failure despite 80 Gy in standard fractionation, particularly in patients with larger tumour size.

Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements.

The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.

Ethical difficulties in clinical practice: experiences of European doctors.

BACKGROUND: Ethics support services are growing in Europe to help doctors in dealing with ethical difficulties. Currently, insufficient attention has been focused on the experiences of doctors who have faced ethical difficulties in these countries to provide an evidence base for the development of these services. METHODS: A survey instrument was adapted to explore the types of ethical dilemma faced by European doctors, how they ranked the difficulty of these dilemmas, their satisfaction with the resolution of a recent ethically difficult case and the types of help they would consider useful. The questionnaire was translated and given to general internists in Norway, Switzerland, Italy and the UK. RESULTS: Survey respondents (n=656, response rate 43%) ranged in age from 28 to 82 years, and averaged 25 years in practice. Only a minority (17.6%) reported having access to ethics consultation in individual cases. The ethical difficulties most often reported as being encountered were uncertain or impaired decision-making capacity (94.8%), disagreement among caregivers (81.2%) and limitation of treatment at the end of life (79.3%). The frequency of most ethical difficulties varied among countries, as did the type of issue considered most difficult. The types of help most often identified as potentially useful were professional reassurance about the decision being correct (47.5%), someone capable of providing specific advice (41.1%), help in weighing outcomes (36%) and clarification of the issues (35.9%). Few of the types of help expected to be useful varied among countries. CONCLUSION: Cultural differences may indeed influence how doctors perceive ethical difficulties. The type of help needed, however, did not vary markedly. The general structure of ethics support services would not have to be radically altered to suit cultural variations among the surveyed countries.