GUIP1: a R package for dose escalation strategies in phase I cancer clinical trials.

BACKGROUND: The main objective of phase I cancer clinical trials is to identify the maximum tolerated dose, usually defined as the highest dose associated with an acceptable level of severe toxicity during the first cycle of treatment. Several dose-escalation designs based on mathematical modeling of the dose-toxicity relationship have been developed. The main ones are: the continual reassessment method (CRM), the escalation with overdose control (EWOC) method and, for late-onset and cumulative toxicities, the time-to-event continual reassessment method (TITE-CRM) and the time-to-event escalation with overdose control (TITE-EWOC) methods. The objective of this work was to perform a user-friendly R package that combines the latter model-guided adaptive designs. RESULTS: GUIP1 is an R Graphical User Interface for dose escalation strategies in Phase 1 cancer clinical trials. It implements the CRM (based on Bayesian or maximum likelihood estimation), EWOC and TITE-CRM methods using the dfcrm and bcrm R packages, while the TITE-EWOC method has been specifically developed. The program is built using the TCL/TK programming language, which can be compiled via R software libraries (tcltk, tkrplot, tcltk2). GUIP1 offers the possibility of simulating and/or conducting and managing phase I clinical trials in real-time using file management options with automatic backup of study and/or simulation results. CONCLUSIONS: GUIP1 is implemented using the software R, which is widely used by statisticians in oncology. This package simplifies the use of the main model-based dose escalation methods and is designed to be fairly simple for beginners in R. Furthermore, it offers multiple possibilities such as a full traceability of the study. By including multiple innovative adaptive methods in a free and user-friendly program, we hope that GUIP1 will promote and facilitate their use in designing future phase I cancer clinical trials.

18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

PURPOSE: The aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection. METHODS: Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI. RESULTS: 18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p < 0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine. CONCLUSION: Tumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Correction to: 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors.

The article 18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors written by Laure Michaud, B. J. Beattie, T. Akhurst, M. Dunphy, P. Zanzonico, R. Finn, A. Mauguen, H. Schöder, W. A. Weber, A. B. Lassman, R. Blasberg.

Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC). METHODS: Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics. RESULTS: Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907,ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS(HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P<0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.03), and patients with body weight loss ≤5% versus >5% (P=0.04). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension,haemorrhagic events, neutropenia, and febrile neutropenia [corrected]. CONCLUSIONS: Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.

Variation in the peritoneal cancer index scores between surgeons and according to when they are determined (before or after cytoreductive surgery).

INTRODUCTION: The prognosis of peritoneal carcinomatosis (PC) is highly dependent on the extent of the PC. This extent is calculated by the peritoneal cancer index (PCI). In the future, the indications for complete cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) should be partially based on the PCI. This raises the question of the concordance between the PCI scores calculated by different surgeons, and a possible variation before and after CRS. OBJECTIVE: To analyze variations in the PCI score between surgeons and according to when it is determined (before and after surgery). PATIENTS AND METHODS: Prospective recording of the PCI score independently calculated by senior and junior surgeons, before CRS (when the surgeon decided to perform this procedure), and after CRS, in 75 consecutive patients. A concordance analysis was conducted. RESULTS: The origins of the PC were colorectal (n = 38), pseudomyxoma (n = 22), mesothelioma (n = 8) and miscellaneous lesions (n = 7). Concordance between the PCI score was very high (close to 90%) among the senior surgeons and junior surgeons before and after CRS. After CRS, the mean PCI score increased by 1.75 (IC-95%: 2.09-1.41). This high concordance was similar whatever the level of the PCI score and whatever the origin of the tumor. CONCLUSION: The PCI is a reliable tool for measuring the extent of PC. It is easy to use and inter-surgeon concordance is high. It increases by approximately 2 before and after CRS.

Association between the nuclear to cytoplasmic ratio of p27 and the efficacy of adjuvant polychemotherapy in early breast cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic and predictive value of p27 expression in patients with early breast cancer. PATIENTS AND METHODS: Quantitative immunofluorescence assays for p27 were done on a tissue microarray that included 823 samples from patients randomized between anthracycline-based chemotherapy and no chemotherapy. Quantification of p27 was done using the AQUA® system (HistoRx, Inc., Branford, CT). Both p27 nuclear expression and the nuclear to cytoplasmic ratio were assessed. RESULTS: Nuclear p27 expression was not predictive for the efficacy of anthracycline-based chemotherapy [adjusted P=0.18 for disease-free survival (DFS)] nor prognostic [95% confidence interval (CI) 0.99-1.01, P=0.49]. However, p27 nuclear/cytoplasmic ratio was predictive for the efficacy of adjuvant chemotherapy (adjusted P=0.016 DFS). The adjusted hazard ratio (HR) for relapse associated with adjuvant chemotherapy was 0.56 (95% CI 0.37-0.84, P=0.005) and 1.06 (95% CI 0.76-1.47, P=0.74) for patients with high and low nuclear/cytoplasmic ratio, respectively. p27 N/C ratio was prognostic in patients treated with chemotherapy (HR for relapse or death for a 1 unit increase in p27 N/C ratio was 0.30, 95% CI 0.12-0.77) but not in the untreated arm (HR for relapse or death was 1.27, 95% CI 0.58-2.8). CONCLUSIONS: This study did not confirm the role of p27 nuclear expression as a prognostic parameter. However, the p27 nuclear/cytoplasmic ratio was predictive in patients treated with anthracycline-based chemotherapy.

Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).

BACKGROUND: The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. RESULTS: Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. CONCLUSIONS: In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.

[Survival and prognostic factors after completion surgery in patients undergoing initial chemoradiation therapy for locally advanced cervical cancer]. / Survie et facteurs pronostiques après chirurgie de clôture chez des patientes atteintes de cancer du col de stade avancé

OBJECTIVE: The aim of this study was to evaluate the prognostic factors of patients undergoing completion surgery for locally advanced-stage cervical cancer after initial chemoradiation therapy (CRT). PATIENTS AND METHODS: Patients fulfilling the following inclusion criteria were studied: stage IB2-IVA cervical carcinoma; tumour initially confined to the pelvic cavity on conventional imaging; pelvic external radiation therapy with delivery of 45 Gy to the pelvic cavity and concomitant chemotherapy (cisplatin 40 mg/m(2) per week) followed by utero-vaginal brachytherapy; completion surgery after the end of radiation therapy including at least a hysterectomy. RESULTS: One-hundred and fifty patients treated between 1998 and 2007 fulfilled inclusion criteria. Nineteen patients had pelvic nodes involved and 19 had para-aortic nodes involved. Seventy-two patients (48%) had complete surgical sterilization of the cervix. Prognostic factors for overall survival in the multivariable analysis were the presence and level of nodal spread (positive pelvic nodes alone: HR = 2.03, positive para-aortic nodes: HR = 5.46; P < 001) and the presence and size of residual disease (RD) in the cervix (RD ≤ 1 cm: HR = 1.92, RD > 1cm: HR = 3.85; P = 02). DISCUSSION AND CONCLUSION: In this series, the presence and size of RD and histologic nodal involvement were the strongest prognostic factors. Such results suggest that the survival of these patients could potentially be enhanced by improving the rate of complete response in the irradiated area and by initially detecting patients with para-aortic spread.

Levels of circulating CD45(dim)CD34(+)VEGFR2(+) progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors.

BACKGROUND: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45(dim)CD34(+)VEGFR2(+) progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). METHODS: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45(-)CD31(+)CD146(+)7-amino-actinomycin (7AAD)(-) cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45(dim)CD34(+)VEGFR2(+)7AAD(-) progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45(dim)CD34(+)VEGFR2(+)7AAD(-) progenitor cells, plasma factors, as well as day 1-day 14 changes in CEC, CD45(dim)CD34(+)VEGFR2(+)7AAD(-) progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45(dim)CD34(+)VEGFR2(+)7AAD(-) progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). CONCLUSION: Monitoring CD45(dim)CD34(+)VEGFR2(+) progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome.

Dose-finding approach for dose escalation with overdose control considering incomplete observations.

We propose a hybrid design, the time-to-event dose-escalation method with overdose control (TITE-EWOC), introducing the time-to-event approach, developed by Cheungit et al., in the EWOC method, developed by Babb et al. The aim of this new design is to decrease the dose-finding trial duration, without impairing the characteristics of the EWOC design, especially the overdose control ability. We conducted a simulation study, exploring four dose­toxicity relationships and three mean inter-patient arrival times. Performances of TITE-EWOC were compared with those of the EWOC method. This study shows that the trial duration can be greatly decreased with the TITE-EWOC, without impacting the proportion of overdosed patients or the number of dose-limiting toxicities by trial, for all explored dose­toxicity relationships, except for very short inter-patient arrival times. The ability of the method to find the true maximum tolerated dose remains unchanged.

[Postoperative morbidity after completion surgery following homogeneous chemoradiation therapy in locally advanced cervical cancer]. / Morbidité de la chirurgie de clôture après radio-chimiothérapie chez des patientes atteintes d'un cancer du col de stade avancé.

OBJECTIVE: To evaluate the morbidity rate in patients following completion surgery (hysterectomy±lymphadenectomy) after chemoradiation therapy (CRT) for an advanced stage cervical cancer. PATIENTS AND METHODS: Patients fulfilling the following inclusion criteria were studied: (1) stage IB2-IVA cervical carcinoma; (2) tumor initially confined to the pelvic cavity; (3) pelvic external radiation therapy with delivery of 45Gy with concomitant chemotherapy (cisplatin 40mg/m(2)/week) followed by utero-vaginal brachytherapy; (4) completion surgery after the end of radiation therapy including at least a hysterectomy. RESULTS: One-hundred and fifty patients treated between 1998 and 2007 fulfilled inclusion criteria. Thirty-seven (25%) patients had 55 post-operative complications (17 had severe complications requiring surgical or radiological treatment). Two deaths related to postoperative morbidity had occurred. The risk of complications was increased with a radical hysterectomy (OR=2.4; P=0.04) and the presence of residual cervical disease (≤1cm: OR=4.3, >1cm: OR=2.5; P=0.01). CONCLUSION: In the present study, the morbidity of completion surgery (based on hysterectomy with or without lymphadenectomy) is very high in patients treated with initial CRT for locally advanced cervical cancer whereas the therapeutic value of such surgery remains unproven.