New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning.

BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.

Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials.

Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23-86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1-13) lines of treatment prior to trial entry. The median [95% confidence interval] progression-free survival and OS times were 3.0 [1.8-3.6] and 17.8 [12.7-30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high-grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies.

Prognostic factors and outcome of patients with hematological malignancies in phase I trials: the Gustave Roussy scoring system.

Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008-February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012-May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1-43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0-5.3] and 19.8 months (95% CI: 16.1-36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09-33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.

Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.

BACKGROUND: Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. METHODS: We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731. FINDINGS: We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths. INTERPRETATION: Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. FUNDING: Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.

Very Long-Term Complete Remission Can Be Achieved in Men With High-Risk Localized Prostate Cancer and a Very High PSA Value: An Analysis of the GETUG 12 Phase 3 Trial.

INTRODUCTION: Serum prostate specific antigen (PSA) is a well-known prognostic parameter in men with prostate cancer. The treatment of men with very high PSA values and apparently no detectable metastases is not fully established. PATIENTS AND METHODS: Ancillary analysis from the GETUG 12 phase 3 trial. Patients with non-metastatic high-risk prostate cancer by bone and computerized tomography (CT) scan were randomly assigned to receive androgen deprivation therapy (ADT) and docetaxel plus estramustine or ADT alone. Relapse-free survival (RFS), clinical RFS, metastases-free survival (MFS), overall survival (OS), and prostate cancer-specific survival (PCSS) were estimated using the Kaplan-Meier method for different levels of PSA (50 ng/mL, 75 ng/mL, and 100 ng/mL). The relationship between PSA and outcomes was studied using residual-based approaches and spline functions. RESULTS: The median follow-up was 12 years (range: 0-15.3). Baseline PSA (<50 ng/mL, n = 328; ≥50ng/mL, n = 85) was associated with improved RFS (P = .0005), cRFS (P = .0024), and MFS (P = .0068). The 12-year RFS rate was 46.33% (CI 40.59-51.86), 33.59% (CI 22.55-44.97), and 11.76% (1.96-31.20) in men with PSA values <50 ng/mL (n = 328), 50-100 ng/mL (n = 68), and ≥100 ng/mL (n = 17), respectively. Exploratory analyses revealed no deviation from the linear relationship assumption between PSA and the log hazard of events. CONCLUSIONS: Men with apparently localized prostate cancer and a high baseline PSA value have a reasonable chance of being long-term disease-free when treated with curative intent combining systemic and local therapy.

Randomized trial comparing two methods of re-irradiation after salvage surgery in head and neck squamous cell carcinoma: Once daily split-course radiotherapy with concomitant chemotherapy or twice daily radiotherapy with cetuximab.

BACKGROUND: A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival. PATIENTS AND METHODS: Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU - hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity). RESULTS: Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms. CONCLUSIONS: Twice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms.

TPF induction chemotherapy increases PD-L1 expression in tumour cells and immune cells in head and neck squamous cell carcinoma.

BACKGROUND: Antiprogrammed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) therapies have demonstrated promising activity in advanced head and neck squamous cell carcinoma (HNSCC), with overall response rates of approximately 20% in unselected populations and survival benefit. Whether induction docetaxel, platinum and fluorouracil (TPF) modifies PD-L1 expression or tumour immune infiltrates is unknown. PATIENTS AND METHODS: Patients with locally advanced HNSCC treated at Gustave Roussy (Villejuif, France) between 2006 and 2013 by induction TPF followed by surgery were retrospectively considered. Patients with paired samples (pre-TPF and post-TPF) were kept for further analysis. PD-L1 expression was quantified by immunohistochemistry according to a validated protocol. The objective of the study was to compare PD-L1 expression on tumour cells (TC) and immune cells (IC) (positivity threshold of ≥5%) before and after TPF. CD8+ and Foxp3+ lymphocytes densities before and after TPF were also quantified. RESULTS: Out of 313 patients receiving induction TPF, 86 underwent surgery; paired samples were available for 21 of them. Baseline PD-L1 expression was ≥5% in two and five samples for TC and IC, respectively. A significant increase of PD-L1 expression was observed after TPF, with 15 samples (71%) presenting a positive staining in IC after induction chemotherapy (P=0.003; Wilcoxon rank-sum test) and eight samples (38%) in TC (P=0.005; Wilcoxon rank-sum test). Tumour-infiltrating CD8+ mean densities also significantly increased post-TPF (P=0.01). There was no significant difference in Foxp3+ expression, CD8/Foxp3 ratio or correlation with outcome. CONCLUSION: TPF induction chemotherapy in advanced HNSCC increases PD-L1 positivity on tumour-infiltrating ICs, as well as CD8+ lymphocytes density. These results warrant independent validation on larger datasets and might help therapeutic strategy in advanced HNSCC.

LKB1/STK11 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value.

BACKGROUND: LKB1/STK11 (STK11) is among the most inactivated tumor-suppressor genes in non-small cell lung cancer (NSCLC). While evidence concerning the biologic role of STK11 is accumulating, its prognostic significance in advanced NSCLC has not been envisaged yet. MATERIALS AND METHODS: This retrospective analysis included consecutive NSCLC patients with available STK11 information who underwent a platinum-based chemotherapy. STK11 mutational status was correlated to clinico-pathological and mutational features. Kaplan-Meier and Cox models were used for survival curves and multivariate analyses, respectively. RESULTS: Among the 302 patients included, 267 (89%) were diagnosed with stage IIIB/IV NSCLC and 25 (8%) harbored a STK11 mutation (STK11mut). No statistical differences were observed between STK11 status and clinico-pathological variables. We detected a significant correlation between STK11 and KRAS status (p=0.008); among the 25 STK11mut patients, 13 (52%) harbored a concomitant KRAS mutation. Overall survival (OS) was shorter for STK11mut (median OS=10.4months) compared to wild-type patients (STK11wt; median OS=17.3months) in univariate analysis (p=0.085). STK11 status did not impact upon OS in multivariate analysis (p=0.45) and non-significant results were observed for progression-free survival. The co-occurrence of KRAS and STK11 mutations suggest a trend toward detrimental effect in OS (p=0.12). CONCLUSIONS: In our cohort enriched for advanced NSCLC patients who received platinum-based chemotherapy, STK11 mutations were not specifically associated with clinico-pathological features and they did not impact upon survival. We confirm the positive correlation between STK11 and KRAS mutations. The co-occurrence of KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

Study of Intrapatient Variability and Reproducibility of Quantitative Tumor Perfusion Parameters Evaluated With Dynamic Contrast-Enhanced Ultrasonography.

OBJECTIVES: Dynamic contrast-enhanced (DCE) ultrasonography (US) is a functional imaging technique enabling quantitative assessment of solid tumor perfusion in metastatic patients treated with antiangiogenic therapies.The objective of this prospective single-center study was to evaluate in real-life conditions (in routine clinical practice) the intrapatient variability and reproducibility of DCE-US parameters. MATERIALS AND METHODS: Each patient provided written informed consent and had 2 DCE-US examinations (preprandial and postprandial) at baseline, day 15, and 1 month after treatment initiation. Perfusion curves were recorded after Sonovue injections to determine 7 perfusion parameters. Dynamic contrast-enhanced US examinations were analyzed in pairs: preprandial and postprandial. Log transformed values were used to determine the variability of the pairs (within-subject coefficient of variation) and their reproducibility (Spearman correlation coefficient). RESULTS: We included 60 patients (23 colon cancers, 36 kidney cancers, and 1 breast cancer) treated with axitinib (26 patients), sunitinib (27 patients), and other antiangiogenic treatments (7 patients). The 60 patients included 38 men (63%) and 22 women (37%) with a median age of 62 (range, 25-82 years). Thirty patients had hepatic and 30 had extrahepatic target lesions. Data were analyzed for 128 pairs of DCE-US: 45 (baseline), 45 (day 15), and 38 (1 month). Preprandial and postprandial values were not significantly different. For area under the curve and area under the washout, the correlation coefficient between preprandial and postprandial values was 0.89; the associated within-subject coefficients of variation were 61% and 64%, respectively. However, the range of individual variations (postprandial value/preprandial value) was less than 2 logs for a range of parameter values of about 4 logs. Variability was independent of the metastatic site. CONCLUSIONS: This study showed that area under the curve and area under the washout are the 2 most reproducible DCE-US parameters.

Prognostic value of HLA-A2 status in advanced non-small cell lung cancer patients.

INTRODUCTION: The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. METHODS: Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. RESULTS: Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0-1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21-84). Incidence of patients with EGFRmut, ALK-positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0-14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4-15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86-1.29], p=0.61). Median progression-free survival was similar in the two cohorts. CONCLUSION: HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy.

Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial.

PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients.