Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. MATERIALS AND METHODS: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days). RESULTS: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells. CONCLUSION: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Quality of life after mastectomy with or without immediate breast reconstruction.

BACKGROUND: Mastectomy with immediate breast reconstruction (IBR) is a surgical strategy in breast cancer when breast-conserving surgery is not an option. There is a lack of evidence showing an advantage of mastectomy plus IBR over mastectomy alone on health-related quality of life (QoL). METHODS: A large prospective multicentre survey, STIC-RMI (support of innovative and expensive techniques - immediate breast reconstruction), was undertaken to study the changes in QoL in patients treated by mastectomy with or without IBR. Patients were recruited between 2007 and 2009. European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 instruments were used to assess QoL before operation, and at 6 and 12 months after surgery. A propensity score was used to compare QoL between mastectomy alone and mastectomy plus IBR, with limited bias. RESULTS: A total of 595 patients were included from 22 French academic hospitals, of whom 407 (68·4 per cent) underwent IBR. One-year data were available for 71·1 per cent of patients. Factors associated with IBR were age, histological tumour type, palpable nodes and an attempt at breast-conserving surgery. At inclusion, QoL was significantly better in the IBR group (P < 0·001) and there was no significant change in either group during 1 year compared with baseline. Results for the QLQ-BR23 functional dimension varied according to propensity score quartiles; IBR had no influence in the lowest quartile. In the upper quartiles, QoL increased slightly over the year among patients who had IBR, whereas it decreased among those who had mastectomy alone (P = 0·037). Satisfaction with the cosmetic outcome strongly influenced QoL, especially in upper quartiles (P < 0·001). However, an unsatisfactory outcome after IBR was still considered a better condition than simple mastectomy. CONCLUSION: The QoL benefit provided by IBR depends on patients' life status at inclusion; young active women with an in situ tumour are more likely to preserve their QoL after IBR.

Adherence with oral oncologic treatment in cancer patients: interest of an adherence score of all dosing errors.

PURPOSE: Patient nonadherence to oral antineoplastic therapy is a well-recognized barrier to effective treatment. In order to identify patients who may need additional support to become adherent, it is important to have a useful tool that takes into account all the parameters of adherence to prescription. The aim of this prospective study was to evaluate adherence of oral antineoplastic agents and to investigate two calculation methods of adherence score. PATIENTS AND METHODS: Twenty-nine cancer patients were enrolled in this study. Fourteen were treated by capecitabine and 15 patients by aromatase inhibitors. Adherence was measured using a medication event monitoring system and adherence score was calculated by a usual method and a composite adherence score that takes into account missed doses and also intake interval errors (between 2 doses and between meals). RESULTS: Across the 6-month evaluation period, average adherence was 95% with the standard calculation (capecitabine group: 89%; aromatase inhibitor group: 99%) versus 83% with the composite index (capecitabine group: 62%; aromatase inhibitor group: 99%) (p = 0.030). The composite calculation permits to highlight more nonadherent patients (29.6 vs. 7.4%), particularly in the capecitabine group (73 vs. 18%, p = 0.001). We report 2 cases identified as nonadherent with composite adherence rate. CONCLUSION: The composite adherence score permits to better evaluate adherence to prescription and to identify barriers to adherence and persistence.

Importance of metabolic changes induced by chemotherapy on prognosis of early-stage breast cancer patients: a review of potential mechanisms.

Weight variation has been reported as a side effect of chemotherapy treatment in early breast cancer patients and has been identified as a factor of poor prognosis. Causes of weight variation during chemotherapy and mechanisms involved in the poor prognosis have been little studied. Here is reviewed the current knowledge about the main causes and mechanisms involved in body weight change. Special emphasis is placed on factors associated with weight variation which could potentially be involved in the risk of relapse in breast cancer survivors. In recent decades, some studies have investigated the causes of weight variation by studying energy balance of breast cancer patients during chemotherapy. Weight gain or loss may be the consequence of energy imbalance through different factors linked with chemotherapy, such as poor treatment tolerance, decreased muscle mass and function, or hormonal alterations. This results in body composition modifications in favour of fat gain and/or lean body mass loss. Increased adipose tissue, especially in the abdominal region, could induce metabolic disturbances such as insulin resistance, through various pathways involving adipokines. These molecules have growth properties and could therefore play a role in cancer relapse. Understanding such mechanisms is key to developing preventive strategies for improving the prognosis of early-stage breast cancer patients.

Prognostic value of initial tumor parameters after metastatic relapse.

Classical prognostic factors of breast cancer are correlated to disease-free survival and overall survival (OS); their precise role is less known on metastatic disease. A total of 511 breast cancer patients without initial metastasis were treated. OS was divided in time to distant recurrence and metastatic survival (MS). Age, Scarff-Bloom-Richardson (SBR) grade, hormone receptor, axillary node involvement, and Nottingham prognostic index predicted MS in univariate analysis. Multivariate analysis retained age, SBR grade, and axillary lymph node involvement as significant independent prognostic factors. Interactions are still present between initial parameters and MS. The clinician has to take into account for treatment choice.

Late lines of treatment benefit survival in metastatic breast cancer in current practice?

Metastatic breast cancer is mostly incurable. Progressively overall survival (OS) has improved but few authors have studied treatment globally versus for each line and demonstrated the interest of chemotherapy (CT) after the third line. We selected recent patients treated during the "taxane/anti-aromatase era" for each line given. 529 received CT and 383 hormonotherapy. OS was assessed; from the date of first metastasis and from Day 1 of each CT line. Median OS was 34.1 months; 226 patients received >3 lines of CT with a steady median OS for late lines, 11.4 months per line (range 10.4-12.6). Clinical benefit after the third line of CT was obtained for 29.2-36.6% of patients. CT lasted 11.7 months "on"versus 20.6 months "off" CT. These results may support the use of more than 3 CT lines; each line can contribute to a longer survival.

Cystemustine in recurrent high grade glioma.

In this study, we have assessed the efficacy of a nitrosourea, cystemustine, in treating patients with recurrent high grade glioma with overall survival analysis as primary end-point. Forty-eight patients with recurrent high grade glioma (24 glioblastomas, 17 astrocytomas and 5 oligodendrogliomas) were treated every 2 weeks with 60 mg/m2 cystemustine by a 15 min-infusion. The median number of treatment cycles was 4 (range 1-17). The median overall survival was 8.3 months (range 1-97) and the 6- and 12-month overall survival rates were 55.3% (95% CI, 41.3-68.6%) and 29.8% (95% CI, 18.6-44.0%), respectively. The objective response rate was 18.8% (95% CI, 7.7-29.9%), and 54.2% of patients had stable disease (95% CI, 40.1-68.3%). Multivariate analysis showed that WHO performance status, histology and response to cystemustine were significant prognostic factors for survival of patients with recurrent glioma. In conclusion, cystemustine has encouraging activity for patients with recurrent high grade glioma.