MGMT promoter methylation status as a prognostic factor for the outcome of gamma knife radiosurgery for recurrent glioblastoma

We conducted this study to determine whether the methylation status of the O⁶-methylguanine-DNA methyltransferase (MGMT) promoter was a prognostic marker for positive outcomes of gamma knife radiosurgery (GKS) for recurrent glioblastoma (GBM). We retrospectively examined 61 patients, who underwent GKS for local recurrent GBM between 2004 and 2015; in all patients, the methylation status of the MGMT promoter was identified via methylation-specific quantitative real-time polymerase chain reaction. All patients underwent surgical resection and were diagnosed histopathologically with GBM. Prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were identified in univariate and multivariate analyses. Twenty-five (41%) had a methylated MGMT promoter, and 36 (59%) had an unmethylated MGMT promoter. The median age at GKS was 58 years. The median tumor volume at GKS was 7.0 cm³, and the median marginal dose was 16 Gy. The median follow-up period after GKS was 7.5 months. The median PFS time after GKS was 8.9 months (95% CI 4.3–13.5 months) in the methylated and 4.6 months (95% CI 3.7–5.5 months) in the unmethylated group (P?=?0.016). The median OS time after GKS was 14.0 months (95% CI 9.3–18.7 months) in the methylated group and 9.0 months (95% CI 6.5–11.5 months) in the unmethylated group (P?=?0.026). Methylation of the MGMT promoter correlated with better PFS and OS after GKS for recurrent GBM. Prospective comparative studies are required to determine whether MGMT methylation directly affects the efficiency of GKS.     

Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer

BackgroundObjective response to dacarbazine, the intravenous form of temozolomide (TMZ), in metastatic colorectal cancer (mCRC) is confined to tumors harboring O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation. We conducted a phase II study of TMZ enriched by MGMT hypermethylation in archival tumor (AT), exploring dynamic of this biomarker in baseline tumor (BT) biopsy and plasma (liquid biopsy).Patients and methodsWe screened 150 mCRC patients for MGMT hypermethylation with methylation-specific PCR on AT from FFPE specimens. Eligible patients (n = 29) underwent BT biopsy and then received TMZ 200 mg/m² days 1–5 q28 until progression. A Fleming single-stage design was used to determine whether progression-free survival (PFS) rate at 12 weeks would be ≥35% [H0 ≤ 15%, type I error = 0.059 (one-sided), power = 0.849]. Exploratory analyses included comparison between MGMT hypermethylation in AT and BT, and MGMT methylation testing by MethylBEAMing in solid (AT, BT) and LB with regard to tumor response.ResultsThe PFS rate at 12 weeks was 10.3% [90% confidence interval (CI) 2.9–24.6]. Objective response rate was 3.4% (90% CI 0.2–15.3), disease control rate 48.3% (90% CI 32.0–64.8), median OS 6.2 months (95% CI 3.8–7.6), and median PFS 2.6 months (95% CI 1.4–2.7). We observed the absence of MGMT hypermethylation in BT in 62.7% of tumors.ConclusionTreatment of mCRC with TMZ driven by MGMT promoter hypermethylation in AT samples did not provide meaningful PFS rate at 12 weeks. This biomarker changed from AT to BT, indicating that testing BT biopsy or plasma is needed for refined target selection.     

Correlation between O<Superscript>6</Superscript>-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide

Epigenetic silencing of the O⁶-methylguanine-DNA-methyltransferase (MGMT) gene by promoter methylation is correlated with improved progression-free survival (PFS) and overall survival (OS) in adult patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. The aim of this study is to determine the correlation between MGMT and survival in elderly patients with GBM treated with radiotherapy (RT) and temozolomide (TMZ). Eighty-three patients aged 70 years or older with histologically confirmed GBM treated with RT plus TMZ between February 2005 and September 2009 were investigated in this study. The methylation status of the MGMT promoter was determined by polymerase chain reaction analysis. Median PFS and OS were 7.5 and 12.8 months, respectively. The MGMT promoter was methylated in 42 patients (50.6%) and unmethylated in 41 patients (49.4%). Median OS was 15.3 months in methylated patients and 10.2 months in unmethylated patients (P = 0.0001). Median PFS was 10.5 months in methylated tumors and 5.5 months in unmethylated tumors (P = 0.0001). On multivariate analysis MGMT methylation status emerged as the strongest independent prognostic factor for OS and PFS (P = 0.004 and P = 0.005, respectively). The results of the present study suggest that MGMT methylation status might be an important prognostic factor associated with better OS and PFS in elderly patients with GBM treated with RT and TMZ.     

O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients

O⁶-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in tumor cell explants with respect to prediction of TMZ response and survival of GBM patients (n = 71). Methylated MGMT gene promoter sequences were detected in 47 of 71 (66%) cases, whereas 37 of 71 (52%) samples were scored positive for MGMT protein expression. Although overall promoter methylation correlated significantly with protein expression (χ² test, P < .001), a small subgroup of samples did not follow this association. In the multivariate Cox regression model, a significant interaction between MGMT protein expression, but not promoter methylation, and TMZ therapy was observed (test for interaction, P = .015). In patients treated with TMZ (n = 42), MGMT protein expression predicted a significantly shorter overall survival (OS; hazard ratio [HR] for death 5.53, 95% confidence interval [CI] 1.76–17.37; P = .003), whereas in patients without TMZ therapy (n = 29), no differences in OS were observed (HR for death 1.00, 95% CI 0.45–2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients.     

A meta-analysis of temozolomide versus radiotherapy in elderly glioblastoma patients

Temozolomide (TMZ) alone has been proposed as a promising alternative to radiotherapy (RT) in elderly glioblastoma (GBM) patients. We report a meta-analysis to systematically evaluate TMZ monotherapy in older GBM patients. A systematic literature search was performed using PubMed, EMBASE and the Cochrane database. Studies comparing TMZ versus RT in elderly patients (≥65 years) with newly diagnosed GBM were eligible for inclusion. Two randomized clinical trials (RCTs) and three comparative studies were included in the analyses, which revealed an overall survival (OS) advantage for TMZ compared with RT (HR [hazard ratio] 0.86, 95 % CI [confidence interval] 0.74–1.00). However, a sensitivity analysis of 2 RCTs only supported its non-inferiority (HR 0.91, 95 % CI 0.66–1.27). Most elderly patients tolerated TMZ despite an increased risk of grade 3–4 (G3–4) toxicities, especially hematological toxicities. The quality of life was similar between the groups. In the MGMT analysis, methylated tumors were associated with a longer OS than unmethylated tumors among elderly patients receiving TMZ monotherapy (HR 0.50, 95 % CI 0.35–0.70). Moreover, in patients with methylated tumors, TMZ was more beneficial than RT alone in improving OS (TMZ vs. RT: HR 0.66, 95 % CI 0.47–0.93) whereas the opposite was true for those with unmethylated tumors (HR 1.32, 95 % CI 1.00–1.76). Although the meta-analysis demonstrated the non-inferiority to RT in improving OS, TMZ alone was not a straightforward solution for elderly GBM patients because of an increased risk of G3–4 toxicities, especially hematological toxicities. MGMT testing might be helpful for determining individualized treatment.     

O<Superscript>6</Superscript>-methylguanine DNA methyltransferase status determined by promoter methylation and immunohistochemistry in gliosarcoma and their clinical implications

O⁶-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3–14.5 months] and 8.3 months (95% CI, 7.4–9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.     

The efficacy and safety of extended adjuvant temozolomide following concurrent radio-chemotherapy among Egyptian patients with newly diagnosed glioblastoma multiforme

Although concurrent radio-chemotherapy and adjuvant temozolomide (TMZ) treatment for 6 cycles has been established as a standard of care for newly diagnosed glioblastoma multiforme (GBM) patients, the recommended duration of adjuvant TMZ remains a matter of debate. Hereby, we aimed to report for the first time our experience from Upper Egypt through comparing survival and toxicity profile between two treatment modalities of adjuvant TMZ (> six cycles versus six cycles) and delineating factors of prognostic significance in Egyptian patients with newly diagnosed GBM treated by radiation therapy with concomitant and adjuvant TMZ. Between June 2016 and February 2018, the medical records of 121 patients were eligible to be retrospectively reviewed to extract the study relevant data. All patients received concurrent radio-chemotherapy, followed by TMZ for 6 cycles in 29 patients (Group 1) and for >6 cycles in 26 patients (Group 2). Patients in Group 1 had a median PFS of 15 months (95% CI: 10.215-19.785), while those in Group 2 had a median PFS of 18 months (95% CI: 16.611-19.389). After a median follow up duration of 20 months (range: 12-41), the median OS was 18 months (95% CI: 13.420-22.580) in Group 1 and 22 months (95% CI: 18.777-25.223) in Group 2. There was no statistically significant correlation between the number of chemotherapy cycles and PFS (P=0.513) or OS (P=0.867). The extent of surgical resection was the only independent prognostic factor for both PFS (P=0.015) and OS (P=0.028) by multivariate analysis. Three grade ≥3 hematologic toxicity were encountered in 3 patients. One in the six-cycle group (neutropenia), and two in the extended cycles group (one had neutropenia and the other one developed thrombocytopenia). No statistically significant difference in the toxicity profile between both groups. The results of our study suggest that extended TMZ therapy is safe and tolerable, however it did not significantly improve PFS or OS as compared to the standard six-cycle course. Larger randomized studies are required to shed more light on this issue.     

Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma

The aim of this paper is to evaluate the efficacy of fractionated stereotactic radiotherapy (FSRT) and concomitant temozolomide (TMZ) as a salvage treatment option in patients with recurrent glioblastoma (GBM). Between May 2006 and December 2009, 36 patients with recurrent GBM received FSRT plus concomitant TMZ at University of Rome La Sapienza, Sant’ Andrea Hospital. All patients had Karnofsky performance score ≥60 and were previously treated with standard conformal radiotherapy (RT) (60 Gy) with concomitant and adjuvant TMZ for 6–12 cycles. The median time interval between primary RT and reirradiation was 14 months. At the time of recurrence, all patients received FSRT plus concomitant daily TMZ at the dose of 75 mg/m², given 7 days per week from the first day of RT. Radiation dose was 37.5 Gy delivered in 15 fractions over 3 weeks. Median overall survival after FSRT was 9.7 months, and the 6- and 12-month survival rates were 84 and 33%, respectively. The median progression-free survival (PFS) was 5 months, and 6- and 12-month PFS rates were 42 and 8%, respectively. In univariate analysis, KPS (P = 0.04), the interval between primary RT and reirradiation (P = 0.02), and O6-methylguanine-DNA-methyltransferase (MGMT) methylation status at the time of diagnosis (P = 0.009) had an effect on survival; however, in multivariate analysis, only MGMT methylation was statistically significant (P = 0.03). In general, FSRT was well tolerated and the treatment was completed in all patients. Neurological deterioration due to radiation-induced necrosis occurred in three patients (8%). FSRT plus concomitant TMZ is a feasible treatment option associated with survival benefits and low risk of complications in selected patients with recurrent GBM. The potential advantages of combined chemoradiation schedules in patients with recurrent GBM need to be explored in future studies.     

Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study

BackgroundIn a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.Patients and methodsIn this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan–Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.ResultsOf 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1–20.6) months for sunitinib and 5.8 (3.8–7.2) months for placebo (HR, 0.32; 95% CI 0.18–0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6–56.4) months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR, 0.73; 95% CI 0.50–1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.ConclusionsBICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.Trial registration numberNCT00428597.     

Practice Patterns and Outcomes for Pemetrexed Plus Platinum Doublet as Neoadjuvant Chemotherapy in Adenocarcinomas of Lung: Looking Beyond the Usual Paradigm

AimsNeoadjuvant chemotherapy (NACT) is the standard of care in non-small cell lung cancers (NSCLC) with locally advanced N2 disease. There is a scarcity of data for the pemetrexed–platinum regimen as NACT. Also, apart from N2 disease, the role of NACT in locally advanced NSCLCs for tumour downstaging is unclear.Materials and methodsNon-metastatic adenocarcinomas of lung treated with pemetrexed–platinum-based NACT were analysed. The patients with locoregionally advanced N2 disease and those who were borderline candidates for upfront definitive treatment were planned for NACT after discussion in a multidisciplinary clinic. In total, four cycles of 3-weekly pemetrexed and platinum were delivered in the combined neoadjuvant and adjuvant setting. A response assessment was carried out using RECIST criteria. Progression-free (PFS) and overall survival were calculated using the Kaplan–Meier method.ResultsOf 114 patients, 96 evaluable patients received NACT with pemetrexed–platinum. The most common indication for NACT was N2 disease at baseline (46.8%). The objective response rate was 36.4% (95% confidence interval 22–52%), including two complete and 32 partial responses, whereas 12.5% of patients had progressive disease on NACT. The median PFS was 14 months (95% confidence interval 10.7–17.3) and the median overall survival was 22 months (95% confidence interval 15.6–28.4) at a median follow-up of 16 months. There was a significant improvement in the overall survival of patients undergoing definitive therapy versus no definitive therapy (median overall survival 25 months [95% confidence interval 19.6–30.4] versus 12 months [95% confidence interval 3.2–20.7], respectively; P = 0.015, hazard ratio 0.56 [95% confidence interval 0.3–0.9]). Among patients who could not undergo definitive chemoradiation upfront due to dosimetric constraints (n = 34), 24 (70.6%) patients finally underwent definitive therapy after NACT.ConclusionsPemetrexed–platinum-based NACT seems to be an effective option and many borderline cases, where upfront definitive therapy is not feasible, may become amenable to the same after incorporation of NACT.     

Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma – a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience

AimsOverall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy.Materials and methodsWe reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1–IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded.ResultsOverall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08–1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1–100) and 64.6% (95% confidence interval 44.6–84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08–0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6–97.0) and 35.0% (95% confidence interval 14.0–56.0), respectively.ConclusionsOur institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.     

Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)

BackgroundThis phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM).Patients and methodsForty-eight patients aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST.ResultsThe median PFS was 10.1 months [95% confidence interval (CI) 7.1–12.3] for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2.ConclusionsSingle-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.     

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer

BackgroundThe composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.Patients and methodsWe examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.ResultsSixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4–6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0–2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6–7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.ConclusionATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.     

Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network

BackgroundXp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients.Patients and methodsPatients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified. Nuclear TFE3 positivity was confirmed by reviewing pathology slides. Responses according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed.ResultsOverall, 53 patients were identified; 23 had metastatic disease, and of these 21 had received targeted therapy (median age 34 years). Seven patients achieved an objective response. In first line, median PFS was 8.2 months [95% confidence interval (CI) 2.6–14.7 months] for sunitinib (n = 11) versus 2 months (95% CI 0.8–3.3 months) for cytokines (n = 9) (log-rank P = 0.003). Results for further treatment (second, third, or fourth line) were as follows: all three patients receiving sunitinib had a partial response (median PFS 11 months). Seven of eight patients receiving sorafenib had stable disease (median PFS 6 months). One patient receiving mTOR inhibitors had a partial response and six patients had stable disease. Median OS was 27 months with a 19 months median follow-up.ConclusionIn Xp11 translocation RCC, targeted therapy achieved objective responses and prolonged PFS similar to those reported for clear-cell RCC.     

Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings

BackgroundML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Patients and methodsEvaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.ResultsOf 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49–0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56–0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53–0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71–1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).ConclusionsBevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.     

Randomized phase II study evaluating veliparib (ABT-888) with temozolomide in patients with metastatic melanoma

BackgroundVeliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models.Patients and methodsIn this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).ResultsPatients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0–5.5), 3.6 (1.9–4.1), and 2 (1.9–3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0–13.1), 13.6 (11.4–15.9), and 12.9 (9.8–14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively.ConclusionsMedian PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.     

Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide

BACKGROUND: Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. METHODS: From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. RESULTS: The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). CONCLUSIONS: The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.     

替莫唑胺联合放疗治疗新诊断的恶性胶质瘤患者:O6-甲基鸟嘌呤-DNA-甲基转移酶促甲基化和Ki-67叮作为评价存活率和治疗反应的指标

Objective: This phase II study aimed at investigating the correlation between O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and protein expression, together with Ki-67 labeling index (LI), to response, time to progression (TTP), and overall survival (OS) in newly diagnosed glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ) concomitant with and adjuvant to radiotherapy (RT).Methods: From June 2005 to August 2008, 34 by TMZ 175 mg/m2 5 days every 4 weeks for 12 doses.MGMT Methylation-specific PCR assay, MGMT protein expression, and Ki-67 expression using immunohistochemistry (IHC) were performed on the tissue blocks.The patients were followed by MRI while MR spectroscopy (MRS) was performed for the stable cases or to confirm progression and accordingly Bevacizumab 10 mg/kg every 2 weeks was added to 7 patients till further progression was proved.Results: 31 cases were evaluable, 12 (38.7%) had unmethylated MGMT, while 19 (61.3%) were methylated.Seventeen cases (55%) were MGMT immunonegative while 14 cases (45%) were immunopositive.The cut off value of Ki-67 LI in relation to survival was 17%, where 15 were < 17% (48.4%), and 16 were ≥ 17% (51.6%).Response evaluation started after the second dose of the adjuvant TMZ and was repeated every 2 months.The overall disease control rate (ODC) was 74.2%, where 2 patients had complete response (CR), 14 had partial response (PR), and 7 had stable disease (SD), while 8 (25.8%) had progressive disease (PD).The ODC was significantly higher among methylated patients and in those with Ki-67 < 17% (P = 0.0003).The median overall TTP was 12 months and the median OS was 20 months for all the patients including those who received Bevacizumab for some stable cases or as a salvage treatment in patients with good PS, the MGMT-methylated patients had a higher median TTP of 13 months (range 8 to 18 months, 95% CI of 9.36 to 12.9), and OS of 24 months (range 12 to 31 months, 95% CI of 16.1 to 21.32), while the unmethylated patients had a median TTP of 6.5 months and a median OS of 12 months, such correlations were highly significant (P = 0.0001).MGMT immunoexpression failed to show significant correlation with MGMT promotor methylation or the outcome of the patients.Patients with Ki-67 < 17% had a median TTP of 16 months and median OS of 24 months compared to 7 and 12.5 months respectively for the patients with Ki-67 ≥17%.Significant correlation was found between the ODC, TTP, and OS with age < 52, near total excision, and TMZ doses received ≥ 10.The commonest grade 3 and 4 toxicities was neutropenia recorded in 3 patients (9.67%), thrombocytopenia in 4 patients (12.9%), and one patient with G3 nausea, vomiting, and constipations (3%), all were medically manageable.Conclusion: MGMT promotor methylation status and Ki-67 LI (but not the MGMT protein expression), could serve as prognostic markers for survival, also MGMT could identify the newly diagnosed GBM patients who will have better response to TMZ.