The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation.

Human liver pyruvate kinase (hlPYK) catalyzes the final step in glycolysis, the formation of pyruvate (PYR) and ATP from phosphoenolpyruvate (PEP) and ADP. Fructose 1,6-bisphosphate (FBP), a pathway intermediate of glycolysis, serves as an allosteric activator of hlPYK. Zymomonas mobilis pyruvate kinase (ZmPYK) performs the final step of the Entner-Doudoroff pathway, which is similar to glycolysis in that energy is harvested from glucose and pyruvate is generated. The Entner-Doudoroff pathway does not have FBP as a pathway intermediate, and ZmPYK is not allosterically activated. In this work, we solved the 2.4 Å X-ray crystallographic structure of ZmPYK. The protein is dimeric in solution as determined by gel filtration chromatography, but crystallizes as a tetramer. The buried surface area of the ZmPYK tetramerization interface is significantly smaller than that of hlPYK, and yet tetramerization using the standard interfaces from higher organisms provides an accessible low energy crystallization pathway. Interestingly, the ZmPYK structure showed a phosphate ion in the analogous location to the 6-phosphate binding site of FBP in hlPYK. Circular Dichroism (CD) was used to measure melting temperatures of hlPYK and ZmPYK in the absence and presence of substrates and effectors. The only significant difference was an additional phase of small amplitude for the ZmPYK melting curves. We conclude that the phosphate ion plays neither a structural or allosteric role in ZmPYK under the conditions tested. We hypothesize that ZmPYK does not have sufficient protein stability for activity to be tuned by allosteric effectors as described for rheostat positions in the allosteric homologues.

A Complex Zeolite Containing Multiple Ring Sizes in a Single Channel: One-Dimensional Zeolite UZM-55.

Zeolites are porous aluminosilicate materials utilized in a variety of sorption, separation, and catalytic applications. The oil refining industry in particular has seen a number of significant advances due to the introduction of new technologies enabled by new zeolites. Of particular importance are zeolites with 10- or 12-membered ring pores, resulting in pore shapes and sizes appropriate for the interaction with small hydrocarbon molecules. Here, the synthesis of a new zeolite UZM-55 is reported and the idealized structure thereof is presented. The most complex structure solved to date, UZM-55 possesses a large triclinic unit cell containing 52 T-sites. The material uniquely contains both 10- and 12-membered ring pores in a single, undulating one-dimensional channel, the first example in a zeolitic material of multiple delimiting rings in a single channel. This discovery opens new opportunities in shape-selective adsorption and catalysis. Demonstrated here is the unique adsorption behavior of UZM-55, shown both experimentally and computationally to adsorb one nonane molecule per unit cell in a linear conformation.

Whole brain radiotherapy after stereotactic radiosurgery or surgical resection among patients with one to three brain metastases and favorable prognoses: a secondary analysis of EORTC 22952-26001.

BACKGROUND: The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses. PATIENTS AND METHODS: We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC). RESULTS: A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]. CONCLUSIONS: Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance. CLINICAL TRIALS NUMBER: NCT00002899.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891.

BACKGROUND: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. MATERIAL AND METHODS: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-FU 1000 mg/m(2) day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) ≤ 1.428, one-sided α = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). RESULTS: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. CONCLUSION: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx.

Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.

Various protein properties are often illuminated using sequence comparisons of protein homologs. For example, in analyses of the pyruvate kinase multiple sequence alignment, the set of positions that changed during speciation ("phylogenetic" positions) were enriched for "rheostat" positions in human liver pyruvate kinase (hLPYK). (Rheostat positions are those which, when substituted with various amino acids, yield a range of functional outcomes). However, the correlation was moderate, which could result from multiple biophysical constraints acting on the same position during evolution and/or various sources of noise. To further examine this correlation, we here tested Zymomonas mobilis PYK (ZmPYK), which has <65% sequence identity to any other PYK sequence. Twenty-six ZmPYK positions were selected based on their phylogenetic scores, substituted with multiple amino acids, and assessed for changes in Kapp-PEP . Although we expected to identify multiple, strong rheostat positions, only one moderate rheostat position was detected. Instead, nearly half of the 271 ZmPYK variants were inactive and most others showed near wild-type function. Indeed, for the active ZmPYK variants, the total range of Kapp,PEP values ("tunability") was 40-fold less than that observed for hLPYK variants. The combined functional studies and sequence comparisons suggest that ZmPYK has evolved functional and/or structural attributes that differ from the rest of the family. We hypothesize that including such "orphan" sequences in MSA analyses obscures the correlations used to predict rheostat positions. Finally, results raise the intriguing biophysical question as to how the same protein fold can support rheostat positions in one homolog but not another.

A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).

BACKGROUND: To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-prognosis germ-cell cancer (GCC). PATIENT AND METHODS: Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but closed with 137, due to slow accrual. RESULTS: One hundred thirty-one patients were included in this analysis. The complete response rates in the HD-CT and in the BEP arm did not differ: (intention to treat) 44.6% versus 33.3% (P = 0.18). There was no difference in FFS between the two treatment arms (P = 0.057, 66 events). At 2 years, the FFS rate was 44.8% [95% confidence interval (CI) 32.5-56.4] and 58.2%, respectively (95% CI 48.0-71.9); but this 16.3% (standard deviation 7.5%) difference was not statistically significant (P = 0.060). Overall survival did not differ between the two groups (log-rank P > 0.1, 47 deaths). CONCLUSION: This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy improves outcome in patients with poor-prognosis GCC.

Independent external validation using the EORTC HNCG-ROG 1219 DAHANCA trial data of NTCP models for acute oral mucositis.

PURPOSE: To externally validate previously published Normal Tissue Complication Probability (NTCP) models developed by separate teams for grade 3 oral mucositis (g3OM). MATERIALS AND METHODS: Two models were validated: a logistic model, based on 144 head and neck cancer (HNC) patients receiving induction chemotherapy followed by chemo-IMRT; a multivariable logistic model for prediction of g3OM for 253 patients receiving radical treatment for the head and neck squamous cell carcinoma (HNSCC). The EORTC HNCG-ROG 1219 DAHANCA trial dataset, consisting of 169 patients was used as the validation cohort. This cohort was treated with accelerated fractionated chemo-IMRT, with/without the hypoxic radiosensitizer Nimorazole for HNSCC. External validity was assessed using the scaled Brier score. Calibration was assessed in terms of calibration curves as well as measures of mean and weak calibration. Hosmer-Lemeshow was used for goodness-of-fit test. Discrimination was calculated using the area under the receiver operating curve (AUC-ROC). RESULTS: The prevalence of g3OM in the validation cohort (35.5%) was similar to that of two development cohorts, i.e. 38.7% and 31.9% for Bhide logistic and Otter multivariable logistic models respectively. The scaled Brier scores showed good overall model performance. Perfect calibration was observed in the prevalence range of 20% to 40%. AUC-ROC was acceptable in external validation (0.67). The Hosmer-Lemeshow test showed good agreement between predicted and observed outcomes for two models. CONCLUSION: The NTCP models were validated and lead to valid predictions in a wide range of diverse treatment techniques and patient characteristics, also when Nimorazole is added as hypoxic radiosensitizer.

Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer.

BACKGROUND: This randomized, phase II study assessed the activity of oblimersen sodium, a Bcl-2 antisense oligonucleotide, administered before docetaxel (Taxotere) to patients with castration-resistant prostate cancer. PATIENTS AND METHODS: Chemotherapy-naive patients with prostate-specific antigen (PSA) progression and testosterone < or = 0.5 ng/ml received docetaxel 75 mg/m2 on day 1 or oblimersen 7 mg/kg/day continuous i.v. infusion on days 1-7 with docetaxel 75 mg/m2 on day 5 every 3 weeks for < or = 12 cycles. Primary end points were confirmed PSA response (Bubley criteria) and major toxic events. RESULTS: Confirmed PSA response was observed in 46% and 37% of 57 and 54 patients treated with docetaxel and docetaxel-oblimersen, respectively. Partial response (RECIST) was achieved in 18% and 24%, respectively. Oblimersen added to docetaxel was associated with an increase in the incidence of grade > or = 3 fatigue, mucositis, and thrombocytopenia. Major toxic events were reported in 22.8% and 40.7% of patients with docetaxel and docetaxel-oblimersen, respectively. CONCLUSIONS: The primary end points of the study were not met: a rate of confirmed PSA response >30% and a major toxic event rate <45% were not observed with docetaxel-oblimersen.

Multicentre analysis of oncological and survival outcomes following anastomotic leakage after rectal cancer surgery.

BACKGROUND: The association between diverting stomas and symptomatic anastomotic leakage after rectal cancer surgery was studied, as well as the impact of leakage on local recurrence, distant metastasis, and disease-free, overall and cancer-specific survival. METHODS: Data from the Swedish Rectal Cancer Trial, Dutch TME trial, CAO/ARO/AIO-94 trial, EORTC 22921 trial and Polish Rectal Cancer Trial were pooled (n = 5187). All eligible patients without distant metastases at the time of low anterior resection were selected (n = 2726); overall survival was studied in patients aged 75 years or less (n = 2480). Multivariable models were used to study the association between diverting stomas and anastomotic leakage, and between leakage and recurrence or survival. RESULTS: Some 9.7 per cent of patients were diagnosed with a symptomatic anastomotic leak; diverting stomas were negatively associated with leakage (11.6 per cent without and 7.8 per cent with a stoma; P = 0.002). Anastomotic leakage was negatively associated with overall survival in the multivariable analysis (hazard ratio (HR) 1.29 (95 per cent confidence interval 1.02 to 1.63); P = 0.034), but not with cancer-specific survival (HR 1.12 (0.83 to 1.52); P = 0.466). CONCLUSION: Diverting stomas were associated with less symptomatic anastomotic leakage. Oncological outcome was not significantly influenced by leakage, but overall survival was reduced.

A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992).

BACKGROUND: The aim of this study is to determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer. PATIENTS AND METHODS: Patients with T3, T4, N1, N2, N3 or M1 cisplatin advanced penile cancer were treated with a combination of irinotecan (60 mg/m(2)) on days 1, 8 and 15 and cisplatin (80 mg/m(2)) administered every 28 days. Patients were treated either in the neo-adjuvant setting for T3 or N1-N2 disease with a maximum of four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. The study was designed with the aim to exclude a response rate (complete response + partial response) <30% (alpha = 10%, power = 95%). RESULTS: Twenty-eight patients were included and evaluated for toxicity, and 26 eligible patients were evaluated for response. Toxicity was acceptable with three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever. There were eight responses (two complete response and six partial response) (30.8%, 80% confidence interval 18.8% to 45.1%): three patients undergoing histological verification after chemotherapy had no evidence of malignancy. CONCLUSION: The study fails to demonstrate a response rate significantly >30%. The observation regarding M0 patients suggests to repeat this study in the neo-adjuvant setting.

The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial.

PURPOSE: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer. PATIENTS AND METHODS: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented. RESULTS: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively. CONCLUSION: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

[Prophylactic cranial irradiation in patients with extensive disease caused by small-cell lung cancer responsive to chemotherapy: fewer symptomatic brain metastases and improved survival]. / Profylactische schedelbestraling bij patiënten met uitgebreid kleincellig longcarcinoom dat reageert op chemotherapie: minder symptomatische hersenmetastasen en betere overleving.

OBJECTIVE: To determine the effect of prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to chemotherapy. DESIGN: Randomised, controlled clinical trial; phase III study (EORTC nr 08993-22993; www.clinicaltrials.gov, nr NCT00016211). METHOD: Patients aged 18-75 years with a functional status according to WHO < or = 2, and with ED-SCLC and any response to chemotherapy, were randomized to observation (standard care) or PCI. The primary endpoint was time to symptomatic brain metastases. If any pre-defined, key symptom suggesting brain metastases presented, a CT or MRI scan of the brain was performed. The size of the study (143 patients per arm) was determined to detect a hazard ratio (HR) of 0.44 at 80% power with 2-sided alpha = 0.05. RESULTS: The study accrued 286 patients. PCI decreased the risk of developing symptomatic brain metastases (HR = 0.27 (95% CI: 0.16-0.44; p < 0.001)). The cumulative incidence of developing brain metastases within 1 year was 40% in the control group (95% CI: 32-49) and 15% in the PCI group (95% CI: 8-21). PCI prolonged disease-free (HR = 0.76; 95% CI: 0.59-0.96, p = 0.02) and overall survival (HR = 0.68; 95% CI; 0.52-0.88, p = 0.003). The 1-year survival rate was 27% (95% CI: 19-36) for the PCI group versus 13% (95% CI: 8-20) for controls. Acute and late treatment toxicity was acceptable. These side effects did not significantly impact on quality of life. CONCLUSIONS: PCI significantly reduced the incidence of symptomatic brain metastases and prolonged both disease-free and overall survival and should be part of standard care in SCLC patients who respond to chemotherapy.

FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist.

BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

[Preliminary results for EORTC trial 22911: radical prostatectomy followed by postoperative radiotherapy in prostate cancers with a high risk of progression]. / Résultats préliminaires de l'essai EORTC 22911: prostatectomie radicale suivie ou non de radiothérapie postopératoire dans les cancers de la prostate à haut risque de récidive.

PURPOSE: Local failure after radiotherapy can arise with cancer extending beyond the capsule and/or involvement of seminal vesicles or positive surgical margins. METHODOLOGY: After undergoing radical prostatectomy 1005 patients were randomly assigned (1999-2001) to a wait and see policy or an immediate postoperative irradiation (60 Gy delivered over 6 weeks); eligible patients had pN0 M0 tumors and one or more pathological risk factors mentioned above. The main end-point was 5-year biochemical progression free survival. RESULTS: After a median follow-up of 5-year biochemical progression free survival was significantly improved in the irradiated group (74%, 98% CI: 68.7-79.3 vs 52.6%, 98% CI: 46.6-58.5; P<0.0001) Clinical progression free survival was also significantly improved (P<0.0009). The cumulative rate of loco-regional failure was also significantly improved (P<0.0009). Grade 2 or 3 late effects were significantly more frequent in the postoperative irradiation group (P=0.0005), but severe toxicity (grade 3 or higher) were rare with a 5-year rate of 2.6% in the wait-and-see group and 4.2% in the postoperative irradiation group (P=0.07). CONCLUSION: Immediate external irradiation after radical prostatectomy improves biochemical progression free survival and local control in patients with positive surgical margin or pT3 prostate cancer who are at high risk of progression. Further follow-up is needed to assess the impact on overall survival.

Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

Radical prostatectomy for locally advanced prostate cancer: results of a feasibility study (EORTC 30001).

The aim of this open, non-randomised, 2-stage feasibility study was to determine whether radical prostatectomy (RP) was safe and could provide cure for good prognosis patients with clinical T3 prostate cancer, in a multicentre setting. Cure was defined as a 3 months post-operative of undetectable serum PSA in combination with the presence of pathologically negative margins in the surgical specimen. Forty patients were enrolled of whom 38 were eligible. Six patients (5 pN+ and 1 pNx) did not meet the inclusion criteria and were excluded leaving 32 evaluable pN0 patients of whom 19 (59.4%, SE=4.26) achieved a complete response (CR) and in whom only two serious toxic events (STEs) were observed. The results of the first phase of the study passed the toxicity criteria (<3 STE's) but failed on the cure rate (>20 CRs). This resulted in discontinuation of the study after the first stage. The main reason for failure was the incidence of positive margins in the resected specimen. Although the study was stopped after the first phase, 28 of the 32 pN0 patients (87.5%) had undetectable serum PSA at 3 months. We continue to believe that RP with extensive resection can be beneficial as monotherapy for T3aN0M0 prostate cancer.

A study from the EORTC new drug development group: open label phase II study of sabarubicin (MEN-10755) in patients with progressive hormone refractory prostate cancer.

Sabarubicin (MEN-10755), a new synthetic anthracycline analogue, was evaluated for safety and efficacy in a multicentre phase II study in patients with advanced hormone refractory prostate cancer (HRPC). Thirty seven patients were included, of which 34 were evaluable for PSA response according to Bubley's criteria. Sabarubicin was administered as a short (30 min) intravenous infusion at a dose of 80 mg/m(2) every 3 weeks. The main toxicity consisted of grade 3/4 neutropenia in 24 patients (64.9%), with grade 3/4 febrile neutropenia occurring in one patient only. Grade 3/4 cardiotoxicity was observed in 4 patients including one ineligible. Other toxicities were mild. Nine patients achieved a PSA response (26.5%), 10 patients had stable disease (29.4%) and 14 patients disease progression (41.2%). One patient (2.9%) had a PSA response that was not confirmed by repeat PSA testing. The objective response rate according to RECIST criteria was 6.7% in 15 patients with measurable disease. The median duration of PSA responses was relatively long 7.1 months (95% CI 4.9-20.7) as was the median time to treatment progression in patients with stable disease. The median overall survival was 18.7 months (95% CI 9.1-N), comparable to results recently observed in taxotere-containing regimens. To confirm and extend these results, further testing of sabarubicin in larger trials is warranted.

Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.

EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% . The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.