Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for MGMT promoter methylation status.

PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status.

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform.

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.

A concurrent ultra-fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma.

We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m(2) for 7 days a week. After a 4-week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra-fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.

Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study.

BACKGROUND: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome. METHODS: Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated. RESULTS: At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05). CONCLUSION: Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.

Appropriate end-points for right results in the age of antiangiogenic agents: future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6 months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.

Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost-utility analysis.

BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of €11,822/QALY for TAX 323 and €6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of €50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).

BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance. PATIENTS AND METHODS: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS). RESULTS: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times. CONCLUSION: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.

PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923).

BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.

Vinorelbine and cisplatin in metastatic squamous cell carcinoma of the oesophagus: response, toxicity, quality of life and survival.

BACKGROUND: Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population. PATIENTS AND METHODS: Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30. RESULTS: All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23-46); the median duration of response was 6.8 months, progression-free survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement. CONCLUSIONS: Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin-5-fluorouracil.

Estimating survival gain for economic evaluations with survival time as principal endpoint: a cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer.

The problem of estimating expected outcomes for the economic evaluation of treatments for which the outcome of principal interest is (quality adjusted) survival time has so far not received sufficient attention in the literature. The best estimate of expected survival is mean survival time, but with censored survival data, the true survival time for all the subjects is not known, so the mean is not defined.A possible solution to this estimation problem is illustrated by a retrospective cost-effectiveness analysis of the addition of hormonal therapy to standard radiotherapy for patients with locally advanced prostate cancer. A recently proposed method is used to approach the problem caused by censored cost data, and the impact of uncertainty is assessed by bootstrap resampling techniques. Mean survival time is estimated by a restricted means analysis with the time point of restriction determined by statistical criteria. When average total costs and mean survival time is evaluated at this time point of restriction, the result is that the combined therapy (radiotherapy plus hormonal therapy) increases mean survival time by about 1 year, while reducing the costs per patient for the French health insurance system by 12 700 FF. The time point of restriction may also be determined by other criteria and mean survival time may be estimated by extrapolating the survival curves by means of various parametric survival distributions. We show that the exact results of the economic evaluation are decisively determined by the restriction time point chosen and the approach taken to estimate mean survival time.

Statistical methodology of phase III cancer clinical trials: advances and future perspectives.

The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.

Cost-effectiveness of the addition of early hormonal therapy in locally advanced prostate cancer: results decisively determined by the cut-off time-point chosen for the analysis.

We present a retrospective cost-effectiveness analysis using data from a randomised controlled trial (EORTC 22863) of the addition of early hormonal therapy with a luteinising hormone-releasing hormone (LHRH) analogue to radiotherapy in the treatment of patients with locally advanced prostate cancer. Data on the use of medical resources were extracted from the hospital charts of 90 patients recruited into the trial by one French hospital. Costs are assessed from the viewpoint of the French healthcare financing system and adjusted for censoring. Expected costs per patient of each treatment is related to the expected outcome, mean survival time, estimated by a restricted means analysis. The time point of restriction is determined by statistical criteria. In the base case analysis with a cut-off time point at 8.58 years, the combined therapy group (COMB) had a gain in mean survival time of 1.06 years (7.05 versus 5.99 years) and a reduction of average total costs of 12700 French francs (FF) (58300 FF versus 71000 FF). The analysis of uncertainty uses bootstrap techniques with 5000 replicates to examine the joint distribution of cost and survival outcomes. In 76% of the cases, COMB results in longer mean survival time and lower costs than the radiotherapy group (RT). In cases where COMB therapy raises costs (13% of the cases), it is rarely by more than 20000 FF per patient, no matter the size of the associated survival gain. It is thus highly likely that COMB should be considered a cost-effective option compared with RT for these patients. The exact result of the economic evaluation is decisively determined by the restriction time point selected for the determination of mean survival time, partly also because the average total costs of the two treatments develop entirely differently as a function of the survival time.