J.-P. De Greve

Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu

Human epidermal growth factor receptor (HER)2/neu kinase domain mutations are found in approximately 1-4% of lung adenocarcinomas with a similar phenotype to tumors with epidermal growth factor receptor (EGFR) mutations. Afatinib is a potent irreversible ErbB family blocker. We determined the tumor genomic status of the EGFR and HER2 genes in non- or light smokers with lung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib. Five patients with a non-smoking history and metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified, three of which were evaluable for response. Objective response was observed in all three patients, even after failure of other EGFR- and/or HER2-targeted treatments; the case histories of these patients are described in this report. These findings suggest that afatinib is a potential novel treatment option for this subgroup of patients, even when other EGFR and HER2 targeting treatments have failed.

Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma

BACKGROUND To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with recurrent high-grade glioma (HGG) after failure of surgery, radiation therapy, and chemotherapy. PATIENTS AND METHODS In this two-arm, open-label, phase II study patients were stratified according to their epidermal growth factor receptor (EGFR) gene amplification status. Cetuximab was administered intravenously at a dose of 400 mg/m(2) on week 1 followed by weekly dose of 250 mg/m(2). The primary end point for this study was the response rate in both study arms separately. RESULTS Fifty-five eligible patients (28 with and 27 without EGFR amplification) tolerated cetuximab well. Three patients (5.5%) had a partial response and 16 patients (29.6%) had stable disease. The median time to progression was 1.9 months [95% confidence interval (CI) 1.6-2.2 months]. Whereas the progression-free survival (PFS) was <6 months in the majority (n = 50/55) of patients, five patients (9.2%) had a PFS on cetuximab of >9 months. Median overall survival was 5.0 months (95% CI 4.2-5.9 months). No significant correlation was found between response, survival and EGFR amplification. CONCLUSIONS Cetuximab was well tolerated but had limited activity in this patient population with progressive HGG. A minority of patients may derive a more durable benefit but were not prospectively identified by EGFR gene copy number.

Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial.

PURPOSE The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

The delay-time distribution of Type Ia supernovae: a comparison between theory and observation

Aims. We investigate the contribution of different formation scenarios for type Ia supernovae in elliptical galaxies. The single-degenerate scenario (a white dwarf accreting from a late main-sequence or red giant companion) is tested against the double-degenerate scenario (the spiral-in and merging of two white dwarfs through the emission of gravitational wave radiation). Methods. We use a population-number synthesis code that incorporates the latest physical results in binary evolution and allows us to differentiate between certain physical scenarios (e.g. description of common-envelope evolution) and evolutionary parameters (e.g. mass-transfer efficiency during Roche-lobe overflow). The obtained theoretical distributions of the delay times of type Ia supernovae are compared, both in morphological shape and in absolute number of events, to those which are observed. The critical dependency of these distributions on certain parameters is used to constrain the values of the latter. Results. We find that the single-degenerate scenario alone cannot explain the morphological shape of the observational delay-time distribution, while the double-degenerate scenario (or a combination of both) can. Most of these double-degenerate type Ia supernovae are created through a normal quasi-conservative Roche-lobe overflow followed by a common-envelope phase, not through two successive common-envelope phases. This may cast doubt on the use in other studies of analytical formalisms to determine delay times. In terms of absolute number, theoretical supernova Ia rates in old elliptical galaxies lie a factor of at least three below the observed ones. We propose a solution involving the effect of rotation on the evolution of intermediate mass binaries.

MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

AIMS To investigate the correlation between O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma. PATIENTS AND METHODS A real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence. RESULTS A subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p=0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p<0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma. CONCLUSIONS MGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.

Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC)

BACKGROUND 18FDG-PET and multislice computerized axial tomography (CT) scan are used for diagnosis, staging and response evaluation in NSCLC patients. The correlation between the response assessment by both imaging techniques and survival was assessed in patients with unresectable stage III NSCLC treated with induction chemotherapy followed by consolidation radiotherapy. METHODS Thirty-one patients, enrolled in a phase II study evaluating the efficacy and toxicity of a novel triplet induction chemotherapy (paclitaxel, carboplatin and gemcitabine) (PACCAGE) before consolidation radiotherapy, were evaluated by CT and 18FDG-PET at baseline and after three cycles of chemotherapy. The correlation between CT and 18FDG-PET response and time to progression and overall survival was analyzed using the Kaplan-Meier estimates of survival and the log rank test. RESULTS Ten patients with a complete response (CR) on 18FDG-PET had a significantly longer time to progression and overall survival than patients with a non-CR (median 19.9 months versus 9.8 months, p=0.026, and median >49 months versus 14.4 months, p=0.004, respectively). Twenty patients with a partial CT response (PR) had a significantly longer time to progression (median 15 months versus 9.4 months, p=0.001) than patients with a non-PR but the difference in overall survival only showed a trend (23.3 months versus 14.4 months, p=0.093). CONCLUSIONS A CR on 18FDG-PET following induction chemotherapy for locally advanced, unresectable NSCLC seems to be a more powerful prognostic marker for survival compared to PR on CT.

The impact of proband mediated information dissemination in families with a BRCA1/2 gene mutation

Since the identification of the BRCA1 (17q21)1 and BRCA2 (13q12–13)2,3 genes as the major predisposition genes for hereditary breast and ovarian cancer (HBOC),4 genetic counselling and predictive testing has progressively been introduced and applied throughout the world. In many centres, the initial approach towards these families has been very cautious, mainly because of lack of prospective data on the effects of preventive measures to be proposed for mutation carriers and the uncertainty of the psychological impact of this information within these families. In the Familial Cancer Clinic of the Vrije Universiteit Brussel (VUB), Belgium, a multidisciplinary team adopted a protocol of ‘non-directive’ counselling based on the international guidelines used for Huntington families.5 Non-directiveness is a form of counselling that includes the presentation of several options without recommending a specific choice, but in the context of this study, non-directiveness is rather focused on the way the counselling team behaves towards other family members. According to this aspect of the protocol, the proband is the major and initially unique interlocutor between the family and the familial cancer team as represented by the counsellor. The proband helps in establishing the family pedigree and is informed about the various aspects of HBOC and predictive genetic testing. After a mutation is found, the relevant information and availability of predictive testing is communicated to the remainder of the family, initially through the proband and subsequently through other family members who come forward for testing. In contrast to persons affected by Huntington’s disease, several options are available to mutation carriers, which can alter their outcome. Recently, prospective data on the effectiveness of some preventive options have emerged, including the short term protection provided by preventive mastectomy compared with preventive screening.6 The availability of effective screening and prophylactic treatment makes “the right …

Tolerance of adjuvant letrozole outside of clinical trials

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study.

PURPOSE Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks. PATIENTS AND METHODS Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria. RESULTS The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis. CONCLUSION Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.

Spin up and hot spots can drive mass out of a binary

Context. The observed distribution of orbital periods of Algols with a B-type primary at birth agrees fairly well with the prediction from conservative theory. Conservative evolution fails, however, to produce the rather large fraction of Algols observed with a high mass-ratio, especially: q ∈ [0.4–0.6]. Aims. In order to keep Algols for a longer time with a higher mass-ratio without disturbing the distribution of orbital periods too much, interacting binaries have to lose a significant fraction of their total mass without losing much angular momentum before or during Algolism. We propose a mechanism that meets both requirements. Methods. In the case of direct impact the gainer spins up: sometimes up to critical velocity. Equatorial material on the gainer is therefore less bound. A similar statement applies to material located at the edge of an accretion disc. The incoming material moreover creates a hot spot in the area of impact. The sum of the rotational and radiative energy of hot spot material depends on the masstransfer-rate. The sum of both energies overcomes the binding energy at a well defined critical value of the mass-transfer-rate. As long as the transfer-rate is smaller than this critical value RLOF happens conservatively. But as soon as the critical rate is exceeded the gainer will acquire no more than the critical value and RLOF runs into a liberal era. Results. Low-mass binaries never achieve mass-transfer-rates larger than the critical value. Intermediate-mass binaries evolve mainly conservatively but mass will be blown away from the system during the short era of rapid mass-transfer soon after the onset of RLOF. ×