Julie Francart

Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine

Chromosomal translocations represent an important prognostic indicator in B-cell chronic lymphocytic leukemia (B-CLL). However, their value had been neither determined in homogeneously treated patients nor compared to that of IgVH mutational status. Sixty-five B-CLL patients were investigated using cytogenetics, interphase fluorescence in situ hybridization (FISH), analysis of IgVH and of TP53 mutational status before treatment with 2-chloro-2′-deoxyadenosine (CdA). Translocations (n=45) were detected in 42% of the patients, including both balanced (n=12) and unbalanced (n=33) types. IgVH was mutated in 43% of the patients. Patients with translocations were more heavily pretreated (P=0.05), presented with more complex karyotypes (P<0.001), 17p abnormalities and TP53 mutations, and had a higher failure rate (59 vs 21% in patients without translocations, P=0.004). Patients with unbalanced translocations displayed a shorter median treatment-free survival (TFS, 6.9 vs 35.9 months, log rank 22.72, P<0.001) and overall survival (OS, 13.0 vs 68.0 months, log rank 16.51, P<0.001), as compared to patients without translocation. In multivariate analysis, unbalanced translocations were independently associated with therapeutic failure, short TFS and short OS. IgVH mutational status was independently associated with risk of failure and TFS, but not OS. In B-CLL patients treated with CdA, translocations are strong predictors of outcome.

Progression-free survival rate as primary end point for phase II cancer clinical trials: application to mesothelioma--The EORTC Lung Cancer Group.

PURPOSEnPhase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma.nnnMATERIALS AND METHODSnThe European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA.nnnRESULTSnThe PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA.nnnCONCLUSIONnThese values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.

A prognostic index for progression-free survival in malignant mesothelioma with application to the design of phase II trials: A combined analysis of 10 EORTC trials.

PURPOSEnFor cytostatic agents or when the response assessment is difficult, adaptations to phase II designs may allow a better assessment of therapeutic activity: first by using the progression-free survival rate (PFSR) as primary end-point instead of the response rate, and second by considering progression-free survival (PFS) risk groups based on a prognostic index (PI). In mesothelioma, current treatments yield disappointingly poor results and there is a need to investigate new regimens. The purpose of this report is to provide a PI for PFS in mesothelioma and reference values for the PFSR.nnnMATERIALS AND METHODSnData on 523 patients included in 10 European Organisation for Research and Treatment of Cancer (EORTC) mesothelioma studies were analysed to identify prognostic factors using a multivariate Cox regression model. Subsequently, a PI and a nomogram for PFS were developed. The PFSRs at 3, 4, 5 and 6 months were estimated.nnnRESULTSnA performance status>0, stage IV disease and mixed or sarcomatous histological type were indicators of a poor prognosis for PFS. From the PI, based on these three variables, four risk groups were defined. The median progression-free survival ranged from 5.3 to 2.1 months in these risk categories. The PFSRs at 3 months were 70.6%, 62.4%, 54.2% and 42.1% in the four categories, respectively.nnnCONCLUSIONnThe PI allows dividing patients into homogeneous risk categories in which PFSRs can be calculated and used to design future phase II mesothelioma trials. Defining homogeneous categories of patients avoids dilution of results between groups and improves the assessment of therapeutic activity.

Regional Variation in Thyroid Cancer Incidence in Belgium Is Associated With Variation in Thyroid Imaging and Thyroid Disease Management

CONTEXTnIncreased thyroid cancer incidence is at least partially attributed to increased detection and shows considerable regional variation.nnnOBJECTIVEnWe investigated whether regional variation in cancer incidence was associated with variations in thyroid disease management.nnnDESIGNnWe conducted a retrospective population-based cohort study that involved linking data from the Belgian Health Insurance database and the Belgian Cancer Registry to compare thyroid-related procedures between regions with high and low cancer incidence.nnnMAIN OUTCOME MEASURESnPrimary outcome measures were rates of TSH testing, imaging, fine-needle aspiration cytology (FNAC), and thyroid surgery. Secondary study outcomes were proportions of subjects with thyrotoxicosis and nodular disease treated with surgery, of subjects treated with surgery preceded by FNAC or with synchronous lymph node dissection, and of thyroid cancer diagnosis after surgery.nnnRESULTSnThe rate of TSH testing was similar, but the rate of imaging was lower in the low incidence region. The rate of FNAC was similar, whereas the rate of surgery was lower in the low incidence region (34 [95% CI 33; 35 ] vs 80 [95% CI 79; 81 ] per 100,000 person years in the high incidence region; P < .05). In the low incidence region compared to the high incidence region, surgery represented a less chosen therapy for euthyroid nodular disease patients (47% [95% CI 46; 48] vs 69% [95% CI 68; 70]; P < .05), proportionally more surgery was preceded by FNAC, more cancer was diagnosed after total thyroidectomy, and thyroid cancer patients had more preoperative FNAC and synchronous lymph node dissection.nnnCONCLUSIONnRegional variation in thyroid cancer incidence, most marked for low-risk disease, is associated with different usage of thyroid imaging and surgery, supporting variable detection as a key determinant in geographic variation.

Growth in Extremely Low Birth Weight Infants up to Three Years

Objective: To evaluate postnatal growth of extremely low birth weight infants (ELBW, <1,000 g) until 36 months of corrected age (CA), and to relate growth outcome to anthropometric parameters at birth, sex, fetal growth status (small or appropriate for gestational age – SGA/AGA), period of admission and major perinatal events. Study Design/Method: Weight (Wt), height (Ht) and head circumference (HC) were assessed in 159 ELBW infants. Data were standardized with Z-scores following Usher and McLean and Sempe growth curves. Uni- and multivariate statistical analysis were performed. Results: The mean birth weight was 851.2 ± 116.5 g. Z-scores decreased from birth to term, at a deeper rate for AGA than for SGA infants (p < 0.005 for Ht, Wt, and HC). Between term and 36 months, growth was better in SGA compared with AGA infants (p = 0.003 for Ht). Multivariate analysis showed that anthropometric parameters at birth were positive determinants for Wt, Ht and HC at term, and also for Wt and Ht at 36 months CA (Z-scores). Oxygen therapy after 36 weeks of post-conceptional age was a negative determinant influencing growth at 36 months CA (Z-scores). Conclusions: Significant catch-up growth took place between birth and 36 months, which was greater for SGA than for AGA infants. Anthropometric parameters at birth and oxygen therapy at 36 weeks post-conceptional age are the main predictive factors for growth at 36 months CA.

High incidence of complications after 2-chloro-2’-deoxyadenosine combined with cyclophosphamide in patients with advanced lymphoproliferative malignancies

The combination of purine analogs with alkylating agents is able to produce a synergistic antitumoral effect. However, the addition of immunosuppressive and DNA-targeting agents might increase purine analog-related complications. The risk for serious complications was evaluated in 38 patients treated with 2-chloro-2’-deoxyadenosine (CDA) and cyclophosphamide (CP). The diagnoses were chronic lymphocytic leukemia (CLL) in 15, Waldenström’s macroglobulinemia in 4, mantle cell lymphoma in 6, follicular non-Hodgkin’s lymphoma (NHL) in 10, and other low-grade NHL in 3 patients. All patients were pretreated (median: 2 lines, range: 1–5) and 23 (61%) were refractory. The patients received a median of two courses (range: 1–5) of 5.6xa0mg/m2 CDA, followed by a median of 200xa0mg/m2 CP, for 3xa0days. The response rate was 51% [complete remission (CR): 14%, partial remission (PR): 38%]. Grade 3/4 infections occurred in 16 (42%) patients. Dose-limiting cytopenias were seen in 22 (58%) patients. In 12 (32%) patients, autoimmune manifestations developed requiring treatment in most of them. Second cancers arose in five (13%) patients (myelodysplastic syndrome/acute myelocytic leukemia in three, lung cancer in two). Multivariate analysis showed that cytopenias, gender (F), prior radiotherapy, and age (>65xa0years) predicted for the complications seen after CDA-CP. To conclude, because of the high incidence of complications, caution is warranted in selecting patients with advanced lymphoid malignancies for the CDA-CP protocol.

Melanoma burden by melanoma stage : assessment through a disease transition model

BACKGROUNDnThe total burden of melanoma has already been studied but little is known about the distribution of this burden amongst localised, node metastatic and distant metastatic stages.nnnMETHODSnDisability-adjusted life years (DALY) assesses disease burden, being the sum of years of life with disability (YLD) and years of life lost (YLL). A melanoma disease model was developed in order to predict the evolution of patients from diagnosis until death. The model was applied to a large cohort of 8016 melanoma patients recorded by the Belgian Cancer Registry for incidence years 2009-2011. DALYs were calculated for each American Joint Committee on Cancer stage, considering stage at diagnosis on the one hand and time spent in localised, node metastatic and visceral metastatic stages on the other. Probabilistic sensitivity analyses and scenario analyses were performed to explore uncertainty.nnnFINDINGSnOur analyses resulted in 3.67 DALYs per melanoma, 90.81 per 100,000 inhabitants, or 32.67 per death due to melanoma. The total YLL accounted for 80.4% of the total DALY. Stages I, II, III and IV patients at diagnosis generated, respectively, 27.8%, 32.7%, 26.2% and 13.3% of the total YLL. For the time spent in each stage, localised melanomas, node metastatic melanomas, and distant metastatic accounted, respectively, for 34.8%, 52.6% and 12.6% of the total YLD. Parametric uncertainty was very limited, but the influence of using pre-2010 Global Burden of Disease approaches was substantial.nnnINTERPRETATIONnThe total DALY for melanoma was consistent with the previous studies. Our results in terms of proportions of DALY/YLL/YLD per stage could be extrapolated to other high-income countries. YLDs generated by localised melanoma which will never metastasize were inferior to YLLs resulting from stage IA melanomas. This result supports the hypothesis that efforts for an earlier diagnosis of melanoma are important.nnnFUNDINGnNone.