Relative Risk Of Relapse Research Articles

TAXTOX – a retrospective study regarding the side effects of docetaxel given as part of the adjuvant treatment to patients with primary breast cancer in Denmark from 2007 to 2009

Background. In 2007 docetaxel was introduced as part of the adjuvant setting offered to high risk breast cancer patients in Denmark. Meta-analyses had shown that taxane-containing chemotherapy reduced the relative risk of relapse and death by 20–30%, apparently with moderate side effects. The treatment was given as three cycles of cyclophosphamide (600 mg/m2) and epirubicin (90 mg/m2) followed by three cycles of docetaxel (100 mg/m2). Because of an apparent high incidence of side effects, especially febrile neutropenia (FN) and non-hematologic side effects, the DBCG (The Danish Breast Cancer Cooperative Group) initiated a retrospective study of adverse reactions to the newly introduced regime and all patients were offered primary prophylaxis with growth factors (G-CSF) pr 1/1-2008. Material and methods. Two medical doctors examined available journals and nurse charts from the 13 oncology departments in Denmark, and graded all side effects according to NCI CTC version 2.0. To be enrolled, the patients should have received three cycles of EC and at least one cycle of docetaxel. The side effects were investigated before and after routine use of G-CSF. Results. One thousand one hundred and forty-three patients entered the study. In 2007 (before G-CSF) the incidence of FN was 25% and 90.6% of the patients completed the planned treatment. In 2008 (after the introduction of G-CSF) the incidence of FN was 10% and 94.5% completed the treatment. The incidence of non-hematological adverse events, in 2007 and 2008 combined, was for neuropathy 35%, mucositis 75%, muscle and joint pain 53%, skin rash 25% and fatigue 43% (all grades). Conclusion. The introduction of G-CSF was justified because of the high incidence of FN. However, it could not have been predicted after reviewing the published literature. The incidence of non-hematological adverse events had been reported in some, but not all adjuvant taxanes studies. In the future, focus should be more on the side effects, especially when introducing new toxic systemic regimes.

Endometrial cancer: prognostic significance of risk classification based on pre-intraoperative findings

The aim of this study was to determine whether a pre-intraoperative prognostic classification of endometrial cancer (EC) patients may accurately predict prognosis. Prognostic factors achievable before and during surgery (histotype, grade, myoinvasion, cervical spread, abdominal spread) were utilized to classify patients in low-risk (endometrial adenocarcinoma, grade 1-2, myoinvasion <50%, no evidence of abdominal spread), and in intermediate/high risk (serous papillary and clear cell, grade 3, myoinvasion >50%, cervical invasion, abdominal spread). Risk classification obtained pre-intraoperatively was compared with the classification obtained from definitive surgical-pathological assessment in 130 consecutive patients with EC treated with surgery. Pre-intraoperative risk assessment correctly identified risk classification in 125 (96%) patients; sensitivity, specificity, PPV and NPV were 98%, 94%, 94%, and 98%, respectively. Median follow-up was 38 months (range 6-93), and 14 (10%) patients relapsed (median time 14 months, range 3-60). Relative risk of relapse was higher in intermediate/high-risk patients with both classifications (pre-intraoperative RR 3.37, CI 0.99-11.5; surgical-pathological RR 4.56, CI 1.2-17.3). As regards survival 11 patients have died, 6 due to endometrial cancer and 5 due to intercurrent disease. Five-years DFS according to pre-intraoperative assessment was 89% and 71% for low-risk and intermediate high-risk patients (p = 0.028), respectively; according to definitive assessment was 91% and 70% for low-risk and intermediate/high-risk patients (p = 0.009), respectively. This classification, giving an accurate risk and prognostic estimate with parameters routinely utilized in clinical practice, may help the surgeon when undertaking the decision to perform limited or extended surgical staging according to tumor and patient characteristics.

Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: a meta-analysis of randomized controlled trials

The purpose of this meta-analysis was to examine the efficacy of maintenance treatments for bipolar disorder. Placebo-controlled or active comparator bipolar maintenance clinical trials of ≥6 months' duration with at least 15 patients/treatment group were identified using Medline, EMBASE, clinicaltrials.gov, and Cochrane databases (1993 to July 2010). The main outcome measure was relative risk for relapse for patients in remission. Twenty trials (5,364 patients) were identified. Overall, lithium and quetiapine were the most studied agents (eight and five trials, respectively). The majority of studies included patients who had previously responded to treatment for an acute episode. All interventions, with the exception of perphenazine+mood stabilizer, showed a relative risk for manic/mixed or depressive relapse below 1.0, although there was variation in the statistical significance of the findings vs. placebo. No monotherapy was associated with a significantly reduced risk for both manic/mixed and depressed relapse. Of the combination treatments, only quetiapine+lithium/divalproex, was associated with a significantly reduced risk vs. comparator (placebo+lithium/valproate) for relapse at both the manic/mixed and depressed poles of bipolar illness. Limitations for the analysis include differences in study durations and definitions of relapse. In conclusion, available maintenance therapies show considerable variation in efficacy. The efficacy of lithium and divalproex has been confirmed, but newer therapies, such as a number of atypical antipsychotics were also shown to be effective in bipolar disorder. Efficacy of all maintenance interventions needs to be balanced against the safety and tolerability profiles of individual agents.

Antibiotic Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73-0.99, P=0.03). There was moderate heterogeneity between results (I(2)=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66-0.98) with no heterogeneity (I(2)=0%) and an number needed to treat 5 (95% CI=3-20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46-0.84), with no heterogeneity (I(2)=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43-0.96). There was moderate heterogeneity (I(2)=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.

Relapse risk in patients with multiple sclerosis after H1N1 vaccination, with or without seasonal influenza vaccination

The safety of vaccination in multiple sclerosis (MS) raises concern, particularly the relapse risk post-vaccination. With the recent H1N1 pandemic, people with chronic diseases, including neurological conditions such as MS, were prioritised for vaccination. Two questions therefore arise in this context: whether vaccination increases the relapse rate, and whether the relapse is more severe postvaccination. Seasonal influenza immunisation does not increase the risk of MS exacerbation; a systematic review found no increased risk of early (3–4 weeks post-vaccination) or late (4–6 months) exacerbations [1]. Likewise, influenza vaccination resulted in no relative increase in disease-activity to controls based on new Gd-enhancing lesions on MRI [2, 3]. The evidence is less clear-cut regarding the pandemic influenza H1N1 vaccine and relapse risk. Reports from the 1970s suggested an increased risk of Guillan-Barre and MS-like syndromes following this vaccine [4], although formal controlled trials did not. Two placebo controlled studies involving 88 and 127 MS patients, reported similar frequency of MS relapses in the H1N1 and placebo-vaccinated groups [5, 6] (12 vs. 14% and 3 vs. 6.5%, respectively). In our acute weekly relapse clinic, we recorded data from 30 consecutive patients between 11/2009 and 01/2010. During this period in the UK, all MS patients were actively offered H1N1 vaccination [7]. Relapse onset date, and H1N1/seasonal influenza vaccination status (with administration date where appropriate) were recorded. The expanded disability status scale (EDSS), multiple sclerosis impact scale (MSIS-29 v 2.0), and use of corticosteroid treatment were also documented. Eighteen (60%) of patients received either/both vaccination prior to relapse onset, leaving 40% not vaccinated (Table 1). Neither the relapse severity (EDSS/MSIS-29 v 2.0) nor the numbers receiving corticosteroid treatment were significantly different (Table 1). The association between relapse rate and vaccination in a relapse clinic can be evaluated using a case-crossover design; as in a previous report of different vaccinations in MS relapse clinics [8]. This method compares vaccine exposure in a specified risk period immediately preceding the relapse to that in several prior control periods of equal duration, thus quantifying the relative relapse risk in the specified post-vaccination period. Using a similar analysis in our 30 patients, 15 received H1N1 vaccination (Fig. 1a, flow chart); of whom 10

High Prognostic Impact of Flowcytometric Minimal Residual Disease Detection In Acute Myeloid Leukemia: Prospective Data From the HOVON/SAKK 42a Study

AbstractAbstract 760Currently, the most important prognostic factors for acute myeloid leukemia (AML) include molecular aberrancies and karyotype of the leukemic blasts. Although these factors have showed to be of utmost importance in upfront risk stratification in current treatment schedules, the treatment outcome of patients within as such defined risk groups is still quite heterogeneous. Therefore, there is an unmet need for therapy-dependent prognostic factors which can be implemented into risk-adapted treatment strategies. Minimal residual disease (MRD) frequency is such a parameter. MRD cells are considered responsible for the outgrowth of AML after treatment, leading to a relapse in 30–40% of the patients in complete remission (CR). In this study, we are the first to report prospective multicenter data on the prognostic impact of MRD frequency in adult AML. In our retrospective study (N.Feller et al. Leukemia 2004), we explored which cut-off points for percentage of MRD cells would define MRD positive (levels above cut-off, MRD+) patients with a relatively poor prognosis, from MRD negative (levels below cut-off, MRD-) patients who showed a longer overall and relapse-free survival (OS and RFS). In search for the most optimal cut-off level which can be used for clinical purpose in risk stratification-directed therapy, we used these cut-offs to evaluate the prognostic value in the current prospective setting. Diagnosis and follow-up samples were collected of 462 patients treated uniformly according to the HOVON/SAKK42a protocol (www.hovon.nl) and MRD frequency was assessed blindly without knowledge of clinical course. MRD detection was accomplished by immunophenotyping by flow cytometry (FCM) through aberrant expression of markers on AML blasts. Together with the expression of normal immature cell markers and/or myeloid lineage markers, this offers a leukemia associated phenotype (LAP). Each LAP was individually designed for each patient in diagnosis bone marrow (BM) or peripheral blood. Subsequently, BM samples obtained during follow-up were analysed for the presence of LAP-positive cells. MRD frequency was expressed as a percentage of leukocytes. The median MRD frequencies of patients in clinical CR after first induction cycle (n=164), second induction cycle (n=182) and consolidation (n=121) were 0.040%, 0.022% and 0.020%, respectively. The cut-off levels for MRD frequency as defined retrospectively were all significant in the identification of patients with adverse (MRD+) and favourable (MRD-) OS and RFS, respectively. After the first cycle, the most significant cut-off was 0.8%, leading to 17 MRD+ patients who showed a median RFS of only 8.6 months, while 147 MRD- patients had a median RFS of >47 months (p=0.003,A). The relative risk of relapse (RR) was 2.9 (95% c.i. 1.4–6.0, p=0.004). After the second induction cycle, a cut-off level of 0.06% was most significant. Above this cut-off, 49 patients showed a median RFS of 7 months, while 133 MRD- patients showed a RFS of more than 47 months (p<0.00001, fig B). The RR was 3.2 (95% c.i. 2.0–5.0, p<0.00001). After consolidation therapy, 11 MRD+ patients with extremely poor prognosis were identified (median RFS 7.3 months vs. >47 months for 110 MRD- patients, p<0.00001, fig C), with a RR of 10.6 (95% c.i. 4.9–22.8, p<0.00001). Multivariate analysis was performed with conventional prognostic factors for AML: cytogenetic risk groups and time to achieve CR. After every cycle of therapy, MRD frequency was an independent prognostic factor for RFS after all cycles (1st cycle: p=0.010, 2nd cycle and consolidation p<0.00001) and for OS after 1st (p=0.023) and 2nd induction cycle (p=0.010). In this prospective multicenter study, already after first induction cycle, MRD detection by FCM was an independent significant factor in the identification of poor prognostic patients. In future treatment studies, risk stratification, e.g. for allogeneic stem cell transplantation, should not only be based on risk estimation determined at diagnosis, but also on MRD frequency as a therapy-dependent prognostic factor. This work was supported by Netherlands Cancer Foundation KWF. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Accurate Detection of Residual Leukemic Stem Cells In Remission Bone Marrow Predicts Relapse In Acute Myeloid Leukemia Patients

AbstractAbstract 759Detecting leukemia initiating cells or leukemic stem cells (LSCs) in acute myeloid leukemia (AML) is a challenge. AML is a heterogeneous disease and since the first studies on LSCs, different immunophenotypic cell compartments have been reported to contain LSCs. For CD34 positive (CD34+) patients, the most important LSC compartment is most likely CD34+CD38-. However, both LSCs and normal hematopoietic stem cells (HSCs) reside in this compartment. Therefore, LSC detection requires the ability to accurately discriminate between LSCs and HSCs. Previous research showed that LSCs, in contrast to HSCs, expressed aberrant markers (AM, including lymphoid lineage markers and the LSC marker CLL-1). Although AM- cells are often presumed to be normal HSCs, AM expression can be absent or very weak on LSCs and AM- cells can therefore be malignant too. We previously described that in 30% of the patients, besides the AM expression, additional FACS parameter (forward scatter (FSC) and sideward scatter (SSC) and/or CD34 expression levels) could also be used to detect LSCs (Terwijn et al., ASH 2009 abstract 399). To prove that the CD34+CD38- fraction contains both normal and malignant SCs, and in addition, to prove that AM- cells can be malignant too, we studied molecular aberrancies (3 cases of FLT3-ITD positive AML) in the relevant cell fractions. 1: CD34+CD38-AM+ cells proved to be FLT3-ITD positive in all three cases. In addition, these cells initiated leukemic engraftment in NOD-SCID IL-2Rγ -/- mice in 2/2 cases. 2: The CD34+CD38-AM- cells with a FSC/SSC low or CD34 high character were FLT3-ITD negative in 3/3 cases and initiated multilineage engraftment in mice in 2/2 cases, indicating that these are HSCs. 3: The CD34+CD38-AM- cells with a FSC/SSC high or CD34 low phenotype were FLT3-ITD positive in 2/2 cases and therefore malignant, indicating that AM expression alone is not always sufficient in discriminating HSCs from LSCs. Since therapy surviving LSCs are thought to be responsible for relapses, we hypothesized that LSC frequency, as a fraction of total WBC, detected in remission bone marrow (BM) would provide prognostic information. Using AM as a primary gating strategy and, when applicable, FSC/SSC and/or CD34 expression, as a secondary gating step, LSC analysis was performed in 112 CD34+ AML patients (<60 years). In 76/112 patients, LSCs were detected using the most specific AM (CLL-1 (n=45), CD7 (n=19), CD11b (n=4), CD56 (n=3), CD22 (n=2), CD19 (n=2) and CD36 (n=1)) as a primary gating strategy. In 20 of these patients, a secondary gating step in FSC/SCC (n=16) and CD34 expression (n=4) refined the malignant population. In 36/112 patients, no AM was expressed on the CD34+CD38- cells, but in 25 cases, FSC/SSC could be used to gate the malignant fraction, in 6 cases combined with CD34 expression. Thus, in total, 101/112 patients were monitored for LSC frequency. After first cycle of chemotherapy, using a cut-off 5 × 10−6, patients with LSC frequency above cut-off (LSC+) showed shorter overall survival (OS, p=0.06) and especially relapse-free survival (RFS, p=0.001) as compared to LSC- patients. Median RFS was 11 months vs >36 months, respectively (fig A). Also after second induction cycle, high LSC frequency (>5 × 10−6) predicted shorter OS and RFS (both p<0.001). Median RFS of LSC+ patients was 8 months, that of LSC- patients >36 months (fig B). After consolidation therapy, 2 × 10−6 was the most optimal cut-off to define LSC+ and LSC- patients. OS and RFS were significantly shorter in LSC+ patients (p=0.037 and p=0.001, respectively), with a median RFS of 13 months vs. > 36 months (figure C). The relative risk of relapse was 5.0 (95% C.I 1.8–14.0) after first induction cycle, 4.7 (95% C.I.2.2-10.1) after second cycle and 8.5 (95% C.I 1.8– 41.4) after consolidation therapy. Multivariate analysis including WBC count, cytogenetic risk profile and the number of cycles needed to reach CR showed that LSC frequency is an independent factor for RFS (1st cycle p=0.01, 2nd cycle p<0.001, consolidation p=0.038). With this gating strategy, 90% of CD34+ AML patients could be monitored for residual LSCs, resulting in accurate prognostic information which is valuable for risk stratification-based treatment. In addition, the prospective isolation of LSCs and HSCs from diagnosis AML BM might identify more selective therapies that eradicate LSCs, while leaving HSCs intact.This work was supported by Netherlands Cancer Foundation KWF. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

AbstractKiller-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

New data on MAGE-A3 cancer immunotherapy may signal new options for patients with melanoma and non-small cell lung cancer

The MAGE-A3 gene, encodes a tumor-specific antigen expressed on tumor cells only and not on normal tissues. When combined with an immunological adjuvant designed to enhance the immune response to the MAGE-A3 antigen, immunization with the MAGE-A3 cancer immunotherapeutic was shown to induce specific T-cell responses and long-lasting clinical objective responses in metastatic melanoma. Data today highlights the encouraging potential of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI). In a Phase II study designed to evaluate the MAGE-A3 ASCI in patients with metastatic melanoma, objective long-term responses were recorded. These melanoma study results represent a second positive signal of clinical activity for the novel cancer immunotherapeutic, following encouraging clinical activity reported in a separate double-blind, placebo-controlled Phase II study of patients with Non-Small Cell Lung Cancer (NSCLC). In addition, we present compelling data regarding the use of the genetic profiling of melanoma in predicting clinical outcomes of treatment with MAGE-A3 ASCI. An independent characterization of biomarkers predictive to clinical response to the MAGE-A3 in the Phase II study in NSCLC provided similar observation resulting in 53% reduction in the relative risk of relapse. Phase II results led to phase 3 trials in both metastatic melanoma (DERMA trial) and stage IV NSCLC (MAGRIT trial) to show the efficacy of de MAGE-A3 ASCI. To date, more than 2,000 patients have been screened to enter in DERMA trial, with 67% MAGE-A3 expressing melanomas leading to 700 inclusions in that trial. Le gène MAGE-A3 code pour un antigène spécifique de la tumeur, exprimé sur les cellules tumorales uniquement et pas sur les cellules normales. L’immunothérapie anticancéreuse spécifique de MAGE-A3 contient l’antigène MAGE-A3 et un immunostimulant destiné à renforcer la réponse immunitaire envers l’antigène. Cette combinaison s’est montrée capable d’induire des réponses immunitaires et cliniques de longue durée chez des patients atteints de mélanome métastatique. Un second signal positif pour ce traitement potentiel a été obtenu avec ce même candidat MAGE-A3 dans une étude de Phase II indépendante réalisée chez des patients atteints de cancer du poumon non à petites cellules (CBNPC). En outre, nous présentons ici l’identification de biomarqueurs capables de prédire, avant traitement, le bénéfice des patients au traitement par MAGE-A3 ASCI. Ces biomarqueurs ont été identifiés dans l’étude de Phase II dans le mélanome, et leur valeur prédictive du bénéfice au traitement a également été montrée dans l’étude de phase II dans le cancer du poumon ; les patients traités par MAGE-A3 ASCI et dont la tumeur présente ces biomarqueurs dérivent un bénéfice plus important du traitement par MAGE-A3 ASCI, de l’ordre de 53 % de réduction relative du risque de rechute. Les résultats de ces études de Phase II ont mené à l’initiation de 2 études de Phase III visant à démontrer l’efficacité de MAGE-A3 ASCI dans le mélanome et le cancer du poumon : l’étude MAGRIT dans le cancer du poumon non à petites cellules, et l’étude DERMA. À ce jour, plus de 2 000 patients ont été screenés pour participer à l’étude DERMA : la tumeur de ∼ 67 % d’entre eux exprimait MAGE-A3 et plus de 700 patients sont entrés dans l’étude.

No clear evidence for an association between GH replacement and relapse of intracranial germ cell tumours: single centre and KIMS experience

GH replacement (GHR) is well established, and has been widely accepted to be safe in patients with a wide spectrum of pituitary pathologies. However, GHR in patients with treated germ cell tumours (GCTs) remains controversial, and its use has been cautioned (1, 2). Anecdotal experience from our centre and elsewhere (1–3) suggests that vigilant monitoring is mandatory in treated GCTs who are GH replaced. There are no published studies of long-term outcome and recurrence rates after GHR in treated GCTs. We have therefore surveyed our long-term experience with GHR in 18 adult patients with previously treated GCTs and a global experience of 142 patients from the KIMS database (Pfizer International Metabolic Database) in this diagnostic category in order to determine whether GHR plays a role in tumour relapse. This is a longitudinal observational study reporting a single centre experience and global experience using the KIMS database. The study groups comprised 18 consecutive patients with GCT treated at St Bartholomew’s Hospital, London (SBH) (median duration of follow-up from diagnosis of GCT 13 years (range 0.5–44)) and 142 patients with GCT enrolled in the KIMS database (median duration of follow-up 14.8 years (0.7–36.4)). The relapse rates pre-GHR and during GHR and relapse-free survival were evaluated. The characteristic and treatments of SBH and KIMS patients are shown in Table 1. In the SBH cohort, there were three relapses prior to GHR. All three patients had a histological diagnosis of non-germinomatous GCT (NGGCT), and had been treated with chemotherapy and/or surgery as primary treatment; radiotherapy was subsequently used after first relapse of disease; none of the patients received radiotherapy or craniospinal irradiation (CSI) as initial treatment. Four patients, two with germinomatous GCT (GGCT) and two with NGGCT, relapsed after GHR. Of the patients demonstrating a first relapse, only one had been treated previously with CSI. One patient relapsed prior to GHR, and was retreated successfully with external beam radiotherapy to the primary site of disease together with chemotherapy, but subsequently also relapsed after GHR. The estimated relapse rates were 240 and 323 per 10-000 patient-years, pre-GHR and during GHR respectively. The relative risk (RR) of relapsing after GHR was 1.34 (95% confidence interval (95% CI): 0.23–7.83; PZ0.73). Five instances of relapse were reported during KIMS follow-up. Of interest, two of these patients had never been treated with GHR (true nao ¨ve) before KIMS entry. The most relevant comparison of relapse rate during versus prior to GHR is for true nao ¨ve patients. This group had a RR of relapse during KIMS of 3.40 (95% CI: 0.26–101.4; PZ0.36). For the semi- and non-nao ¨ve patients (previously treated with GH within 6 months or !6 months before KIMS entry), the RR of relapse during KIMS was statistically similar to the true nao ¨ve group, or 2.62 (95% CI: 0.45–15.3; PZ0.27). RR for nao ¨ve versus semi- or non-nao ¨ve patients (including pre KIMS experience) was 1.36 (95% CI: 0.28–5.46; PZ0.65), indicating similar reported relapse rates between true nao ¨ve and those not true nao ¨ve. For all KIMS patients, the estimated relapse rates were 26.6 and 77.2 per 10-000 patient-years, pre-KIMS and during KIMS entry respectively. The RR of relapse during KIMS for all patients was 2.90 (95% CI: 0.73–12.13; PZ0.13). Our results do not support the hypothesis that GHR increases the recurrence of GCT. In view of the relative rarity of intracranial GCT, we elected to utilise longitudinal follow-up and calculation of relapse frequency expressed per patient years. Despite the variation in treatment modalities, there appeared to be similar relapse rate before and after exposure to GHR in the SBH cohort. Of particular interest, most relapses were NGGCT, which is well known to have a higher risk of relapse. Furthermore, the risk of relapse is also enhanced with the lack of use of radiotherapy as primary treatment. In general patients with NGGCT and those not treated with CSI appeared to have a worse relapsefree survival but no statistical significance was observed. The data from the KIMS do not provide evidence for an association between GHR and relapse. The KIMS relapse rate appears to be lower pre-KIMS than during KIMS, but the difference was not statistically significant. The disparity in recurrence frequency between the SBH and

Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study

Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer. In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS). At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported. IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.

Benefit of the Sequential Administration of Docetaxel after Standard FEC Regimen for Node-Positive Breast Cancer: Long-Term Follow-Up Results of the FNCLCC-PACS 01 Trial.

Abstract Objective: To evaluate the long-term impact on disease-free survival (DFS) and on overall survival (OS) of the sequential administration of docetaxel (D) following FEC100 among patients (pts) with node positive, operable breast cancer.Patients and Methods: Pts with localized, resectable, non pre-treated, unilateral breast cancer were randomly assigned to receive either Arm A: 6 cycles of FEC100 (5FU/epirubicin/cyclophosphamide 500/100/500 mg/m² day 1, every 3 weeks), or Arm B: 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) 100 mg/m² (day 1, every 3 weeks). First chemotherapy cycle was to be started no more than 42 days after surgery. Radiotherapy was mandatory after conservative surgery and hormone therapy was given for 5 years if tumors were positive for at least one hormone receptor. Main inclusion criteria were: age &amp;lt; 65 years, at least one positive node, no metastasis and normal cardiac, hematologic and renal functions. The main end-point of this prospective, non blinded, randomized, multicentre phase III trial was the 5-year DFS. These results have been already published (Roché et. al. J Clin Oncol. 2006 24(36):5664-71). Since this first analysis, survival data have been updated.Results: Between June 1997 and March 2000, 1999 pts were recruited. Main pts characteristics were well balanced between the 2 arms: median age 50 years, conservative surgery 57%, grade III 39%, both HR negative 21%, both HR positive 60%, 1-3 involved nodes 62%. Treatment was completed for 95% and 93.4% of pts in arms A and B, respectively.As of 15 April 2009, with a median long term follow-up of 92.8 months, 639 pts have experienced at least one event: 124 loco regional relapses, 421 metastasis, 68 contra lateral breast cancer, and 26 deaths as first event. A total number of 71 second cancers and 383 deaths have been registered.8-year DFS rates were 65.8% with FEC and 70.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse with FEC-D (HR = 0.846 [95%CI 0.724 – 0.988], p=0.03).8-year OS rates were 78% with FEC and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 25% reduction in the relative risk of death with FEC-D (HR = 0.754 [95%CI 0.616 – 0.922], p=0.006).Conclusion: Initial report of 5-year benefit in DFS and OS with sequential administration of FEC followed by D are fully confirmed at 8 years. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 603.

Prediction of Metastasis in Node-Negative, Hormone Receptor Positive, Tamoxifen Adjuvant Treated Primary Breast Cancer Patients Using Ki-67 (IHC) and RT-PCR Based 14-Gene Prognostic Signature.

Abstract Background: Risk estimation based on the recommendations of St. Gallen Consensus commonly decides for additional cytostatic therapy in node-negative (N-), hormone receptor positive (HR+) primary breast cancer patients. High proliferative activity in the HR+ subtype confers a 19-fold relative risk of relapse compared with HR+ tumors of low proliferative activity. Furthermore immunohistochemically determined Ki-67 is characterized as a Luminal B marker that identifies a high risk subgroup in HR+, N- breast cancer patients.Aim of this investigation was to compare risk estimation using Ki-67 (%) with the results of a RT-PCR based multi-gene prognostic signature. Methods: Tumor tissues of totally 321 unselected primary breast cancer patients were formalin fixed and routinely processed for immunohistochemical determination and scored for protein expression of ER, PgR and Ki-67. HER2 was determined using dd-PCR. Content of both hormone receptors and proliferation activity were evaluated counting positively coloured nuclei from at least 100 tumor cells. The median follow up was 61 months. To calculate the cut off for high proliferation Ki-67 values were subjected to a log rank CART analysis. High proliferation was defined by Ki-67 of 19% and more. With this cut off it was possible to distinguish significantly various patient cohorts (N-, pT1, postmenopausal) into two different risk groups regarding metastasis free survival. The definition of low risk was low proliferation and HER2 negativity, of high risk high proliferation or HER2 positivity. The risk for metastasis of 16 new primary breast cancer patients was estimated based on two surrogate risk groups and the multi-gene prognostic signature. Results: Tamoxifen adjuvant treated HR+, HER2-, low proliferating (Ki-67 &amp;lt;19%), N- low risk patients (N= 68) and HR+, HER2-, high proliferating/HR+, HER2+, N- high risk patients (N= 84) showed a recurrence rate of 2.94% and 27.4%, respectively (P&amp;lt; .000). In the ongoing observation study all 5 low proliferating HER2- tumors had a low risk gene prognostic signature. From 11 high proliferating HER2- patients one patient had a low risk gene signature (9%), 3 patients a moderate risk gene signature (27%) and 7 patients a high risk gene signature (64%). Conclusion: Despite the small number of patients investigated up to now (N= 16) the preliminary results appear to show that low proliferative activity is associated with a low risk gene prognostic signature, whereas high proliferation means only in part a high risk gene prognostic signature. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6025.

A randomized, double‐blind, placebo‐controlled study of maintenance treatment with adjunctive risperidone long‐acting therapy in patients with bipolar I disorder who relapse frequently

No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. This study included patients with bipolar disorder type I with > or = four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25-50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.

Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors

Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II-IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P = .17). The development of grades II-IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P = .03; RR 0.2. P = .01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.

Correlation of a family history of cancer with risk of relapse and death in pediatric cancer patients

10029 Background: The association between family history of cancer (FHC) and outcome remains uncertain. Relapse and survival of children with FHC has not been well studied. Such information would be valuable for prognosis, refining treatment protocols, and long-term follow-up in pediatric patients with FHC. Methods: An historical cohort study of all pediatric patients diagnosed with cancer at Lucile Packard Children's Hospital at Stanford from 1999 - 2002 was performed (n = 363, mean age: 8.4 yrs [0–28 yrs]). FHC among 1st, 2nd and 3rd degree relatives was obtained from the first 10 consecutive encounters in the electronic medical record. Relapse, secondary malignancy, and survival data were also acquired. The relative risks for these endpoints were calculated between patients with FHC among 1st and/or 2nd degree relatives and those with negative FHC. Patients without documented FHC were excluded (n = 100). Results: 108 (41%) newly diagnosed pediatric patients had reported FHC (1st Degree: n = 14 [5%], 2nd Degree: n = 58 [22%], 3rd Degree: n = 36 [14%]). Patients with reported FHC among 1st and/or 2nd degree relatives were at increased relative risk [RR] for relapse (1.96, 95% confidence interval [CI] 1.27–3.02) compared to patients with negative FHC (n = 191). In particular, patients with Hodgkin Disease (HD) and FHC (n = 12) were more likely to relapse (RR 1.79, 95% CI 1.19–2.72) and at increased risk of death (RR 1.72, 95% CI 1.18–2.53), compared to HD with negative FHC (n = 8). Similarly, patients diagnosed with ALL and FHC (n = 22) had increased risk of death (RR 2.25, 95% CI 1.06–4.8) compared to ALL patients with negative FHC (n = 56). For patients diagnosed with any pediatric cancer and positive FHC in 1st degree relative, RR of death was significantly elevated (3.74, 95% CI 1.20–11.70). Conclusions: Pediatric cancer patients with positive FHC among 1st and/or 2nd degree relatives appear to have higher relative risk of relapse compared to those with negative FHC. Additionally, an increased risk of death was associated with HD and ALL patients with positive FHC. Patients with 1st degree relative with malignancy had an increased risk for death compared to those without cancer among 1st degree relatives. These findings may reflect underlying genetic predispositions in children which contribute to outcome. No significant financial relationships to disclose.

Meta-análise de ensaios clínicos de intervenção familiar na condição esquizofrenia

The present study aimed to assess the efficacy of cognitive-behavioral family interventions by relatives of schizophrenic patients under community care, specifically targeting relapse and family burden as outcomes. Independent researchers conducted the analyses of the pertinence and quality of trials identified through a search strategy, following a previously developed protocol. Eleven randomized or quasi-randomized trials were selected. The summary relative risk of relapse using the fixed effects model was favorable to family intervention, with estimated efficacy reaching nearly 60% (50%-70%). Summary relative risk in the cognitive-behavioral therapy trials subgroup [RR = 0.43 (0.28-0.67)] was equivalent to that of the behavioral therapy subgroup [RR = 0.37 (0.23-0.60)] and the "pragmatic" subgroup [RR = 0.37 (0.21-0.66)], although the "pragmatic" trials were generally analyzed for effective treatment. The difference in summary overall risk of relapse was nearly 30% using the random effects model. Only four trials analyzed family burden as outcome, including different dimensions of burden. Results of individual trials were generally favorable to family intervention, for both the objective and subjective dimensions.

Treating children with acute lymphoblastic leukemia and Down syndrome: Pharmacokinetics provides insight into vincristine therapy

Treating children with acute lymphoblastic leukemia and Down syndrome: Pharmacokinetics provides insight into vincristine therapy

Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia

Vincristine is a key drug in the treatment of childhood and adult acute lymphoblastic leukemia (ALL), and many other childhood malignancies. Despite decades of wide clinical use, no data on the correlation between vincristine pharmacokinetics and long-term clinical outcome have been published. We here report clinical data (median follow-up time 10.5 years, range 7.3-12 years) for 86 children with B-cell precursor ALL, in whom vincristine kinetics were studied on treatment day 1. The median total plasma clearance was 429 and 331 ml/min per m(2) and the area under the plasma concentration-time curve (AUC) was 4.49 and 5.40 mg/l x min in relapse and non-relapse patients, respectively (not significant). In standard risk patients, where treatment depends more heavily on vincristine than in other subgroups, the relative risk (RR) of relapse was significantly increased for patients with clearance values above median (RR 5.2; P = 0.036), or AUC values below median (RR 5.8; P = 0.025). Our data suggest a relationship between the antileukemic effect and the systemic exposure of the drug, which warrants further studies.

Methylated NEUROD1 Promoter is a Marker for Chemosensitivity in Breast Cancer

Chemotherapy can be an integral component of the adjuvant management strategy for women with early stage breast cancer. To date, no tool is available to predict or monitor the efficacy of these therapies. The aim of this proof-of-principle study was to assess whether NEUROD1 DNA methylation is able to predict the response to neoadjuvant and adjuvant chemotherapy. Recently, we showed that NEUROD1 DNA is differentially methylated in neoplastic versus nonneoplastic breast tissue samples. In this study, we used MethyLight and analyzed NEUROD1 methylation in (a) 74 breast cancer tissue samples, (b) two independent sets of pretreatment core biopsies of 23 (training set) and 21 (test set) neoadjuvantly treated breast cancer patients, and (c) pretherapeutic and posttherapeutic serum samples from 107 breast cancer patients treated with adjuvant chemotherapy. High-grade tumors showed higher NEUROD1 methylation levels. Estrogen receptor-negative breast cancers with high NEUROD1 methylation were 10.8-fold more likely to respond with a complete pathologic response following neoadjuvant chemotherapy. Patients with positive serum pretreatment NEUROD1 methylation, which persisted after chemotherapy, indicated poor relapse-free and overall survival in univariate and multivariate analyses (relative risk for relapse, 6.2; 95% confidence interval, 1.6-24; P = 0.008, and relative risk for death, 14; 95% confidence interval, 1.6-120; P = 0.02). These data support the view that NEUROD1 methylation is a chemosensitivity marker in estrogen receptor-negative breast cancer.