Treatment Decision Algorithm Research Articles

Outcomes in Children with Severe Aplastic Anemia Receiving Bone Marrow Transplantation from an HLA-Matched Family Donor or Intensive Immunosuppressive Therapy As First-Line Treatment,

Abstract 3421Bone marrow transplantation (BMT) from an HLA-matched family donor (MFD) is the treatment of choice for severe aplastic anemia (SAA) in children. For children without an MFD, immunosuppressive therapy (IST) with a combination of antithymocyte globulin and cyclosporine has been successful. However, this treatment approach is based on the results of comparative studies between these therapies conducted in the 1980s, and the outcomes of both BMT and IST have improved markedly over the past three decades. Therefore, updated evidence for treatment decisions in pediatric SAA is required. In the present study, we compared the outcomes of children with SAA who received IST (subjects enrolled in the prospective multicenter trials of IST conducted by the Japan Childhood Aplastic Anemia Study Group) or BMT from an MFD (subjects registered in the Transplant Registry Unified Management Program conducted by the Japan Society for Hematopoietic Cell Transplantation). The influence of potential risk factors on overall survival (OS) and failure-free survival (FFS) was assessed according to first-line treatment, time period of treatment (1992–1999 and 2000–2009), age and other variables related to each treatment. FFS was defined as survival with treatment response. Death, primary or secondary graft failure, relapse and secondary malignancy were considered treatment failures in patients who received BMT. Death, relapse, disease progression requiring stem cell transplantation from an alternative donor or 2nd IST, clonal evolution and evolution to paroxysmal nocturnal hemoglobinuria were considered treatment failures in patients who received IST. Between 1992 and 2009, 599 children with SAA younger than 17 years received BMT from an MFD (n=213) or IST (n=386) as first-line treatment. While the OS did not differ between patients receiving IST and BMT (88±2% vs. 90±2% at 15 years), FFS was significantly inferior in patients receiving IST as compared to those receiving BMT (54±3% vs. 84±3% at 15 years, P<0.0001). There was no significant improvement in outcomes over the two time periods; OS and FFS at 10 years in 1992–1999 vs. 2000–2009 were 87±2% vs. 93±2% and 66±3% vs. 67±3%, respectively. On multivariate analysis, age <10 years was identified as a favorable factor for OS (P=0.007) and choice of first-line IST was the only unfavorable factor for FFS (P<0.0001). These updated data support the current algorithm for treatment decisions, which recommends BMT when an MFD is available. Disclosures:No relevant conflicts of interest to declare.

Abstract P5-13-11: Medico-Economic Assessment of the Genomic Grade Index on Adjuvant Treatment Strategy in Elston-Ellis Grade 2, Estrogen Receptor Positive, HER2 Negative, Node Negative, Small Size Breast Carcinomas

Abstract Background: Elston-Ellis grading (EE) is one of the key criteria for adjuvant therapy decision in ER+/HER2-/pN0/pT1 -2 tumors. The genomic grade index (GGI) is a 97-gene micro-array assay able to identify tumors of high or low genomic grade. GGI has been developed in order to improve the prognosis determination, especially in EE2 tumors which represent a significant proportion of breast carcinomas and where the inter-assessor variability is the highest. The aim of the present study was to model the influence of the GGI on adjuvant treatment decision in EE2 patients, using a cohort of ER+/HER2-/pN0/pT1-2 tumors. Methods: A randomly selected series of pT1-2, pN0 breast cancers from the Institut Curie 1995-1996 cohort was profiled using Affymetrix HGU133 Plus 2.0 gene chips. The GGI was calculated using Ipsogen Mapßuant Dx®. Treatment decisions were made for EE2 cases based on the Institut Curie adjuvant treatment guidelines (www.curie.fr). The treatment decision algorithm was firstly run using the grade as defined by Elston Ellis, and secondly using the GGI (undetermined cases were classified as grade2). Results: Out of 72 EE2 tumors, 35 were classified as GGI-1 (49%) and 13 (18%) as GGI-3. Based on EE, 7% of patients would have received adjuvant chemotherapy (ACT) alone (all were ER-/PR-), 50% adjuvant hormonal therapy (AHT) alone, and 43% both. Using the GGI, 7% (n=5) of patients would have been spared AHT and 10% (n=7) ACT. In the ER+/HER2- subgroup of 62 pts, 58% of patients would have received AHT alone and 42% AHT+ACT based on EE; GGI would have lead to a 14% reduction in AHT prescription and to a 26% reduction in ACT prescription. Conclusion: Applying the Genomic Grade Index instead of the Elston Ellis Grade to determine the adjuvant treatment strategy in a series of EE2/ER+/HER2-/pN0/pT1-2 breast carcinomas would lead to a 14% and 27% reduction in the administration of, respectively, adjuvant hormone-therapy and chemotherapy. Adjuvant treatment decision: models based on Elston-Ellis or Genomic Grading Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-11.

Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients

Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes. From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion. A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600,000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009). The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.

Biomarkers of Resistance to Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer

Genomics and proteomics have held out the promise of individualized medicine for the last 10 or 20 years, but clinical medicine has not yet delivered on this promise. Some cancers, such as breast cancer and some hematologic malignancies, have been at the forefront of individualized therapeutic approaches by integrating molecular biomarkers into treatment decision algorithms. Until recently, the treatment of colorectal cancer (CRC) has lagged behind these other cancers in this regard and therapeutic decisions have been solely empirical. Data from various clinical trials and translational studies have now opened the door for individualized treatment approaches by identifying patients with metastatic CRC who are most likely to benefit from antibodies against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab. Activating mutations of KRAS, a downstream mediator of EGFR signaling, has been shown to render EGFR antibodies ineffective, such that analyzing tumors for these mutations has become mandatory before the use of EGFR antibodies is considered in CRC. Beyond KRAS, several additional biomarkers are currently being investigated as potential positive or negative predictors for the efficacy of EGFR-targeted therapy. Most of these markers are alterations of molecules integrated in the EGFR pathway. This review will focus on the type and quality of evidence that has been gathered to date to predict resistance to monoclonal antibodies against EGFR in CRC. (Clin Cancer Res 2009;15(24):7492-501).

Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment

Concerns About Consensus Guidelines for QTc Interval Screening in Methadone Treatment

Treatment of arteriovenous malformations of the brain

The treatment of ruptured and unruptured brain arteriovenous malformations (AVMs) is driven by the need to prevent incident or recurrent intracranial hemorrhages. Improving feasibility of the rapidly developing endovascular, neurosurgical, and radiotherapeutic procedures leads to invasive treatment of an increasing number of neurologically intact patients with accidentally diagnosed AVMs. Recent data confirm that the natural history risk of unruptured AVMs is significantly lower than the risk of those presenting with rupture, and the treatment risk of invasive management of unruptured AVMs seems higher than their natural history risk. The treatment decision algorithm for these patients remains unsettled, as no randomized clinical trial data exist on the benefit of invasive AVM treatment for patients with bled or with unbled AVMs. The recently launched study A Randomized Trial of Unruptured Brain AVMs (ARUBA) will be the first trial randomizing patients with nonhemorrhaged AVMs to invasive versus conservative management.