Months For High-risk Patients Research Articles

PS 02-02 Effect Ganoderma lucidum Polysaccharide Peptides as Anti-hypertension, Anti-lipid, Anti-oxidant, Anti-inflammation in High Risk Patients of Atherosclerosis

Objective: Ganoderma lucidum is a type of mushroom that has been used for thousand years throughout Asia. It is known to demonstrate numerous health benefiting properties including antioxidant, anti-inflammation, anticancer effects, hypoglycemic and blood cholesterol reducing properties. This research was conducted to determine the efficacy of Ganoderma lucidum polysaccharide peptides (PSP) as anti-inflammation and antioxidant in cardiovascular disease. Design and Method: This is a true experimental study with pre- and post-test design of 37high-risk patients of cardiovascular disease based on the Framingham Risk Score that was conducted for 3 months. They were advised to consume PSP 3x250 mg as adjuvant to their previous medications, and they did some examination. Statistical analysis was conducted using paired t-test for parametric data and Wilcoxon test for non-parametric data. Results: From 37 patients we found that the administration of PSP 3x250 mg could reduce total cholesterol level by 3.48 ± 46.9 mg/dl (p = 0.672). Both pre- and post-test of total cholesterol are significantly correlated (r = 0.618, p = 0.000). PSP administration, however, increased HDL cholesterol levels by 7.84 ± 10.79 (p = 0.000). The systolic blood pressure decreased from 130.14 ± 43.37 mmHg to 118.24 ± 55.68 (p = 0.109), and the diastolic blood pressure decreased from 80 ± 25.74 mmHg to 73.24 ± 33.85 mmHg (p = 0.102). Despite a great reduction of blood pressure to normal range, it was not statistically significant. The reduction of anti-inflammatory markers interleukin-6, from 279.75 ± 120.76 to 29.32 ± 26.44 (p = 0.000) and TNF alpha, from 13447.84 ± 2199.46 to 544.85 ± 292.06 (p = 0.000) were significant. Malondialdehyde (MDA) level also decreased significantly with PSP for 3 months (114.13 ± 24.56 to 36.84 ± 28.39, p = 0.000). Conclusions: The administration of polysaccharide peptides Ganoderma lucidum for three months in high-risk patients with hypertension can reduce the blood pressure within normal range, improve total cholesterol level and significantly play role as anti-inflammation and antioxidant in cardiovascular disease.

Biomarkers: evaluation of clinical utility in surveillance and early diagnosis for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second most common cause of death from cancer worldwide. Strategies to surveil and diagnose HCC in an earlier stage are urgently needed since this is when curable interventions can be offered to achieve long-term disease-free survival. Over the past few decades, research has suggested measuring alpha-fetoprotein (AFP) concentration and performing abdominal ultrasound (US) as part of routine surveillance of HCC every 6 months for high-risk patients, and many HCC guidelines worldwide have also recommended these examinations. Over the past 5 years, however, the role of serum biomarkers in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by some Western countries. In Asian countries, serum biomarkers such as AFP, the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxyprothrombin (DCP) are still recommended for HCC surveillance and are being used as an adjunctive diagnostic tool in accordance with HCC guidelines. Moreover, novel biomarkers including Dickkopf-1 (DKK1), midkine (MDK), and microRNA (miRNA) are being studied in this regard. China accounts for 50% of HCC cases worldwide, so identifying biomarkers of HCC is paramount. Recent studies have indicated the clinical utility of simultaneous measurement of AFP and DCP for the early detection of HCC in China. They are predominantly used for cases caused by HBV infection. Additional large-scale prospective studies should be conducted to establish the utility of these biomarkers.

Moderate Hypofractionation with Simultaneous Integrated Boost in Prostate Cancer: Long-term Results of a Phase I–II Study

AimsTo report 5 year outcome and late toxicity in prostate cancer patients treated with image-guided tomotherapy with a moderate hypofractionated simultaneous integrated boost approach. Materials and methodsIn total, 211 prostate cancer patients, 78 low risk, 53 intermediate risk and 80 high risk were treated between 2005 and 2011. Intermediate- and high-risk patients received 51.8 Gy to pelvic lymph nodes and concomitant simultaneous integrated boost to prostate up to 74.2 Gy/28 fractions, whereas low-risk patients were treated to the prostate only with 71.4 Gy/28 fractions. Daily megavoltage computed tomography (MVCT) image guidance was applied. Androgen deprivation was prescribed for a median duration of 6 months for low-risk patients (for downsizing), 12 months for intermediate-risk and 36 months for high-risk patients. The 5 year biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), overall survival and late gastrointestinal and genitourinary CTCAE.v3 toxicity were assessed. The effect of several clinical variables on both outcome and gastrointestinal/genitourinary toxicity was tested by uni- and multivariate Cox regression analyses. ResultsAfter a median follow-up of 5 years, the late toxicity actuarial incidence was: genitourinary ≥ grade 2: 20.2%; genitourinary ≥ grade 3: 5.9%; gastrointestinal ≥ grade 2: 17%; gastrointestinal ≥ grade 3: 6.3% with lower prevalence at the last follow-up visit (≥ grade 3: genitourinary: 1.9%; gastrointestinal: 1.9%). Major predictors of ≥ grade 3 genitourinary and gastrointestinal late toxicity were genitourinary acute toxicity ≥ grade 2 (hazard ratio: 4.9) and previous surgery (hazard ratio: 3.4). The overall 5 year bRFS was 93.7% (low risk: 94.6%; intermediate risk: 96.2%; high risk: 91.1%), overall survival and CSS were 88.6% (low risk: 90.5%; intermediate risk: 87.4%; high risk: 87%) and 97.5% (low risk: 98.7%; intermediate risk: 95%; high risk: 94.3%), respectively. Risk classes and androgen deprivation were not significantly correlated with either bRFS, overall survival or CSS. Twelve patients experienced a biochemical relapse but none experienced clinically proven local and/or pelvic recurrence. ConclusionA satisfactory 5 year outcome with an acceptable toxicity profile was observed. The combination of image-guided radiotherapy–intensity-modulated radiotherapy, high equivalent 2 Gy dose (EQD2) with a moderate hypofractionated approach and extensive prophylactic lymph node irradiation also leads to very good outcome in high-risk patients.

Development of a ten-signature classifier using a support vector machine integrated approach to subdivide the M1 stage into M1a and M1b stages of nasopharyngeal carcinoma with synchronous metastases to better predict patients' survival.

The aim of this study was to develop a prognostic classifier and subdivided the M1 stage for nasopharyngeal carcinoma patients with synchronous metastases (mNPC). A retrospective cohort of 347 mNPC patients was recruited between January 2000 and December 2010. Thirty hematological markers and 11 clinical characteristics were collected, and the association of these factors with overall survival (OS) was evaluated. Advanced machine learning schemes of a support vector machine (SVM) were used to select a subset of highly informative factors and to construct a prognostic model (mNPC-SVM). The mNPC-SVM classifier identified ten informative variables, including three clinical indexes and seven hematological markers. The median survival time for low-risk patients (M1a) as identified by the mNPC-SVM classifier was 38.0 months, and survival time was dramatically reduced to 13.8 months for high-risk patients (M1b) (P < 0.001). Multivariate adjustment using prognostic factors revealed that the mNPC-SVM classifier remained a powerful predictor of OS (M1a vs. M1b, hazard ratio, 3.45; 95% CI, 2.59 to 4.60, P < 0.001). Moreover, combination treatment of systemic chemotherapy and loco-regional radiotherapy was associated with significantly better survival outcomes than chemotherapy alone (the 5-year OS, 47.0% vs. 10.0%, P < 0.001) in the M1a subgroup but not in the M1b subgroup (12.0% vs. 3.0%, P = 0.101). These findings were validated by a separate cohort. In conclusion, the newly developed mNPC-SVM classifier led to more precise risk definitions that offer a promising subdivision of the M1 stage and individualized selection for future therapeutic regimens in mNPC patients.

Abstract 1350: Genetic variations in apoptosis pathway are associated with survival in late stage non-small cell lung cancer.

Abstract Dysregulation of apoptosis pathway plays an essential role in carcinogenesis, tumor progression, and resistance to chemotherapy. We hypothesized that genetic variations in genes involved in the apoptosis pathway may affect the survival in late stage non-small cell lung cancer (NSCLC) patients. To test this hypothesis, we genotyped 583 tagging SNPs in 598 late stage NSCLC patients and analyzed their associations with survival individually and jointly. Seven SNPs were statistically significantly associated with overall survival after correction for multiple comparisons (q&amp;lt;0.1). The most significant SNP was rs17592236 on FOXO1 gene under the dominant model (OR: 2.54, 95%CI: 1.71-3.78, p=4.15x10−6). We also observed a significant cumulative effect. Compared to the reference group (patients with no more than two risk alleles), those having five or more risk alleles were much more likely to die within seven months (HR: 3.58, 95% CI: 2.55-5.04, p&amp;lt;0.001). Notably, the median survival time (MST) was significantly reduced by up to 15 months in high risk patients when compared to the reference group (MST: 22.2 months, p&amp;lt;0.001). Survival tree analysis revealed potential higher order gene-gene interactions among these SNPs. Our results provided evidence that genetic variations in the apoptosis pathway modulate NSCLC survival and may serve as biomarkers to differentiate NSCLC patients with different prognosis. Citation Format: Xiang Shu, Charles Lu, Joe Y. Chang, Jack A. Roth, Xifeng Wu. Genetic variations in apoptosis pathway are associated with survival in late stage non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1350. doi:10.1158/1538-7445.AM2013-1350

Early Regression of Left Ventricular Mass Associated with Diastolic Improvement after Transcatheter Aortic Valve Implantation

The aim of this study was to investigate the effects of transcatheter aortic valve implantation (TAVI) on left ventricular (LV) hypertrophy and diastolic function in patients with severe aortic valve stenosis (AVS). There are few and conflicting data on LV mass remodeling and LV diastolic function after TAVI. Echocardiography and clinical assessment were performed at baseline and at 6 months in high-risk patients affected by severe AVS who underwent TAVI. One hundred thirty-five patients successfully underwent TAVI. Peak transvalvular aortic pressure gradient and mean transvalvular aortic pressure gradient were reduced from 87 ± 25 to 18 ± 7 mm Hg and from 54 ± 14 to 9 ± 4 mm Hg, respectively (P < .001), accompanied by significant clinical improvement. The mean LV ejection fraction improved from 50 ± 13% to 54 ± 11% during follow-up (P= .009). At 6-month follow-up, interventricular septal wall thickness regressed from 14 ± 2 to 12 ± 1 mm and posterior wall thickness from 13± 3 to 11 ± 2 mm (P < .001). LV mass and LV mass index decreased from 332 ± 106 to 228 ± 58 g (P < .001) and from 191 ± 58 to 132 ± 30 g/m(2) (P < .001), respectively. Ninety-seven patients (72%) showed improvements in LV diastolic filling pattern. The mean e' value increased from 4.1 ± 1.7 to 5.6 ± 2.2 cm/sec, and the mean E/e' ratio decreased from 24 ± 7 to 17 ± 6 (P < .001) after TAVI. Significant LV mass reverse remodeling associated with improvement in LV systolic and diastolic function was found in patients with severe AVS 6 months after TAVI. These changes may have relevant clinical prognostic value.

An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy. The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes. RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P(interaction) = 0.042). Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC.

MDS-Specific Comorbidity Index (MDS-CI) Identifies Overall Survival Differences in Myelodysplastic Syndrome Patients,

Abstract 3793MDS-specific comorbidity index (MDS-CI) is a score reported by the Pavia group for myelodysplastic syndromes (MDS) patients. This score is a time-dependent index developed for predicting the effect of comorbidities on outcome of these subjects. We applied this score on a total of 450 MDS patients: comorbidities were recorded at the time of diagnosis and considered by medical staff for the analysis. All patients were consecutively diagnosed and followed at our institute in a period between January 1992 and December 2006. Statistical analysis was carried out using SPSS software; survival was defined as time from diagnosis to last contact or death for any cause. Median age of the whole population was 69 years (range 21–88), with a prevalence of male sex (ratio m/f 1.6). Overall, we found the presence of one or more comorbidities in 94% of the examined patients. The most common comorbidities were cardiac disorders observed in 40% of patients, followed by diabetes with organ damage recorded in 22 cases. Application of MDS-CI score identified 300 patients with score 0, 55 patients with score 1, 80 patients with score 2 and 15 patients with score >2. We found significant differences in OS according to MDS-CI stratification: from 38 months for low risk patients (score 0) to 22 months for high-risk patients (score >2, p=0.02). We then evaluated the prognostic effect of MDS-CI on patients stratified according to WPSS prognostic index. WPSS application was possible in 330 of 450 patients who entered the analysis (73%), due to cytogenetic availability of data: we identified 112 patients (34%) with very low/low risk, 137 patients (41.5%) with intermediate risk and 81 patients (24.5%) with high/very high risk. As reported by the Pavia group, we assessed prognostic relevance of comorbidities in very low/low risk WPSS patients, intermediate and high/very high-risk patients. We found in the first category a significant difference in OS stratification: from 48.5 months for patients with score 0 to 20.4 months for patients with score >2 (p=0.002). In WPSS intermediate risk we found similar significant OS difference: from 32.3 months for patients with score 0 to 18.3 months for patients with score 2 (p=0.001). Conversely, we did not find significant differences in WPSS high/very high-risk patients. We also found significant correlations between presence of comorbidities at baseline, as stratified with MDS-CI, and risk of non-leukemic death: from 22% in patients without comorbidities to 75% in patients with score >2 according to MDS-CI (p=0.002). Our analysis showed the efficacy of MDS-CI on a large series of MDS consecutively seen, diagnosed and followed in a single center while strengthening the results reported by the Pavia group: in fact, the value of comorbidities was confirmed in a cohort of patients similar to that observed in the original paper, in terms of median age (69 years in our series vs 66 years in the Pavia series), but with higher percentage of patients with intermediate WPSS risk (41.5% in our series vs 18% in the Pavia population). MDS-CI is a very valid tool capable to differentiate MDS patients with very low/low and intermediate WPSS risk in terms of OS and non-leukemic death risk. Disclosures:Alimena:Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Novel biomarker panel predicts prognosis in human papillomavirus‐negative oropharyngeal cancer

AbstractBACKGROUND:New treatment strategies for locally advanced head and neck squamous cell carcinoma combine induction chemotherapy and chemoradiation. Identifying the predictors of outcome in sequentially treated patients is critical for focusing therapeutic research. In this analysis, the authors evaluated human papillomavirus type 16 (HPV‐16) status and the expression levels of a defined set of biomarkers to identify predictors of response to this treatment modality.METHODS:In total, 114 patients with oropharyngeal cancer (OPC) who were treated on the TAX 324 trial (cisplatin and fluorouracil with or without docetaxel in patients with locally advanced head and neck squamous cell carcinoma) had pretreatment biopsy specimens that were evaluable for HPV‐16 DNA and immunohistochemical expression of the following biomarkers: beta‐tubulin II (βT‐II), glutathione S‐transferase (GST‐π), p53, and B‐cell lymphoma 2 (Bcl‐2). Patients were categorized into risk groups based on their HPV status and biomarker expression levels.RESULTS:Patients with high‐risk OPC were defined by HPV‐negative status and either elevated expression of βT‐II or levels of at least 2 of the other 3 adverse markers (elevated GST‐π, elevated p53, or low Bcl‐2). All other HPV‐negative patients were categorized as moderate risk. In total, 55 patients were HPV‐positive, and 59 patients were HPV‐negative, with 34 were categorized as high risk and 25 categorized as moderate risk. The median survival for HPV‐positive patients was not reached. The median survival was 44.2 months for moderate‐risk patients (95% confidence interval, 20.9 months to not reached) and 12.1 months for high‐risk patients (95% confidence interval, 7.5‐19.7 months). The 24‐month survival rate was 89% for HPV‐positive patients, 67% for moderate‐risk patients, and 29% for high‐risk patients (P &lt; .0001).CONCLUSIONS:The molecular data set in this study readily differentiated between 2 distinct groups of patients with locally advanced, HPV‐negative OPC. This risk‐stratification strategy may serve as a guide for treatment selection. Cancer 2012;. © 2011 American Cancer Society.

Confirmation of the Mantle Cell Lymphoma International Prognostic Index (MIPI) in An Independent Prospective Patient Cohort.

Abstract 138 Background:The Mantle Cell Lymphoma (MCL) International Prognostic Index (MIPI) has been recently developed as first prognostic index especially designed for patients with advanced stage MCL (Hoster et al., Blood 2008). The MIPI is based on four easily available prognostic factors (age, ECOG performance status, leukocyte count, and LDH). It was internally validated using a bootstrap strategy, and several authors reported its validity on larger patient cohorts (Salek et al., ASH 2008, Geisler et al., EHA 2009). We evaluated the prognostic relevance of the MIPI using the pooled data of two currently recruiting randomized trials (MCL Younger and MCL Elderly) of the European MCL Network (Dreyling et al., ASH 2007). Methods:Outcome parameters were primarily overall survival (OS) and secondarily time to treatment failure (TTF). Kaplan-Meier curves according to the MIPI prognostic groups were compared by means of the log rank test and univariate Cox regression. We checked the value of the MIPI prognostic factors within multiple Cox regression. We also evaluated the simplified MIPI and exploratively included patients with stage II into the analyses. Since randomization is ongoing, all analyses were blinded for treatment arms. Results:Currently, 606 patients with advanced stage MCL were evaluable, 317 in MCL Younger and 289 in MCL Elderly. Median age was 63 years (range 32 – 87), 6% had an ECOG performance status > 1, median LDH/ULN ratio was 0.95 (0.29 – 12.2), and median leukocyte count 7,600/μl (1,075/μl – 396,000/μl). The MIPI classified 220 patients (36%) into the low risk (LR), 187 (31%) into the intermediate risk (IR) and 199 (33%) into the high risk (HR) group. With a median follow-up of 19 months and 116 events, the probability for OS at 24 months was 91%, 77%, and 58% for LR, IR, and HR (medians not reached in LR, IR vs. 28 months in HR patients, p < 0.0001), corresponding to a hazard ratio of 2.7 for IR vs. LR (95% CI, 1.5 – 4.9, p = 0.001) and 2.6 for HR vs. IR (95% CI, 1.7 – 4.0, p < 0.0001). The four MIPI prognostic factors were independently prognostic for OS (p < 0.0001 each). In MCL Younger, the distribution to LR, IR, and HR groups was 61%, 23%, and 16%, as compared to 9%, 40%, and 51% in MCL Elderly, the difference reflecting the strong prognostic impact of age. According to preliminary subgroup analyses, 2-years OS rates were 92%, 76%, and 58% (p < 0.0001) in MCL Younger, and 85%, 78%, and 58% (p < 0.0001) in MCL Elderly. The MIPI also separated LR, IR, and HR group with respect to TTF, with medians of 49, 36, and 20 months (p < 0.0001) and a hazard ratio of 2.2 for IR vs. LR (95% CI, 1.4 – 3.4, p = 0.0004) and 2.0 for HR vs. IR (95% CI, 1.4 – 2.8, p = 0.0001). The simplified MIPI classified 36%, 32%, and 33% to LR, IR, and HR groups with high concordance to the MIPI (weighted kappa 0.82). Two-years OS rates were 90%, 79%, 58% for LR, IR, HR according to the simplified MIPI (p < 0.0001) with a hazard ratio of 2.4 for IR vs. LR (95% CI, 1.3 – 4.2, p = 0.003) and 2.5 for HR vs. IR (95% CI, 1.7 – 3.8, p < 0.0001). Inclusion of 32 patients with stage II MCL did not essentially change the results. Discussion:We could confirm the prognostic relevance of the MIPI in a large independent patient cohort treated within current randomized trials. Therefore, the MIPI may be used for risk stratification in future clinical trials, for the comparative interpretation of the results of different trials, for the evaluation of new biological prognostic factors, and may finally lead to risk-adapted treatment decisions in advanced stage MCL. Disclosures:Hoster:Roche: travel support. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Unterhalt:Roche: travel support.

Family History of Cancer Rather Than p53 Status Predicts Efficacy of Pegylated Liposomal Doxorubicin and Oxaliplatin in Relapsed Ovarian Cancer

The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations. Seventy-two women received a median of 7.5 courses of PLD at 30 to 35 mg/m2 plus oxaliplatin at 70 mg/m2, and associations between BRCA1/2 and TP53 status and overall survival (OS) were determined. Thirty-eight had a short platinum-free interval (PFI; <12 months), and 34 had a long PFI (> or =12 months). Nine patients had BRCA1 mutations, and 1 had a BRCA2 mutation. Platinum sensitivity was associated with OS (P = 0.0001). At a median follow-up of 9.3 months, objective response rate, median time to progression, and OS were 47.3%, 5.8 months, and 12.9 months, respectively, in short PFI compared with the 76.5%, 11.5 months, and 47.7 months in long PFI. p53 status did not correlate to these parameters. The median time to progression was 11.5 months for high-risk patients versus 6.5 months for patients with sporadic cancer (P = 0.0188), and the median OS from the start of treatment was 48.7 and 16.2 months (P = 0.0032), respectively. Toxicity was mostly grade 1 or 2. High response rates in the long-PFI patients indicate that this treatment is beneficial and well tolerated. Platinum sensitivity and positive family history and/or a BRCA1/BRCA2 mutation are a useful predictor of response.

Survival in Patients with Newly Diagnosed Myeloma Undergoing Therapy with Lenalidomide and Dexamethasone: Impact of High-Risk Cytogenetic Risk Status on Outcome

Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex).Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests.Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002).Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. [Display omitted]

Outcome of patients with myelodysplastic syndromes – experience from a single institution in South Australia

To study disease characteristics of adult patients with myelodysplastic syndromes (MDS) in South Australia and to analyse their outcome and survival. One hundred and eight adult patients with confirmed MDS from marrow biopsies in the 76-month period before April 2006 were retrospectively included in an MDS database. The median age at diagnosis of this cohort was 70 years, with skewing of refractory anaemia with excess blasts and refractory cytopenia with multilineage dysplasia in the younger patients. Clonal cytogenetic abnormalities were present in 42% of patients. Median survival was 48 months, and secondary transformation to acute myeloid leukaemia was seen in 27%. Survival, according to the World Health Organization subtypes in ascending order, was refractory anaemia with excess blasts, refractory anaemia, refractory anaemia with ringed sideroblast, refractory cytopenia with multilineage dysplasia and del(5q). The International Prognostic Scoring System score stratified MDS patients into different risk groups and effectively discriminated significantly different survivals, ranging from a median 4 months for high-risk patients to 72 months for low-risk patients. An MDS database provides useful information regarding the disease characteristics and survival of MDS patients in South Australia and confirms the prognostic usefulness of the International Prognostic Scoring System. The future prospective collection of results will be invaluable in evaluating the effect of novel therapies on patient prognosis.

The International Prognostic Scoring System for Waldestrom's Macroglobulinemia (ISSWM) Is Applicable in Patients Treated with Rituximab-Based Regimens.

Introduction: An ISSWM was recently proposed (Morel et al, ASH 2006), which was based on a large number of patients treated primarily with alkylating agents and /or nucleoside analogues. The ISSWM based on 5 adverse covariates wich defined 3 risk groups: low, intermediate and high risk with 5-years survival rates of 87%, 68% and 36% respectively. In our current analysis, we assessed the impact of this system in patients with WM who received primary treatment with rituximab-based regimens.Patients and methods: Ninety-three previously untreated, symptomatic patients who received treatment either with single agent rituximab (21 patients) or with the combination of dexamethasone, rituximab, and cyclophosphamide (72 patients) were classified according to the ISSWM, which is based on 5 adverse covariates: age> 65 years, hemoglobin ≤11.5 g/dl, platelet count ≤ 100 x 109/L, β2- microglobulin <3mg/L, serum monoclonal protein concentration >70g/L. Low risk is defined by the presence of ≤ 1 adverse characteristics except age, high risk by the presence of >2 adverse characteristics and intermediate risk by the presence of 2 adverse characteristics or age >65 years.Results: The disease features of the 93 patients were typical of symptomatic WM: age > 65 years in 63%, males 65%, B-symptoms in 22%, splenomegaly in 29%, lymphadenopathy in 34%. 15% of patients were rated as low risk, 65% as intermediate risk and 20% as high risk. Criteria for initiation of therapy included cytopenia, hyperviscosity, constitutional symptoms, organomegaly or IgM-related disorders. Overall, 62% of patients were alive at 6 years. Median survival was not reached for low and intermediate risk and was 38 months for high risk patients (p=0.006). There was a clear separation of the survival curves in the three groups. At the time of last follow-up the percentage of patients alive was 100%, 82% and 58% for patients classified as low, intermediate and high-risk group respectively.Conclusions: The recently proposed ISSWM is applicable in patients with WM who receive primary treatment with rituximab-based regimens and may serve as a basis to compare outcomes in different studies.

Cost-effectiveness of the Taxus paclitaxel-eluting stent in the Swedish healthcare system

Objective. To analyse the cost-effectiveness of Taxus compared to a bare-metal stent in patients with coronary artery disease in the Swedish healthcare setting. Design. A decision-analytic model combining clinical data on revascularization rates with Swedish unit costs for medical resources and utility data from the literature. Results. For patients of moderate risk, the average cost per patient at 12 months is 72 200 SEK for Taxus and 66 900 SEK for a bare-metal stent, while the average cost for high risk patients is nearly equivalent (73 000 vs. 71 700 SEK). The cost per revascularization avoided is generally favourable, while the incremental cost per QALY gained varies depending on the assumptions made; from 2 351 000 SEK for patients of moderate risk at 12-months to cost saving at 24 months for high risk patients. Budget impact scenarios at 12 months are cost-neutral. Conclusion. The Taxus stent is cost-effective in high risk patients, particularly at 24 months. Although it may be less cost-effective for the general population, there is still a substantial offset of initial procedure costs through lower rate of repeat revascularizations.

Comparison of mutational changes in involved N1 lymph nodes with those in primary tumors in stage II non–small cell lung cancer: a pilot study

Objectives Surgical resection is the standard treatment for stage II non–small cell lung cancer, but recurrence rates approach 60%. This study compared mutational changes in involved lymph nodes and primary tumors from patients with stage II non–small cell lung cancer to determine whether risk factors for recurrence could be identified. Methods Forty patients with resected stage II non–small cell lung cancer (excluding T3 N0 disease) were studied. Microdissection was performed on primary tumors and lymph nodes. Analysis was performed across 9 genomic loci by using polymerase chain reaction amplification. The ratio of fractional allelic loss between involved lymph nodes and primary tumors was used to stratify patients into high-risk (fractional allelic loss ratio of ≥1) and low-risk (fractional allelic loss ratio of <1) groups. Results The median age of the patients was 68 years (range, 42-85 years). Median follow-up was 30 months. Fractional allelic loss was greater in patients with squamous carcinomas compared with that in adenocarcinomas, but survival was similar (35 vs 39 months). The median survival was 35 months in high-risk patients and was not reached in low-risk patients ( P = .3). Disease-free survival was 24 months in high-risk patients and was not reached in low-risk patients ( P = .35). In the subset with adenocarcinoma (n = 18), median survival was 24 months in the high-risk group; no deaths occurred in low-risk patients ( P = .01). Also, disease-free survival was 14 months in high-risk patients and was not reached in the low-risk patients ( P = .05). Conclusions Squamous cancers demonstrate greater mutational changes than adenocarcinomas; this does not affect outcome. The patients with low-risk adenocarcinomas demonstrated superior outcomes compared with those of other patients. These results should be confirmed in larger studies.

Does the Therapy According to Stage Improve Response and Survival in Multiple Myeloma Patients?

The records of 104 patients (1972-80) with Multiple Myeloma (MM) were reviewed and a staging system was used dividing patients into Low Risk (LR) and High Risk (HR) groups, according to individual factors. Serum-calcium and serum creatinine, haemoglobin and the percentage of bone marrow plasma cells (BMPC), at the time of diagnosis, had predictive value on survival. This group of patients had already received treatment independent of these risk categories. Subsequently during 1980 to 1988, 114 evaluable patients with MM entered a prospective study using two treatment regimens according to that same staging system: LR patients were treated with Melphalan + Prednisone (MP) and HR patients with Vincristine, Melphalan, Cyclophosphamide and Prednisone (VMCP) for a minimum of six cycles. In the event of no response to the initial therapy given, a more aggressive regimen was then used: VMCP for LR patients and VAP or BAP (Vincristine or BCNU, Adriamycin, Prednisone) for the HR group for six to twelve cycles. The rate of response for Low and High Risk category was 42% and 73%, respectively. The median duration of response to initial therapy was 19 months for LR and 11 months for HR patients. Furthermore therapy chosen according to stage resulted in an improvement in survival compared to the earlier 1972-80 series. This was particularly significant for HR patients who benefited by an obvious decrease in the number of early deaths, due to progression of disease, when the combined regimens were used. The study indicates that therapy according to risk categories seems to be a worthwhile approach, MP being an appropriate initial treatment for LR while combination chemotherapy may be better for HR patients.