Overall Survival In High-risk Patients Research Articles

Follow-up of patients receiving rituximab for diffuse large B cell lymphoma: an overview of systematic reviews

The advent of rituximab has significantly improved the clinical outcomes of patients with diffuse large B cell lymphoma (DLBCL). Although rituximab is considered safe and effective, data on its long-term use are limited, which suggests that patients should undergo systematic, long-term follow-up aiming to identify delayed or yet undescribed adverse reactions and optimize treatment effectiveness. This study presents an overview of systematic reviews of strategies for follow-up of DLBCL patients receiving rituximab and documents the current state of knowledge on efficacy and safety in this population. A highly sensitive strategy was used to identify systematic reviews of randomized clinical trials (RCTs) in the Cochrane Library, Embase, Lilacs, MEDLINE, and Scirus databases. A handsearch of medical and government agency websites was also conducted. Seven studies were included, among them there were RCTs of patients who used CHOP/CHOP-like chemotherapy plus rituximab for three to eight cycles every 14 to 21days as induction therapy, whereas some studies used maintenance therapy for 3 to 24months. Only one study described a follow-up model for management of adverse drug reactions. The benefits of rituximab for induction therapy of DLBCL were demonstrated, although there is no evidence of significant improvement in the overall survival of high-risk patients or those with HIV-related lymphoma. Rituximab therapy was associated with increased rates of fever, infection, and grade 3/4 hematological toxicity, as well as higher infection-related mortality in HIV-positive patients. Although one study addressed the management of adverse reactions to rituximab, our search did not yield any publications on systematic follow-up strategies for these patients. This finding suggests that such instruments should be developed and validated to optimize the effectiveness and long-term safety of novel therapies.

ARISER: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC—Results and implications for adjuvant clinical trials.

4507^ Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N+/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0–1), yielding a range of 0.0–3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR=0.99, p=0.74) or OS advantage (HR=1.01, p=0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (>2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR=0.55; p=0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.

Iron chelation therapy in myelodysplastic syndromes: we need more evidence, not more guidelines

Iron chelation therapy in myelodysplastic syndromes: we need more evidence, not more guidelines

Overall Survival by Prognosis Score in High-Risk Myelodysplastic Syndromes (MDS) Patients Receiving Decitabine Treatment: Results From Clinical Experience

Abstract 5024Background The DNA-targeted hypomethylating agent, decitabine, has made a real impact on response rate in Myelodysplastic Syndromes (MDS) patients, and may improve overall survival in high-risk patients. Aim: To describe overall survival by prognosis score in decitabine-treated MDS patients. Methods: From May 2007 to January 2011, MDS patients who received decitabine were followed at centers in Argentina and South Korea. Patients ≥18 years of age with de novo MDS (all WHO Subtypes and CMML type-1 and type-2) were included, provided they had received ≥4 cycles of decitabine (recommended dose, 20 mg/m2 IV over 1 hour × 5 days every 4 weeks) and had stable disease or better by IWG 2006 criteria. Median life expectancy was determined according different categories of the MD Anderson and International Prognostic Scoring Systems (MDAPSS and IPSS). Decitabine treatment was effective when the patient outlived the median life expectancy. Results: Sixty-one patients received ≥4 cycles of decitabine and had stable disease or better. Median age was 61 years and 69% were male. All patients had de novo MDS with ECOG ≤2. Median time from MDS diagnosis was 24 months. Baseline WHO classification was: RA (0%); RARS (2%); RCMD (18%); RCMDRS (3%); RAEB-1 (13%); RAEB-2 (30%); MDS/MPD (2%); AML/MDS (5%); CMML type-1 (21%); and CMML type-2 (6%). Forty one percent had comorbidities. Patients received a median of 8 cycles of decitabine (range, 4–18). Forty four percent died during the study and 31% progressed to AML. Median overall survival was higher than life expectancy among patients with high-risk MDS by MDAPSS (Kantarjian H. et al. Cancer 2008; 113: 1351) and by IPSS (Greenberg P. et al. Blood 1997; 89: 2079). Survival exceeded life expectancy for 90%, 100%, and 86% of patients with MDAPSS 7–8, MDAPSS ≥9, and IPSS Int-2 + High, respectively. Conclusion: High-risk MDS patients who received ≥4 cycles of decitabine and had stable disease or better showed improvement in survival compared with predicted life expectancy published in literature.Median OS, MonthsPredictedActual*p-ValueMDAPSS (N=61)0–454395–625697–81431> 96230.014IPSS (N=58)Int-14237Int-2 + High14 to 5290.001*Kaplan-Meier and log-rank Test (Mantel-Cox). Disclosures:No relevant conflicts of interest to declare.

The End of an Era: Shall We Move Forward?

The End of an Era: Shall We Move Forward?

275 Cost-effectiveness in Canada of azacitidine for the treatment of higher risk myelodysplastic syndromes and acute myeloid leukemia

The open-label, prospective, observational study aimed to evaluate whether decitabine (DAC) plus thalidomide versus DAC monotherapy improved progression-free (PFS), overall survival (OS) and acute myeloid leukemia-free survival (AML-FS) for risk-tailored elderly patients with myelodysplastic syndromes (MDS).Enrolled 107 patients (age: 65–82 years) received DAC (52/107) or DAC plus thalidomide (55/107) therapy for MDS.35/52 patients (67.3%) with DAC therapy reached overall response (OR), compared with 36/55 patients (65.5%) in DAC + thalidomide regimen (P > 0.05). DAC + thalidomide administered did not gain more profits of PFS and OS than DAC monotherapy. Risk-tailored analysis showed that DAC + thalidomide therapy did not enhance PFS (48.9% versus 42.8%, P > 0.05) and OS (78.6% versus 71.2%, P > 0.05) when compared with simple DAC regimen. Nevertheless, DAC + thalidomide markedly improved OS over DAC monotherapy (50.6% versus 40.2%, P < 0.05) in high risk profile. Meanwhile, low risk group was superior to high risk group in AML-FS (57.2% versus 21.3%, P < 0.01), but DAC + thalidomide still did not prolong 2-year AML-FS when compared with DAC (32.4% versus 27.8%, P < 0.05). Moreover, thalidomide had a favorable toxicity profile as a single agent. In comparison with DAC monotherapy, the DAC + thalidomide regimen was relatively well tolerated. There was no severe non-hematological toxicity appearing in elderly patients with MDS.The study demonstrated that DAC + thalidomide improved 2-year OS for high risk patients. Thalidomide's proven activity and low toxicity profile made it an alternative treatment option for risk-tailored elderly patients with MDS.

Evidence for Cytogenetic and Fluorescence in Situ Hybridization (FISH) Risk Stratification of Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies.

Abstract 1802Poster Board I-828 BackgroundHeterogeneity in multiple myeloma (MM) leads to disparate outcomes with a wide variation in overall survival (OS). Based upon the evidence predominantly gathered from newly diagnosed patients treated with standard chemotherapy and/or transplantation, the current Mayo (mSMART) prognostic model uses a combination of metaphase cytogenetics, fluorescence in-situ hybridization (FISH) and plasma cell labeling index (PCLI) for risk-stratification at diagnosis of MM. The objective of our study was to evaluate the significance of this stratification model in the era of novel therapies, and to assess the independent prognostic value of each of the components in the model. MethodsData were abstracted from a cohort of 1556 consecutive patients with MM who presented to our institution between January 1999 and March 2009 within ninety days of diagnosis of MM A total of three hundred and eighty six patients had been evaluated with conventional cytogenetics near diagnosis in addition to interphase FISH. Out of this cohort, three hundred and sixty six patients had availability of all the three tests, including the slide-based PCLI. High-risk MM was defined as presence of any one or more of the following: cytogenetics: hypodiploidy, monosomy of chromosome 13 or deletion 13q ; FISH: deletion of p53 (locus 17p13) or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23); PCLI ≥3%. Survival estimates were created using the Kaplan-Meier method and compared by log-rank tests. The impact of each of the three tests was assessed by a multivariate (MV) analysis using Cox proportional hazards model. ResultsThe median OS of the cohort of 366 patients was 65 months from presentation. One hundred and twelve (31%) patients were deemed high risk by any one or more of the three tests: Metaphase cytogenetics, FISH or PCLI (current mSMART definition of high-risk MM). The median OS of high risk patients was 52 months versus 71 months for standard-risk (P=0.007). We then studied the prognostic value of the three tests separately. Patients classified as high risk by FISH had a median OS of 35 months versus 65 months for the standard risk, HR= 2.3, P<0.001. Similarly, cytogenetics alone was also able to classify patients into high and standard risk with a comparable HR of 2.1 (P=0.008, median survival 37 vs. 64 months). In contrast, PCLI did not have a significant prognostic value (HR =1.41, P=0.32). This was confirmed on multivariate analysis in a model that included all 3 tests. FISH (HR=2.36, P=0.001) and cytogenetics (HR=1.99; P=0.017) emerged as independent determinants of prognosis in the multivariable analysis, while PCLI (HR=1.03, P=0.93) did not provide additional prognostic value. We then examined whether the prognostic value of FISH contributed additionally in patients classified into high and standard risk by conventional cytogenetics, and vice versa. Those classified as high risk by cytogenetics (n=44, 11 %), were further categorized into 2 groups by additional prognostic information obtained by FISH (median survival 18 vs. 52 months; P=0.005). Similarly, those classified as standard risk by cytogenetics (n=342, 89 %), were further categorized into 2 groups (median survival 52 vs. 71 months; P=0.017) by additional FISH-based stratification. Similarly, high-risk patients defined by FISH (n=65, 17 %) were further classified into 2 groups with significant difference in median OS (18 vs. 52 months, P=0.004), based on the presence or absence of high-risk features on cytogenetics. In contrast, no additional prognostic information was gained by cytogenetics in patients who were stratified as standard risk by FISH alone (n=321, 83%). ConclusionOur study validates high risk features defined by FISH and conventional cytogenetics in the mSMART risk stratification model among patients treated after the introduction of novel therapies. Either test identifies a high risk cohort with a hazard ratio of approximately 2 (median survival ∼37 versus ∼65 months). In patients known to have high risk disease by one of the two tests, knowledge of the other appears to add additional prognostic value. DisclosuresFonseca:Amgen, BMS, Celgene, Otsuka, Genzyme and Medtronic: Consultancy. Gertz:celgene, millennium: Honoraria. Dispenzieri:celgene: Research Funding. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Metastatic renal cell carcinoma management

To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC) patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Outcomes of Patients with Differentiated Thyroid Carcinoma Following Initial Therapy

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

Monoclonal antibody therapy of cancer

The most significant recent advances in the application of monoclonal antibodies (mAbs) to oncology have been the introduction and approval of bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody, and of cetuximab (Erbitux), an anti-epidermal growth factor antibody. In combination with standard chemotherapy regimens, bevacizumab significantly prolongs the survival of patients with metastatic cancers of the colorectum, breast and lung. Cetuximab, used alone or with salvage chemotherapy, produces clinically meaningful anti-tumor responses in patients with chemotherapy-refractory cancers of the colon and rectum. In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer. These exciting recent results provide optimism for the development of mAbs that bind novel targets, exploit novel mechanisms of action or possess improved tumor targeting. Progress in the clinical use of radioimmunoconjugates remains hindered by complexity of administration, toxicity concerns and insufficiently selective tumor targeting.

Implantable devices versus antiarrhythmic drug therapy in recurrent ventricular tachycardia and ventricular fibrillation

The implantable cardioverter defibrillator (ICD) protects patients from sudden cardiac death due to ventricular tachyarrhythmias. The capability of an improved overall survival of high-risk patients in comparison to the best pharmacologic therapy has been evaluated over the last few years in prospective randomized trials. In patients with a history of resuscitated ventricular fibrillation (VF) or unstable ventricular tachycardia (VT), the ICD was superior to therapy with amiodarone in 3 large trials involving 2,024 patients. At 2-year follow-up, ICD therapy was associated with a relative reduction in the risk of death of 20% to 30%. With respect to primary prevention of arrhythmogenic death, data are less convincing. The Multicenter Automatic Implantable Defibrillator (MADIT) study proved superiority of ICD therapy over medical treatment in coronary patients with depressed left ventricular function, nonsustained VT, and inducible but not suppressible sustained VT/VF. The second trial, the Coronary Artery Bypass Graft (CABG)-Patch trial, failed to show a similar superiority in 900 patients with an ejection fraction of ≤35% and an abnormal signal-averaged electrocardiograph undergoing coronary artery bypass grafting. Thus, the role of device therapy for primary prevention of sudden death has not been established. Future prospective studies are needed to clarify this issue.