International Staging System Classification Research Articles

The importance of cytogenetic and molecular aberrations in multiple myeloma

Multiple myeloma (MM) is a heterogeneous clonal malignancy of plasma cells characterized by cytogenetic and molecular abnormalities. Chromosomal abnormalities are present at diagnosis and can evolve during the progression of MM. Metaphase karyotyping and fluorescence in situ hybridization are considered the standard diagnostic procedures performed in clinical practice. These test results are required to determine the Revised International Staging System classification, treatment algorithms, and short- and long-term prognoses. Given the dynamic development of cytogenetic and molecular research, we should expect further progress in better understanding the biology of MM and changes to patient care in the coming years.

The Impact of Socioeconomic Risk Factors on the Survival Outcomes of Patients With Newly Diagnosed Multiple Myeloma: A Cross-analysis of a Population-based Registry and a Tertiary Care Center

BackgroundMultiple myeloma (MM) is a heterogeneous clonal plasma cell disorder leading to differences in clinical outcomes such as overall survival (OS) among patients. We hypothesized that with expensive, novel therapeutic agents and paradigm shifts to maintain continuous therapy and improvement in OS, patients with MM are subject to the pressures of financial toxicity and the need for social support, which may be of prognostic importance. Materials and MethodsIn this study, we examined the records of 122,458 patients from the National Cancer Database (NCDB) to determine the significance of socioeconomic factors such as estimated annual household income and education level, which were based on the patient’s ZIP Code and the United States Census Bureau’s 5-year report from 2008 to 2012. These socioeconomic factors, in addition to marital status, were then assessed individually and as a cumulative socioeconomic score for prognostic significance in a cohort of 2543 patients treated at a tertiary care center utilizing known biologic risk factors, such as cytogenetic risk, International Staging System classification, and serum lactate dehydrogenase levels. ResultsOnly marital status and estimated annual household income at diagnosis negatively impacted OS in a univariate analysis, but not in the context of a multivariable analysis incorporating known biologic risk factors. ConclusionFuture analyses in other academic and non-academic centers located in urban and rural regions are required to understand the socioeconomic drivers of OS disparity among patients with MM observed nationally.

Combination of Genetic Aberration With International Staging System Classification for Stratification of Asian Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

The aim of the study was to contribute to the development of adaptive risk stratification methods specific to Asian multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). We conducted this study to evaluate the prognostic impact of genetic abnormalities detected by fluorescent in situ hybridization (FISH) on survival outcomes in combination with the International Staging System (ISS) classification in 161 MM patients. This was a single-center retrospective longitudinal cohort study of newly diagnosed MM patients undergoing ASCT within 12 months from initial diagnosis. A single-center retrospective cohort study of newly diagnosed MM. Patients were divided into 3 groups according to risk stratification: 1) low-risk, patients without del(17p13) nor t(14;16) or t(4;14) and ISS I/II; 2) high-risk, patients with t(4;14), regardless of ISS stage; 3) intermediate-risk, all remaining patients. The median PFS for the low-risk group was 18 months versus 13 months for the intermediate group (p=0.047, HR=1.527, 95%CI=1.006-2.316) versus 10 months for the high-risk group (p<0.001, HR=2.656, 95%CI=1.572-4.490). An ISS/FISH-based prognostication strategy was developed that can predict PFS for Asian MM patients undergoing ASCT.

Successful Management of Transplant-Ineligible Patients with Refractory/Relapsed Multiple Myeloma By Using a Biweekly or Longer Modified Bortezomib Schedule As Interval Maintenance therapy

Background: Substantial efficacy has been demonstrated with bortezomib (Bor)-containing regimens for the treatment of refractory/relapsed (RR) patients with transplant-ineligible (TI) multiple myeloma (MM). However, the dosing schedules for induction therapy and the significance of maintenance therapy using Bor in clinical settings have yet to be standardized. Discontinuations and dose reduction of Bor owing to severe adverse events (AEs) such as peripheral neuropathy (PN) and infection are frequent causes of adjustments to the standard 9 cycles of Bor/dexamethasone (BD) therapy used for induction in clinical practice. We have previously demonstrated that a change in Bor administration to a schedule of weekly or longer intervals had similar or greater efficacy for patients with RR-MM including transplant-eligible (Tokuhira M, et al. Leuk Res. 35:591-7, 2011). To investigate the efficacy of this modified Bor dosing schedule in the treatment focusing of TI-RR-MM, we retrospectively analyzed 22 patients receiving weekly-BD induction followed by a modified schedule of biweekly or longer intervals using Bor as maintenance therapy in a single institution.Methods: Data on the 22 TI-RR-MM patients treated with BD therapy in our institution were retrospectively analyzed. The induction therapy consisted of intravenous injections of Bor (1.3 mg/m2) on days 1, 8, 15, and 22 in combination with dexamethasone (10–20 mg) on days 1 and 2 after Bor infusion, every 5 weeks. After BD induction, Bor maintenance was initiated with a schedule of biweekly or longer intervals. The dose of BD could be reduced based on AEs or other social aspects at the discretion of the treating physician. Overall survival (OS) was defined as the period between BD initiation of treatment to the last follow-up.Results: The median age of patients at the time of BD induction was 72.6 years (range, 49–84 years), and the subtypes of MM were the IgG type in 14 patients, IgA type in 6 patients, and BJP in 2 patients. Twelve patients were men and 10 were women. On the basis of the International Staging System classification, the clinical stage was I in 3 patients, II in 16 patients, and III in 3 patients. The median number of prior treatment regimens was 2.0 (range, 1–6). The median follow-up duration was 4.3 years (inter-quartile range, 3.0–7.8 years). Ten patients were alive, and 12 patients had died at the time of reporting. The median duration from the start of the first line treatment to BD initiation was 1.8 years (range, 0.1–14.8 years). The median number of BD induction cycles was 2.0 (range, 1–6), and 8 patients (36%) achieved a partial response (PR), although the other 14 patients (64%) showed stable disease or only a minimal response. Although AEs such as PN and gastrointestinal tract symptoms developed in 10 of 22 patients during BD induction, all 22 patients could move on to the maintenance phase. The median duration of Bor maintenance was 14.5 months (range, 1.8–76.5 months). Three patients were still receiving maintenance therapy at the time of reporting. Six patients (27.2%) received maintenance therapy for over 2 years, and 3 (13.6%) received it for over 4 years. The median OS was 3.6 years (range, 0.4–6.5 years), and the duration of Bor therapy from induction to the last administration was 2.5 years. The median progression free survival was 1.6 years (range, 0.3–6.5 years). During maintenance therapy, 5 patients achieved a PR. The reasons for cessation of Bor maintenance therapy were AEs in 8 patients and progressive disease in 11 patients. No patient died during Bor administration in this study.Discussion: We retrospectively analyzed 22 TI-RR-MM patients receiving modified BD therapy. Pantani L et al. reported the results of using BD therapy for 85 RR-MM patients, and demonstrated that twice-weekly Bor administration resulted in a clinical response rate of 19% and a median OS of 22 months (Ann Hematol, 2014). Although the clinical response rate in our study was inferior to that of Pantani L et al., the median OS in our study was superior (3.6 years) than those of previous reports. Because the majority of patients in this study were frail or elderly, the early decision to change to maintenance therapy before they developed severe AEs resulted in a good clinical outcome and a longer OS. Continuing BD therapy without a satisfactory molecular response might be an attractive therapeutic approach for TI-RR-MM patients. DisclosuresNo relevant conflicts of interest to declare.

International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols

Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies. The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens. Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low-risk myeloma, whereas the grave prognosis of high-risk disease was International Staging System-independent. After adjusting for gene expression profiling-defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low-risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2. In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk-based treatment assignment.

Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation

Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization, which overcomes the problem of the lack of dividing cells required for conventional cytogenetics. We analyzed the prognostic value of 12 frequent chromosomal abnormalities detected by fluorescent in situ hybridization in a series of patients (n=315) with newly diagnosed, symptomatic multiple myeloma. All patients underwent frontline autologous stem cell transplantation according to the GMMG-HD3- or GMMG-HD4-trial protocols or analogous protocols. Univariate statistical analyses revealed that the presence of del(13q14), del(17p13), t(4;14), +1q21 and non-hyperdiploidy was associated with adverse progression-free and overall survival rates independently of the International Staging System (ISS) classification. Multivariate analyses showed that only t(4;14) and del(17p13) retained prognostic value for both progression-free and overall survival. According to the presence or absence of t(4;14) and del(17p13) and the patients' International Staging System classification, the cohort could be stratified into three distinct groups: a group with a favorable prognosis [absence of t(4;14)/del(17p13) and ISS I], a group with a poor prognosis [presence of t(4;14)/del(17p13) and ISS II/III] and a group with an intermediate prognosis (all remaining patients). The probabilities of overall survival at 5 years decreased from 72% in the favorable prognostic group to 62% (hazard ratio 2.4; P=0.01) in the intermediate and 41% (hazard ratio 5.6; P<0.001) in the poor prognostic groups. These results have implications for risk-adapted management for patients with multiple myeloma undergoing high-dose chemotherapy followed by autologous stem cell transplantation and suggest that new treatment concepts are urgently needed for patients who belong to the poor prognosis group. As targeted therapies evolve, different treatment options might have variable success, depending on the underlying genetic nature of the clone.

Mieloma múltiplo: características clínicas e laboratoriais ao diagnóstico e estudo prognóstico

O mieloma multiplo (MM) caracteriza-se por expansao clonal plasmocitaria na medula ossea e producao de imunoglobulina monoclonal, promovendo progressivamente destruicao ossea, falencia renal, supressao da hematopoietica e infeccoes. A identificacao de fatores clinicos e laboratoriais ao diagnostico e importante para predizer sobrevida. O sistema de estadiamento de Durie e Salmon (1975) e o mais utilizado e baseia-se na correlacao entre parâmetros clinico-laboratoriais a massa tumoral. A combinacao de β2 microglobulina e albumina serica resultou em um sistema de estadiamento simples e confiavel, conhecido como Sistema Internacional de Estadiamento (ISS), que tem sido reconhecido atualmente. O objetivo deste trabalho foi analisar as caracteristicas clinicas e laboratoriais, ao diagnostico, de pacientes portadores de MM e estudo de sobrevida. Realizou-se estudo de coorte nao concorrente de 101 pacientes portadores de MM atendidos no Servico de Hematologia do Hospital das Clinicas da UFMG, que receberam diagnostico no periodo de abril de 1994 a 31 de outubro de 2006, atraves da coleta de dados contidos em prontuarios medicos. Os pacientes foram acompanhados ate maio de 2007. Foi feita analise descritiva das caracteristicas ao diagnostico e estudo de sobrevida, utilizando-se analise univariada pela tecnica do produto-limite de Kaplan & Meier e teste de Log-Rank para comparacao das curvas; ja na analise multivariada, utilizou-se regressao multipla de Cox. A mediana de idade dos pacientes foi de 63 anos de idade, 47,5% eram homens e 52,5% mulheres, sendo 50,6% brancos, 33,3% negros e 16,1% pardos. Manifestacoes clinicas mais comuns foram: dor ossea (83,2%), fraqueza (70,3%) e perda de peso (40,6%). Radiografia de esqueleto mostrou alteracoes em 83,8% dos casos. Em relacao ao sistema de estadiamento proposto por Durie & Salmon, 63 (62,4%) pacientes encontravam-se em estadio III, 32 (31,7%) em estadio II e apenas 6 (5,9%) no estadio I ao diagnostico. Utilizando a classificacao do Sistema Internacional de Estadiamento (ISS) obtiveram-se 22 (30,1%) pacientes no estadio III, 31 (42,5%) no estadio II e 20 (27,4%) no estadio I ao diagnostico. Sobrevida global media foi de 66,52 meses, com mediana de seguimento de 20 meses. Na analise univariada foram significantes: creatinina (p=0,006), hemoglobina (p=0,001), estadiamento de Durie & Salmon (p=0,009) e ISS (p=0,014); e na multivariada somente a hemoglobina (p=0,012) correlacionou-se a sobrevida. A maior parte dos pacientes apresentava estadio clinico avancado ao diagnostico com repercussao na sobrevida.

Immunoglobulin isotypes in multiple myeloma: laboratory correlates and prognostic implications in total therapy protocols

Immunoglobulin isotypes in multiple myeloma: laboratory correlates and prognostic implications in total therapy protocols

Survival is better predicted with a new classification of stage III unresectable non-small cell lung carcinoma treated by chemotherapy and radiotherapy

The 1997 International staging system (ISS) classification separated stage III non-small cell lung cancer (NSCLC) into stages IIIA and IIIB. In a previous study including unresectable NSCLC initially treated with chemotherapy, we analysed survival according to tumour (T) and node (N) stages and derived a classification into stages IIIβ (T3-4N3) and IIIα (other TN stage III) that had a better discrimination on survival distribution. The aim of this study was to validate these results in a further set of patients. Patients with unresectable stage III NSCLC included in a phase III trial assessing the role of increased dose chemotherapy (SuperMIP: mitomycin 6 mg/m 2, ifosfamide 4.5 g/m 2, cisplatin 60 mg/m 2, carboplatin 200 mg/m 2) in comparison to standard chemotherapy MIP (mitomycin 6 mg/m 2, ifosfamide 3 g/m 2, cisplatin 50 mg/m 2), before thoracic irradiation (60 Gy in 30 fractions over 6 weeks) were the subject of this study. Survival distributions were assessed by the method of Kaplan–Meier. Survival comparisons were made by the log-rank test. Multivariate analyses using Cox regression models, included all potential prognostic factors for survival with a P-value <0.2 in univariate analysis. According to the 1997 International staging system classification, 328 eligible patients were included in the study. There was no imbalance between the two arms. Five parameters were significantly associated ( P≤0.05) with survival in univariate analysis: European lung cancer working party (ELCWP) staging (IIIα[ n=294 pts] versus IIIβ [ n=46]), Karnofsky index, weight loss, platelet count and haemoglobin level. These variables as well as the 1997 ISS staging, white blood cell (WBC) count, LDH and sodium levels were included in a multivariate analysis. Two models were constructed, including either the ELCWP or the 1997 ISS. In model 1 (ISS included), Karnofsky index (HR 0.69; 95% confidence interval (CI) 0.47–1.00; P=0.05) and haemoglobin (HR 1.49; 95% CI 1.11–1.99; P=0.007) were found significant. In model 2, including ELCWP staging, two variables were associated with survival: ELCWP staging (HR 1.68; 95% CI 1.20–2.35; P=0.002) and haemoglobin (HR 1.54; 95% CI 1.15–2.07; P=0.01). Conclusion: In initially unresectable stage III NSCLC treated by chemotherapy and radiotherapy, we validated the results of our previous study. The classification into stages IIIβ (T3-4N3M0) and IIIα (other TN stage III) better discriminates the patients in term of survival than the 1997 ISS classification.

P53 and bcl-2 protein expression in non-small-cell lung carcinoma.

The diagnostic significance of p53 and bcl-2 proteins in epithelial non-small-cell lung cancers was examined, and the relationship between these proteins expression and other disease parameters, including stage of the disease and tumor differentiation, were studied. We analyzed p53 and bcl-2 proteins expression in 60 imprint smears of freshly resected lung tumors (37 squamous and 23 adenocarcinomas) using the immunocytochemical technique. There were seven patients with stage I disease, 24 with stage II, 23 with stage IIIa, and six with stage IIIb disease, according to the International Staging System classification. Sixteen of the tumors were bcl-2 positive and 25 were p53 positive. Twenty tumors were negative for both bcl-2 and p53 (33.3%). Statistical analysis showed no association between the incidence of p53 or bcl-2 positivity. Adenocarcinoma or squamous carcinoma analysis showed significant associations between p53 positivity and poor differentiation and advanced disease stage as well as bcl-2 and early disease stage and well-differentiated tumors. There was also an association between the stage of the disease and the degree of differentiation of the tumors. In conclusion, bcl-2 positivity must be considered a good prognostic sign. On the other hand, p53 positivity seems to indicate, even in tumors at a relatively early stage, that a serious aggressive tumor which will not be easily eradicated is present.