27 Can Sarcopenia be Used to Estimate Outcomes in Elderly Patients Treated with Chemoradiotherapy for Bladder Cancer?

2021 ◽  
Vol 50 (Supplement_1) ◽  
pp. i7-i11
Author(s):  
M Corden
Keyword(s):  
Skeletal Muscle ◽  
Bladder Cancer ◽  
Proportional Hazards Model ◽  
Performance Status ◽  
Survival Function ◽  
Age Distribution ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
International Consensus ◽  
Skeletal Muscle Index

Abstract Introduction Ageing is a risk factor for bladder cancer, with a median age at diagnosis of 71 years. In addition, sarcopenia shows promise as a prognostic biomarker for bladder cancer. This study evaluates sarcopenia as a predictor of overall survival (OS) for older patients treated with chemoradiotherapy for bladder cancer. Methods 185 bladder cancer patients treated (from 2010–2017) with chemoradiotherapy were available for analysis. Pre-therapeutic computed tomography scans were identified and single slices at the L3 level were identified. Machine learning software was used to segment skeletal muscle and obtain its cross-sectional area. This was normalised against height squared to calculate a skeletal muscle index for each patient. Sarcopenia was defined using international consensus definitions (<39 cm2/m2 in females and < 55 cm2/m2 in males). Differences in survival function between patients ≤75 and > 75 years were visualised using Kaplan–Meier curves. Age distribution between sarcopenic and non-sarcopenic patients was also explored. Finally, a multivariable Cox proportional hazards model was conducted to investigate interactions between sarcopenia and increased age with respect to OS. Results Of 185 patients, 114 (61.6%) were sarcopenic and 71 (38.4%) were non-sarcopenic; 101 (54.6%) and 84 (45.4%) patients were ≤ 75 and > 75 years old respectively. No differences in OS were observed between the two age groups (p = 0.50). There was no interaction between sarcopenia and age as a continuous variable was observed with respect to OS (p = 0.682); however, when age was categorised an interaction was seen (p = 0.058). Nevertheless, after adjusting for performance status, T-stage, hydronephrosis, albumin, haemoglobin, neutrophil and lymphocyte counts, the interactions between age and sarcopenia were no longer observed (age continuous, p = 0.474; age categorized, p = 0.765). Conclusions Patients with bladder cancer over 75 years of age have a modest increase in probability of developing sarcopenia but this does not impact on OS.

scholarly journals Rapid Depletion of Subcutaneous Adipose Tissue during Sorafenib Treatment Predicts Poor Survival in Patients with Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1795
Author(s):  
Kenji Imai ◽  
Koji Takai ◽  
Takao Miwa ◽  
Daisuke Taguchi ◽  
Tatsunori Hanai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Sorafenib Treatment ◽  
Skeletal Muscle Index ◽  
Subcutaneous Adipose

The aim of this study was to assess the annualized changes in body composition, including skeletal muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) before, during, and after sorafenib treatment in patients with hepatocellular carcinoma (HCC). This retrospective study evaluated 61 HCC patients treated with sorafenib. Annualized changes (Δ; cm2/m2/year) in skeletal muscle index (SMI), SAT index (SATI), and VAT index (VATI), which were defined as the cross-sectional areas (cm2) of those areas on computed tomography normalized by the square of one’s height (m2), before (pre), during (during), and after (post) sorafenib treatment, were calculated. Patients within the 20th percentile cutoffs for these indices were classified into the rapid depletion group and the effects of these values on survival were analyzed using the Kaplan-Meier analysis and Cox proportional-hazards model. Annualized depletion rates of SMI (ΔSMIpre: −3.5, ΔSMIduring: −3.5, ΔSMIpost: −8.0) and VATI (ΔVATIpre: −3.2, ΔVATIduring: −2.8, ΔVATIpost: −15.1) accelerated after the cancellation of sorafenib, whereas that of SATI (ΔSATIpre: −4.8, ΔSATIduring; −7.6, ΔSATIpost; −8.0) had already accelerated during sorafenib treatment. Patients with rapid depletion of ΔSATIduring experienced significantly worse survival rates (p < 0.001), and it was an independent predictor of survival (p = 0.009), together with therapeutic effect (p < 0.001). Rapid depletion of SAT during sorafenib treatment can be used to predict survival in patients with HCC.

Polymorphisms in Inflammation Genes and Bladder Cancer: From Initiation to Recurrence, Progression, and Survival

2005 ◽  
Vol 23 (24) ◽  
pp. 5746-5756 ◽  
Author(s):  
Dan Leibovici ◽  
H. Barton Grossman ◽  
Colin P. Dinney ◽  
Randal E. Millikan ◽  
Seth Lerner ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Clinical Outcome ◽  
Proportional Hazards Model ◽  
Smoking Status ◽  
Recurrence Risk ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Peroxisome Proliferator ◽  
Necrosis Factor Alpha ◽  
Muscle Invasive

Purpose Since chronic inflammation contributes to tumorigenesis, we hypothesized that the risk and clinical outcome of bladder cancer (BC) might be modulated by genetic variations in inflammation genes. Methods Using the TaqMan method, we genotyped single nucleotide polymorphisms in interleukin (IL) -6 (−174 G→C), IL-8 (−251 T→A), tumor necrosis factor-alpha (TNF-α; −308 G→A), and peroxisome proliferator-activated receptor γ (PPARG; Pro12Ala), and determined their associations with BC initiation and clinical outcome. Results We found that the IL-6 variant genotype (C/C) was associated with an increased BC risk (OR, 1.77; 95% CI, 1.25 to 2.51). There were joint effects between the variant IL-6 genotypes and smoking status, and between the variant genotypes of IL-6 and other genes. To assess effect on recurrence, we grouped non-muscle-invasive BC patients according to intravesical Bacillus Calmette-Guerin (BCG) treatment status: no BCG, induction BCG (iBCG), and maintenance BCG (mBCG). In the Cox proportional hazards model, the variant IL-6 genotype was associated with an increased recurrence risk (hazard ratio [HR], 4.60; 95% CI, 1.24 to 17.09) in patients receiving mBCG. The variant PPARG genotype was associated with a reduced recurrence risk (HR, 0.41; 95% CI, 0.20 to 0.86) among untreated patients. In patients with non-muscle-invasive BC, the variant IL-6 genotype was associated with an increased progression risk (HR, 1.88; 95% CI, 0.80 to 4.11). In patients with invasive BC, variant IL-6 was associated with improved 5-year overall and disease-specific survival (HR, 0.43; 95% CI, 0.19 to 0.94 and HR, 0.39; 95% CI, 0.15 to 1.00, respectively). Conclusion Inflammation gene polymorphisms are associated with modified BC risk, treatment response, and survival.

scholarly journals Prognostic Effect of Preoperative Psoas Muscle Hounsfield Unit at Radical Cystectomy for Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5629
Author(s):  
Yusuke Sugino ◽  
Takeshi Sasaki ◽  
Manabu Kato ◽  
Satoru Masui ◽  
Kouhei Nishikawa ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Univariate Analysis ◽  
Psoas Muscle ◽  
Hounsfield Unit ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Cross Sectional

Radical cystectomy (RC) is the standard treatment for patients with advanced bladder cancer. Since RC is a highly invasive procedure, the surgical indications in an aging society must be carefully judged. In recent years, the concept of “frailty” has been attracting attention as a term used to describe fragility due to aging. We focused on the psoas muscle Hounsfield unit (PMHU) and analyzed its appropriateness as a prognostic factor together with other clinical factors in patients after RC. We retrospectively analyzed the preoperative prognostic factors in 177 patients with bladder cancer who underwent RC between 2008 and 2020. Preoperative non-contrast computed tomography axial image at the third lumbar vertebral level was used to measure the mean Hounsfield unit (HU) and cross-sectional area (mm2) of the psoas muscle. Univariate analysis showed significant differences in age, sex, clinical T stage, and PMHU. In multivariate analysis using the Cox proportional hazards model, age (hazard ratio (HR) = 1.734), sex (HR = 2.116), cT stage (HR = 1.665), and PMHU (HR = 1.758) were significant predictors for overall survival. Furthermore, using these four predictors, it was possible to stratify the prognosis of patients after RC. Finally, PMHU was useful as a simple and significant preoperative factor that correlated with prognosis after RC.

Treatment of metastatic disease with immune checkpoint inhibitors nivolumab and pembrolizumab: Effect of performance status on clinical outcomes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18689-e18689
Author(s):  
Leah Wells ◽  
Michael Cerniglia ◽  
Audrey C. Jost ◽  
Gregory Joseph Britt
Keyword(s):  
Disease Control ◽  
Proportional Hazards Model ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Time To Death ◽  
Significant Difference ◽  
Line Of Therapy

e18689 Background: While guidelines exist for appropriate use of chemotherapy in the metastatic setting based on performance status, such recommendations are less readily available for immune checkpoint inhibitors (ICIs). We sought to determine if there is a relationship between Eastern Cooperative Oncology Group (ECOG) performance status and outcomes on immunotherapy in patients treated for metastatic disease at our community-based oncology practice. Methods: 253 patients were identified as receiving nivolumab or pembrolizumab for stage IV malignancy at Cancer Centers of Colorado-SCL Health, between June 2018 and November 2020. Patients initiated on therapy after May 2020 were excluded from analysis, due to insufficient (less than 6 months) follow-up time. The remaining 183 patients were included in a retrospective cohort study comparing patients with ECOG 0, ECOG 1, and ECOG 2-4. Sex, age, type of cancer, and line of therapy were collected. Time on therapy was also calculated. Best response to therapy was determined (disease control or progressive disease). These baseline factors and outcomes were compared using ANOVA for numeric variables and chi-square tests of association for categorical variables. Time from initiation of ICI to death or hospice was also investigated and compared using a log-rank test. In addition, a multivariate Cox proportional hazards model was developed for the outcome, time to death/hospice, versus the predictors ECOG status, age, gender, and line of therapy. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated. Results: Of the 183 patients included in analysis, 31.7% had an ECOG of 0, 48.6% an ECOG of 1, and 19.7% an ECOG of 2-4. Non-small cell lung cancer and melanoma represented the majority of patients in each group. Gender and line of therapy did not differ between groups. There was a significant difference in age (p = 0.02) with mean age 62, 66, and 70 in ECOG 0,1, and 2-4, respectively. 54.6% of patients remained on therapy for at least 6 months (182 days), and there was no significant difference between groups in ability to complete 6 months of therapy (p = 0.32). For ECOG 0, 1, and 2-4, disease control was achieved in 67.2%, 59.6 %, and 41.7%, respectively (p = 0.048). Analysis of time to death/hospice with a log rank test and Kaplan Meier plot showed a significant difference between groups (p < 0.001). A multivariate Cox proportional hazards model revealed that patients with ECOG 0 had significantly longer time to death/hospice compared to patients in both other groups, after controlling for age, gender, and line of therapy (ECOG 1 vs. 0: HR 2.5, CI 1.27-4.9; ECOG 2-4 vs. 0: HR 2.83, CI 1.31-6.13). Conclusions: In this single institution retrospective study of patients receiving nivolumab or pembrolizumab for metastatic cancer, ECOG 0 was associated with disease control and increased time before death or transition to hospice.

Association of Surgical Resection, Disability, and Survival in Patients with Glioblastoma

2019 ◽  
Vol 80 (04) ◽  
pp. 262-268 ◽  
Author(s):  
Yahya Ahmadipour ◽  
Monika Kaur ◽  
Daniela Pierscianek ◽  
Oliver Gembruch ◽  
Marvin Darkwah Oppong ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Extent Of Resection ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Hazards Model ◽  
Surgical Modality ◽  
Supratotal Resection

Objective Extent of resection (EOR) and Karnofsky Performance Status (KPS) are at odds in glioblastoma (GBM) surgery, that is, the anticipated postoperative disability limits the EOR. This study analyzes the correlation of different surgical modalities with the resulting physical status and survival of patients with GBM. Methods A total of 565 patients with primary GBM were operated on in a single institution between 2006 and 2014. Possible surgical modalities comprised supratotal resection (SLR), gross total resection (GTR; ≥ 95% by volume), tumor debulking (TDB; ≤ 95% by volume), and stereotactic biopsy (SB). Pre- and postoperative KPS before and up to 4 weeks after surgery as well as overall survival (OS) rate were determined retrospectively. Hazard ratio (HR) and 95% confidence intervals were calculated using a Cox proportional hazards model. Results Median postoperative KPS was ≥ 70, irrespective of surgical modality. Mean OS was 12.5 months. Multivariate analysis revealed age ≥ 70 years (HR: 1.93), preoperative KPS < 70 (HR: 2.15), and unmethylation in MGMT promoter (HR: 1.27) as independent factors for worse OS. Regarding surgical modality, SB was associated with the worst survival (HR: 2.3) followed by TDB (HR: 1.36). SLR was inferior to GTR (HR: 1.27). Conclusion Higher EOR in patients with GBM does not seem inevitably correlated with increasing functional impairment, but better survival, provided there is a balanced preoperative indication. Nevertheless, SLR does not seem to be superior to GTR. Whenever possible, maximal safe resection should be considered in patients with GBM, even if an EOR ≥ 95% is not possible.

scholarly journals Preoperative Radiation Therapy Followed by Reexcision May Improve Local Control and Progression-Free Survival in Unplanned Excisions of Soft Tissue Sarcomas of the Extremity and Chest-Wall

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Hina Saeed ◽  
David M. King ◽  
Candice A. Johnstone ◽  
John A. Charlson ◽  
Donald A. Hackbarth ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Proportional Hazards Model ◽  
Performance Status ◽  
Soft Tissue Sarcomas ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Preoperative Radiation ◽  
Free Survival ◽  
Unplanned Excision

Background. The management for unplanned excision (UE) of soft tissue sarcomas (STS) has not been established. In this study, we compare outcomes of UE versus planned excision (PE) and determine an optimal treatment for UE in STS.Methods. From 2000 to 2014 a review was performed on all patients treated with localized STS. Clinical outcomes including local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) were evaluated using the Kaplan-Meier estimate. Univariate (UVA) and multivariate (MVA) analyses were performed to determine prognostic variables. For MVA, Cox proportional hazards model was used.Results. 245 patients were included in the analysis. 14% underwent UE. Median follow-up was 2.8 years. The LR rate was 8.6%. The LR rate in UE was 35% versus 4.2% in PE patients (p<0.0001). 2-year PFS in UE versus PE patients was 4.2 years and 9.3 years, respectively (p=0.08). Preoperative radiation (RT) (p=0.01) and use of any RT for UE (p=0.003) led to improved PFS. On MVA, preoperative RT (p=0.04) and performance status (p=0.01) led to improved PFS.Conclusions. UEs led to decreased LC and PFS versus PE in patients with STS. The use of preoperative RT followed by reexcision improved LC and PFS in patients who had UE of their STS.

scholarly journals Prognostic Nomogram for Patients With Unresectable Pancreatic Cancer Treated With Gemcitabine Plus Nab-paclitaxel or FOLFIRINOX: Real-world Results From a Multicenter Retrospective Study (NAPOLEON study).

2020 ◽  
Author(s):  
Taro Shibuki ◽  
Toshihiko Mizuta ◽  
Mototsugu Shimokawa ◽  
Futa Koga ◽  
Yujiro Ueda ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Risk Stratification ◽  
Proportional Hazards Model ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Calibration Plot ◽  
Unresectable Pancreatic Cancer

Abstract Background No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FFX).Methods This analysis was conducted using clinical data of patients with unresectable pancreatic cancer undergoing GnP or FFX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6-, 12-, and 18-month survival probabilities was generated, validated by using the concordance index (C-index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points; TNP).Results A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19-9. The C-indexes of the nomogram were 0.77, 0.72 and 0.70 for 6-, 12-, and 18-month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the TNP yielded clear separations of the survival curves. The median survival times in the low-, moderate-, and high-risk groups were 15.8, 12.8 and 7.8 months (P<0.05), respectively.Conclusions: Our nomogram is a convenient and inexpensive tool to accurately predict survival in patients with unresectable pancreatic cancer undergoing treatment with GnP or FFX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

scholarly journals Survival of Patients with Hepatocellular Carcinoma in Renal Insufficiency: Prognostic Role of Albumin-Bilirubin Grade

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1130
Author(s):  
Shu-Yein Ho ◽  
Chia-Yang Hsu ◽  
Po-Hong Liu ◽  
Chih-Chieh Ko ◽  
Yi-Hsiang Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Renal Insufficiency ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Performance Status ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Prognostic Role ◽  
The Impact

Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). The prognostic role of albumin-bilirubin (ALBI) grade in this special setting is unclear. We aimed to investigate the role of ALBI grade associated with the impact of RI on HCC. A prospective cohort of 3690 HCC patients between 2002 and 2016 were retrospectively analyzed. The Kaplan–Meier method and multivariate Cox proportional hazards model were used to determine survival and independent prognostic predictors. Of all patients, RI was an independent predictor associated with decreased survival. In multivariate Cox analysis for patients with RI, α-fetoprotein level ≥20 ng/mL, tumor size >3 cm, vascular invasion, distant metastasis, presence of ascites, performance status 1–2, performance status 3–4, and ALBI grade 2 and grade 3 were independent predictors of decreased survival (all p < 0.05). In subgroup analysis of patients with RI undergoing curative and non-curative treatments, the ALBI grade remained a significant prognostic predictor associated with decreased survival (p < 0.001). In summary, HCC patients with RI have decreased survival compared to those without RI. The ALBI grade can discriminate the survival in patients with RI independent of treatment strategy and is a feasible prognostic tool in this special patient population.

Comparison of outcomes with pembrolizumab monotherapy (P) versus combination with chemotherapy (P+C) in advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21579-e21579
Author(s):  
Kartik Sehgal ◽  
Ritu R. Gill ◽  
Poorva Bindal ◽  
Anita Geevarghese Koshy ◽  
Danielle C McDonald ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Nsclc ◽  
Proportional Hazards Model ◽  
Smoking Status ◽  
Performance Status ◽  
Objective Response ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Ecog Performance Status

e21579 Background: P and P+C are standard-of-care (SOC) treatment options for advanced NSCLC. However, they have not yet been directly compared in clinical trials. Methods: We conducted a retrospective cohort study of patients with advanced NSCLC who initiated treatment with SOC P±C at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. All radiographic scans were independently evaluated by a thoracic radiologist using iRECIST. Survival time was defined from the start of P±C. Kaplan-Meier and Cox proportional hazards model were utilized. Results: Of 103 patients with median follow up of 17.7 months, 74 (71.8%) had received P, while 29 (28.2%) had received P+C. In PD-L1 tumor proportion score (TPS) unselected population, there were no significant differences in age, sex, smoking status, driver mutation, tumor mutational burden (TMB), line of therapy, ECOG performance status (PS) or immune-related adverse events (irAE) between P and P+C groups. 71.6% in P vs 13.8% in P+C had PD-L1 TPS ≥50% (p < 0.001). There were no significant differences between the two groups in objective response rate (ORR), disease control rate (DCR), unadjusted progression-free survival (PFS) or unadjusted overall survival (OS) (Table). Multivariable adjustment for confounding factors between P+C vs P revealed no differences in OS [hazard ratio (HR) for death, 1.53, 95% CI 0.55 – 4.25] or PFS [HR for progression/death, 1.75, 95% CI 0.63 – 4.91]. Further stratification into PD-L1 TPS ≥50% and < 50% showed no significant differences between P+C vs. P in adjusted OS [HR for death, TPS < 50%- 1.54 (95% CI 0.59 – 4.03); TPS ≥50%- 0.71 (95% CI 0.11 – 4.52)] or PFS [HR for progression/death, TPS < 50%- 1.58 (95% CI 0.72 – 3.48); TPS ≥50%- 0.64 (95% CI 0.06 – 6.93)]. ECOG PS and development of irAE influenced OS in all groups, while TMB was relevant in PD-L1 ≥50% only. Conclusions: Our study shows no significant differences in outcomes with P vs P+C in advanced NSCLC in a real-world setting, albeit with limitations of single-center design, limited sample size, different line settings and lack of disease burden stratification. Ongoing phase III trials comparing front line P vs P+C will definitively address the long-term clinical benefits -if any- of combining cytotoxic chemotherapy with anti-PD-1 drugs. [Table: see text]

Effects of Azacitidine (AZA) Vs Conventional Care Regimens (CCR) in Elderly (≥75 years) Patients (Pts) with Myelodysplastic Syndromes (MDS) from the AZA-001 Survival Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3629-3629 ◽  
Author(s):  
John F Seymour ◽  
Pierre Fenaux ◽  
Lewis B. Silverman ◽  
Ghulam J Mufti ◽  
Eva Hellström-Lindberg ◽  
...  
Keyword(s):  
Active Treatment ◽  
Subgroup Analysis ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Performance Status ◽  
Treatment Options ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Risk Of Death

Abstract Background. A recent phase III trial (AZA-001) showed AZA is the first treatment to significantly extend overall survival (OS) in higher-risk MDS patients (pts) (Blood2007;110:817). MDS incidence increases with age resulting in limited treatment options, particularly for those ≥75 years of age, given the poor tolerability and ineffectiveness of cytotoxic therapies. This subgroup analysis compared the effects of AZA vs CCR on OS, hematologic improvement (HI), transfusion independence (TI), and tolerability in pts ≥75 yrs of age. Methods. Higher-risk MDS (FAB: RAEB, RAEB-T, CMML and IPSS: Int-2 or High) pts were enrolled. All pts were pre-selected by site investigators – based on age, performance status, and comorbidities – to receive 1 of 3 CCR: best supportive care only (BSC); lowdose ara-C (LDAC), or intensive chemotherapy (IC). Pts were then randomized to AZA (75 mg/m2/d SC × 7d q 28d), or to CCR. Those randomized to AZA received AZA; those randomized to CCR received their pre-selected treatment. Randomization was stratified based on FAB subtype (RAEB and RAEB-T) and IPSS (Int-2 or High). Erythropoiesis stimulating agents were disallowed. OS was assessed using Kaplan-Meier (KM) methods and HI and TI were assessed per IWG 2000. To adjust for baseline imbalances, a Cox proportional hazards model was used, with ECOG status, LDH, number of RBC transfusions, Hgb, and presence or absence of -7/del(7q) at baseline as variables in the final model. Adverse events (AEs) were evaluated using NCI-CTC v. 2.0. Results. Of all enrolled pts (N=358, median age 69 yrs), 87 pts (24%) were ≥75 yrs of age (AZA n=38, CCR n=49 [BSC, n=33; LDAC, n=14; IC, n=2]). The majority of pts randomized to CCR received BSC only, suggesting clinicians are generally reticent to use active treatment in this population. Similar to the overall AZA-001 results, treatment with AZA was associated with prolonged survival in pts ≥75 yrs of age, with KM median OS in the AZA group not reached at 17.7 months of follow-up, vs KM median OS for CCR at 10.8 months (HR: 0.48 [95%CI: 0.26, 0.89]; p=0.0193). In these pts, OS rates at 2 years were significantly higher in the AZA group vs CCR: 55% vs 15% (p=0.0003). Two-fold more RBC transfusion-dependent pts at baseline in the AZA group achieved TI vs CCR: 10/23 (44%) vs 7/32 (22%), p=0.1386, respectively. Similarly, more pts in the AZA group achieved HI (major + minor) vs CCR: 58% vs 39%, (p=0.0875), respectively. As previously reported, AZA was generally well tolerated. Anemia, neutropenia, and thrombocytopenia were seen in 42%, 66%, and 71% of pts in the AZA group, respectively, vs 47%, 26%, and 40% in the CCR group, who were predominately receiving BSC only. Infections were reported by 79% and 60% of AZA and CCR pts, respectively. Discontinuations due to an AE occurred in 13% of AZA and 8% of CCR pts ≥75 yrs of age. Conclusion. Data from this subgroup analysis indicate pts ≥75 yrs of age with higher-risk MDS receiving active treatment with AZA experience significantly prolonged 2-year OS and reduced risk of death. AZA is generally well tolerated in this elderly patient population.

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