Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC) from a phase III randomized trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4644-4644 ◽  
Author(s):  
Guru Sonpavde ◽  
Gregory Russell Pond ◽  
Stephen John Clarke ◽  
Janette L. Vardy ◽  
S. L. Wang ◽  
...  
Keyword(s):  
Prognostic Model ◽  
Risk Model ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Castration Resistant Prostate Cancer ◽  
Phase Iii Trial ◽  
Neutrophil Lymphocyte Ratio ◽  
Potential Marker ◽  
The Impact

4644 Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score was calculated and patients were categorized into risk groups to assess model performance. Results: Data from patients without missing data (n=806) were used to construct an optimal model. The factors used in the model that remained individually significant in multivariate analysis were: log-LDH (HR 2.77 [95% CI=2.23, 3.44], p<0.001), hemoglobin (0.81 [0.76, 0.87], p<0.001), log-NLR (1.63 [1.38, 1.92], p<0.001), >1 organ involved (1.53 [1.24, 1.88], p<0.001), log-alkaline phosphatase (1.14 [1.01, 1.30], p=0.041) and log-PSA (1.07 [1.00, 1.13], p=0.036). No clear cutpoints were identified; thus, these prognostic factors were used to group patients into 3 equally sized risk categories. Low, medium and high risk patients (n=268-270 per group) had median (95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model with readily available variables significantly discriminated between outcomes in post-docetaxel mCRPC and may provide valuable information in future studies. High NLR was associated with an independent poor prognostic impact, and warrants prospective validation.

scholarly journals Updated Prognostic Model for Predicting Overall Survival in First-Line Chemotherapy for Patients With Metastatic Castration-Resistant Prostate Cancer

2014 ◽  
Vol 32 (7) ◽  
pp. 671-677 ◽  
Author(s):  
Susan Halabi ◽  
Chen-Yen Lin ◽  
W. Kevin Kelly ◽  
Karim S. Fizazi ◽  
Judd W. Moul ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Model ◽  
Risk Groups ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Phase Iii Trial ◽  
Castration Resistant ◽  
Validation Set ◽  
Line Chemotherapy

Purpose Prognostic models for overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) are dated and do not reflect significant advances in treatment options available for these patients. This work developed and validated an updated prognostic model to predict OS in patients receiving first-line chemotherapy. Methods Data from a phase III trial of 1,050 patients with mCRPC were used (Cancer and Leukemia Group B CALGB-90401 [Alliance]). The data were randomly split into training and testing sets. A separate phase III trial served as an independent validation set. Adaptive least absolute shrinkage and selection operator selected eight factors prognostic for OS. A predictive score was computed from the regression coefficients and used to classify patients into low- and high-risk groups. The model was assessed for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The model included Eastern Cooperative Oncology Group performance status, disease site, lactate dehydrogenase, opioid analgesic use, albumin, hemoglobin, prostate-specific antigen, and alkaline phosphatase. Median OS values in the high- and low-risk groups, respectively, in the testing set were 17 and 30 months (hazard ratio [HR], 2.2; P < .001); in the validation set they were 14 and 26 months (HR, 2.9; P < .001). The tAUCs were 0.73 (95% CI, 0.70 to 0.73) and 0.76 (95% CI, 0.72 to 0.76) in the testing and validation sets, respectively. Conclusion An updated prognostic model for OS in patients with mCRPC receiving first-line chemotherapy was developed and validated on an external set. This model can be used to predict OS, as well as to better select patients to participate in trials on the basis of their prognosis.

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4142-4142
Author(s):  
Lucy Xiaolu Ma ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Disease ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
First Line ◽  
Kras Mutations ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Translational Research Program ◽  
The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

Overall survival (OS) and metastasis-free survival (MFS) by depth of prostate-specific antigen (PSA) decline in the phase III PROSPER trial of men with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with enzalutamide (ENZA).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 94-94
Author(s):  
Maha H. A. Hussain ◽  
Cora N. Sternberg ◽  
Eleni Efstathiou ◽  
Karim Fizazi ◽  
Qi Shen ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Reference Group ◽  
Specific Antigen ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Analysis Model ◽  
Increased Risk ◽  
Psa Nadir ◽  
Post Hoc

94 Background: The PROSPER trial demonstrated prolonged MFS and OS for men with nmCRPC and rapidly rising PSA treated with ENZA vs placebo, both in combination with androgen deprivation therapy (ADT). The final survival analysis of PROSPER (Sternberg et al. NEJM 2020) recently reported a median OS of 67.0 months (95% CI, 64.0 to not reached) with ENZA and 56.3 months (95% CI, 54.4 to 63.0) with placebo (hazard ratio [HR] for death, 0.73; 95% CI, 0.61 to 0.89; P = .001). Post hoc analyses of PROSPER evaluating PSA dynamics have demonstrated longer MFS with greater PSA decline (Hussain et al. ESMO Sept 19-21, 2020. Poster 685P) and increased risk of metastases in patients with even modest PSA progression vs those without (Saad et al. Eur Urol 2020). Here we further explored the relationship between PSA dynamics and outcomes in PROSPER using uniquely defined PSA subgroups of decline. Methods: Eligible men in PROSPER had nmCRPC, a PSA level ≥ 2 ng/mL at baseline, and a PSA doubling time ≤ 10 months. Men continued ADT, were randomized 2:1 to ENZA 160 mg once daily vs placebo, and had PSA evaluation at week 17 and every 16 weeks thereafter. This post hoc analysis evaluated OS and MFS for 4 mutually exclusive subgroups defined by PSA nadir using men with PSA reduction < 50% as the reference group. The HR is based on an unstratified Cox proportional hazards analysis model. Results: 1401 men were enrolled in PROSPER; 933 were treated with ENZA and PSA data were available for 905. Measured at nadir, 38% of these men achieved PSA reduction ≥ 90% (actual nadir < 0.2 ng/mL), and another 27% achieved PSA reduction ≥ 90% (actual nadir ≥ 0.2 ng/mL). Among men in the placebo arm of PROSPER only 3/457 reported PSA reduction ≥ 90%. Median OS and MFS increased with increasing depth of PSA decline (Table). Conclusions: In men with nmCRPC and rapidly rising PSA treated with ADT plus ENZA, there was a close relationship between the degree of PSA decline and survival outcomes. Defining PSA by both percent decline and actual decline below 0.2 ng/mL revealed a previously under-appreciated relationship between these PSA metrics and highlights the importance of PSA nadir as an intermediate biomarker in nmCRPC. Clinical trial information: NCT02003924. [Table: see text]

scholarly journals The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial

1998 ◽  
Vol 9 (5) ◽  
pp. 535-541 ◽  
Author(s):  
M.M. Borner ◽  
M. Castiglione ◽  
M. Bacchi ◽  
W. Weber ◽  
R. Herrmann ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Low Dose ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Advanced Colorectal Carcinoma ◽  
The Impact

Impact of Different Chemotherapy Regimen in Comorbid Patients with Advanced Chronic Lymphocytic Leukemia: Metaanalysis of Two Phase-III-Trials of the German CLL Study Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2840-2840 ◽  
Author(s):  
Paula Cramer ◽  
Valentin Goede ◽  
Petra Jenke ◽  
Raymonde Busch ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chemotherapy Regimen ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Concomitant Disease ◽  
Two Phase ◽  
Phase Iii Trials ◽  
The Impact ◽  
Dose Reductions

Abstract Introduction: Since chronic lymphocytic leukemia (CLL) is a disease of elderly patients (pts) comorbidity is a frequent feature which has already been shown to be associated with survival-shortening in lymphoma patients. It has been hypothesized that intensity of chemotherapy may interfere with treatment outcome, but the precise mechanisms underlying the impact of comorbidity are still not understood. Consequently, comorbitity currently keeps away oncologists from administering intense combined (immuno−)chemotherapy to pts with CLL and concomitant diseases. Patients & methods: 554 pts treated in two different phase-III-trials of the GCLLSG were eligible for this analysis: 362 pts (65%) younger than 65 years were treated on the CLL4-protocol with Fludarabine (F) or Fludarabine-Cyclophosphamide (FC) and 192 pts (35%) aged 65 years and older on the CLL5-protocol with F or Chlorambucile (Clb). The mean age for all pts was 61 years; 68% of the pts were male. Results: Comorbidity was present in 53% of the pts, 25% had at least two comorbidities. The most common comorbidities were: hypertension (19%), lipometabolic disorders (16%), diabetes mellitus (10%) and coronary heart disease (7%). Progression free survival (PFS) and overall survival (OS) were significantly shorter in comorbid pts (median OS: 43,5 vs. 51,6 months, p=0,01; median PFS: 20,3 vs. 23,5 months, p=0,03). Survival was also impaired if pts had a higher number of comorbidities (PFS & OS: p=0,0001) or more severe concomitant diseases (PFS: p=0,007, OS: p=0,0000). Whereas this impact of comorbidity on OS was not significant in the FC- and Clb-arm, comorbid pts treated with F had a significantly shorter survival (median OS: 38,29 vs. 51,58 months, p=0,0452). Notably only the younger F-treated comorbid pts were affected by this disadvantage (CLL4: p=0,0221). Although myelotoxicity, infections and all grade III–IV adverse effects were not influenced by comorbidity, pts with concomitant disease had a higher rate of treatment terminations (38% vs. 25%, p=0,002). The higher percentage of dose reductions and treatment terminations for comorbid pts were only significant in the subgroup of F-treated pts (dose reduction: 31% vs. 19,1%, p=0,029; treatment termination in the younger CLL4-pts: 28,2% vs. 18,0%, p=0,023). Administration of more intense chemotherapy-regimen improved the survival of pts with concomitant disease (median OS: FC: not reached, F: 38,29 and Clb: 33,72 months, p=0,0248; median PFS: FC: not reached, F: 18,8 and Clb: 14,1 months, p=0,0000). A multivariate analysis on the prognostic impact of comorbidity and different chemotherapy regimen will be presented. Conclusions: Due to the here presented results the wide impact of comorbidity in CLL pts is apparent. It should be considered when it comes to treatment decisions eventhough this population was selected due to the strict criteria of the clinical trial. The mechanism of survival shortening in comorbid pts with CLL is not yet understood, but seems to be related with dose reductions and treatment terminations. Additional harm to these pts by an insufficient treatment and a poor control of the CLL ought to be avoided. As more intense chemotherapy-regimen, like FC are feasible for pts with comorbidity, more trials surveying these therapies in pts with more severe concomitant disease are needed.

Sign in / Sign up

Export Citation Format

Share Document