Prognostic Score For Overall Survival Research Articles

Preoperative MRI-based multiparametric model for survival prediction in hepatocellular carcinoma patients with portal vein tumor thrombus following hepatectomy

PurposeTo develop a predictive model integrating clinical and MRI features for postoperative survival in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). MethodBetween January 2008 and May 2021, consecutive HCC patients with PVTT who underwent preoperative contrast-enhanced MRI and surgical resection at a tertiary hospital were retrospectively enrolled. The MR images were independently reviewed by two blinded radiologists. Univariate and multivariate Cox regression analyses were performed to construct a prognostic score for overall survival (OS). ResultsNinety-four patients were included (mean age, 50.1 years; 84 men). During a median follow-up period of 15.3 months, 72 (76.6%) patients died (median OS, 15.4 months; median disease-free survival [DFS], 4.6 months). The sum size of the two largest tumors (hazard ratio [HR], 3.050; p < 0.001) and tumor growth subtype (HR, 1.928; p = 0.006) on MRI, serum albumin (HR, 0.948; p = 0.02), and age (HR, 0.978; p = 0.04) were associated with OS and incorporated in the prognostic score. Accordingly, patients were stratified into a high-risk or low-risk group, and the OS in the high-risk group was shorter than that in the low-risk group for the entire cohort (11.7 vs. 25.0 months, p < 0.001) and for patients with Cheng’s type I (12.1 vs. 25.9 months, p = 0.002) and type II PVTT (11.7 vs. 25.0 months, p = 0.004). The DFS in the high-risk group was shorter than that in the low-risk group for the entire cohort (4.5 vs. 6.1 months, p = 0.001). ConclusionsBased on the sum size of the two largest tumors, tumor growth subtype, albumin, and age, the prognostic score allowed accurate preoperative risk stratification in HCC patients with PVTT, independent of Cheng’s PVTT classification.

Distant Metastasis Velocity as a Novel Prognostic Score for Overall Survival After Disease Progression Following Stereotactic Body Radiation Therapy for Oligometastatic Disease

In patients with extracranial oligometastatic disease, distant failure (DF) after local ablative therapies is common. Prognostic scores to guide salvage treatment decision making are currently lacking. Analogous to brain metastasis velocity, we propose distant metastasis velocity (DMV) as a prognostic score for overall survival (OS) and widespread failure-free survival (WFFS) after DF following metastasis-directed stereotactic body radiation therapy (SBRT). Patients with ≤5 metastases from solid organ malignancies treated with SBRT to all lesions at our institution from 2014 to 2019 were screened, and patients who developed DF were included in this retrospective analysis. DMV was defined as metastases per month, determined at DF, and transformed into a 3-level categorical variable with cut points that minimized the log-rank P value for OS. Simple and multiple linear regression was used to predict DMV based on different patient and treatment variables. The association of DMV and other variables with OS was studied by univariable and multivariable Cox regression. Three hundred eighty-five patients were screened, of which 303 developed DF and were included. The median DMV was 0.7 metastases per month. Patients with <0.5, 0.5 to 1.5, and >1.5 metastases per month were classified as low, intermediate, and high DMV, and had a median OS of 37.1, 26.7, and 16.8 months, respectively (P < .0001). On multivariable analysis, DMV was a strong independent predictor of OS, with a hazard ratio of 0.31 for low (P < .001) compared with high DMV. Lower DMV was significantly associated with longer WFFS (P=.04). The cumulative metastases volume at baseline (regression coefficient β=0.03, P=.04) and oligoprogressive/-persistent disease (β=1.91, P=.10) predicted higher DMV. DMV is a novel metric strongly associated with OS and WFFS after DF following SBRT in patients with oligometastatic disease and should be evaluated for decision making about the optimal multimodality salvage treatment strategy. The prognostic value of DMV should be validated in prospective studies.

Salvage surgery in recurrent sinonasal cancers: Proposal for a prognostic model based on clinicopathologic and treatment-related parameters.

BackgroundEvidence on survival and major prognosticators after salvage surgery in recurrent sinonasal cancers (SNC) is limited.MethodsA retrospective, single‐center study of recurrent SNC treated with salvage surgery between 1997 and 2019 was conducted. Univariate and multivariable analyses were performed to define a prognostic score for overall survival (OS).ResultsOne hundred and eighteen patients were included. Recurrent SNC originated mostly in the naso‐ethmoidal box (67.8%) and were mainly epithelial (76.2%), high‐grade (49.2%), and locally advanced (rpT4, 60.1%) malignancies. Negative margins were achieved in 56.6% of cases. Two‐ and 5‐year OS were 71.7% and 56%, respectively. The prognostic model included treatment modality for primary tumor, histology, rpT class, margin status, perineural invasion, and adjuvant radiotherapy and stratified patients into three prognostic groups (5‐year OS: 84.4%, 44.9%, and 0%, respectively).ConclusionsTreatment of recurrent SNC can result in good long‐term survival estimates with limited morbidity. Our score can provide excellent prognostic stratification.

Preoperative magnetic resonance imaging-based prognostic model for mass-forming intrahepatic cholangiocarcinoma.

As most staging systems for intrahepatic cholangiocarcinoma (iCCA) are based on pathological results, preoperative prognostic prediction is limited. This study aimed to develop and validate a prognostic model for the overall survival of patients with mass-forming iCCA (MF-iCCA) using preoperative magnetic resonance imaging (MRI) and clinical findings. We enrolled a total of 316 patients who underwent preoperative MRI and surgical resection for treatment-naive MF-iCCA from six institutions, between January 2009 and December 2015. The subjects were randomly assigned to a training set (n=208) or validation set (n=108). The MRIs were independently reviewed by three abdominal radiologists. Using MRI and clinical findings, an MRI prognostic score was established. We compared the discrimination performance of MRI prognostic scores with those of conventional pathological staging systems. We developed an MRI prognostic score consisting of serum CA19-9 and three MRI findings (tumour multiplicity, lymph node metastasis and bile duct invasion). The MRI prognostic score demonstrated good discrimination performance in both the training set (C-index, 0.738; 95% confidence interval [CI], 0.698-0.780) and validation set (C-index, 0.605; 95% CI, 0.526-0.680). In the validation set, MRI prognostic score showed no significant difference with AJCC 8th TNM stage, MEGNA score and Nathan's stage. Our MRI prognostic score for overall survival of MF-iCCA showed comparable discriminatory performance with pathological staging systems and might be used to determine an optimal treatment strategy.

Clinical Significance of Preoperative Naples Prognostic Score in Patients With Non-Small Cell Lung Cancer.

Background: Naples Prognostic Score (NPS) is a novel score based on inflammatory-nutritional indicators. We aimed to analyze the prognostic value of the Naples Prognostic Score in non-small cell lung cancer (NSCLC) patients following surgery. Methods: A total of 319 NSCLCpatients following surgery were analyzed in the retrospective cohort study. We analyzed the predictive value of Naples Prognostic Score for overall survival and recurrence-free survival in postoperative non-small cell lung cancer patients by using Kaplan-Meier survival curves and multivariate Cox regression analysis. At the same time, the time-dependent ROC and the area under curves were also created to compare the accuracy of different scoring systems. Results: According to NPS, we divided all patients into 3 groups，120 patients were divided into group 0, 161 patients were divided into group 1, and 38 patients were divided into group 2. The median survival time for all patients is 32 months, and the median survival times for different groups were 35 months, 31 months, and 28 months, respectively. The overall survival and recurrence-free survival survival curves of different groups were significantly different (both P < .05), and patients in the higher NPS groups had a disappointing prognosis. NPS may be an independent prognostic factor for overall survival and recurrence-free survival, according to the results of multivariate analysis (both P < .05). The area under curve showed that the accuracy of the NPS was significantly better than other score systems. Conclusions: The NPS is closely related to the long-term survival prognosis of patients with NSCLC, especially in stage III patients.

Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer.

Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients &Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognosticscore for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results:ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3-2.7; p=0.0019), PFS (HR: 2.0; 95% CI: 1.4-2.9; p<0.0001) and PFI (HR: 1.9; 95% CI: 1.4-2.8; p=0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.

An enhanced prognostic score for overall survival of patients with cancer derived from a large real-world cohort.

By understanding prognostic biomarkers, we gain insights into disease biology and may improve design, conduct, and data analysis of clinical trials and real-world data. In this context, we used the Flatiron Health Electronic Health Record-derived deidentified database that provides treatment outcome and biomarker data from >280 oncology centers in the USA, organized into 17 cohorts defined by cancer type. In 122694 patients, we analyzed demographic, clinical, routine hematology, and blood chemistry parameters within a Cox proportional hazard framework to derive a multivariable prognostic risk model for overall survival (OS), the 'Real wOrld PROgnostic score (ROPRO)'. We validated ROPRO in two independent phase I and III clinical studies. A total of 27 variables contributed independently and homogeneously across cancer indications to OS. In the largest cohort (advanced non-small-cell lung cancer), for example, patients with elevated ROPRO scores (upper 10%) had a 7.91-fold (95% confidence interval 7.45-8.39) increased death hazard compared with patients with low scores (lower 10%). Median survival was 23.9 months (23.3-24.5) in the lowest ROPRO quartile Q1, 14.8 months (14.4-15.2) in Q2, 9.4 months (9.1-9.7) in Q3, and 4.7 months (4.6-4.8) in Q4. The ROPRO model performance indicators [C-index= 0.747 (standard error 0.001), 3-month area under the curve (AUC)= 0.822 (0.819-0.825)] strongly outperformed those of the Royal Marsden Hospital Score [C-index= 0.54 (standard error 0.0005), 3-month AUC= 0.579 (0.577-0.581)]. We confirmed the high prognostic relevance of ROPRO in clinical Phase 1 and III trials. The ROPRO provides improved prognostic power for OS. In oncology clinical development, it has great potential for applications in patient stratification, patient enrichment strategies, data interpretation, and early decision-making in clinical studies.

A prognostic score for overall survival in patients treated with abiraterone in the pre- and post-chemotherapy setting.

Background: Therapy resistance remains a serious dilemma in metastatic castration-resistant prostate cancer (mCRPC) with primary or secondary resistance frequently occurring against any given therapy. Available prognostic models for Abiraterone Acetate (AA) are specifically designed for either pre- or post-chemotherapy settings and mostly based on trial datasets not necessarily reflecting real-life. Results: A score of 0–2 (low-risk) is associated with an OS-probability of 80.0% (95%CI: 71.3–90.6) and 50.5% (95%CI: 38.7–66.0) after 1 and 2 years while a score of 3–4 (high risk) is associated with an OS-probability of 35.3% (95%CI: 22.3–55.8) and 5.7% (95%CI: 1.5–21.8), respectively. The bootstrapping survival analysis of the scoring-system revealed a median c-index of 0.80 (IQR: 0.79–0.82). Material and Methods: We developed a scoring-system using four real-life parameters 117 mCRPC patients treated with AA either pre- or post-chemotherapy. These parameters were evaluated using COX regression analysis. The scoring-system consists of binary-categorized parameters; when any of these exceeds the given cut-off, one point is added up to a final score ranging between 0–4 points. The final score was stratified by a median threshold of 2 into low- and high-risk groups. We evaluated the discriminative ability of our scoring-system using concordance probability (C-index) and Kaplan–Meier-analysis and applied a 100-times bootstrap for survival analysis. Conclusions: Our study introduces a novel prognostic scoring-system for OS of real-life mCRPC patients receiving AA treatment irrespective of the line of therapy. The scoring-system is simple and can be easily utilized based on PSA and LDH values, neutrophil to lymphocyte ratio, and ECOG performance status.

Development and validation of a prognostic score for overall survival integrating baseline metabolically active tumor volume measured by 18F-FDG PET/CT and clinical factors for metastatic colorectal cancer patients.

3543 Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p &lt; 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p &lt; 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI &lt; 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p &lt; 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.

A prognostic score for survival in patients older than 65 years with Diffuse Large B-Cell Lymphoma.

Available prognosis scores for patients with diffuse large B-cell lymphoma (DLBCL) included a limited number of patients ≥ 65 years of age, and most of them did not include comorbidities. Here, we propose a prognostic score for overall survival (OS) for this group of patients. Patients ≥ 65 years with DLBCL treated at a single national reference center were included. Clinical features including comorbidities and biochemical parameters were analyzed. We included 141 patients. Response rate in the whole group was 77%. Based on multivariate analysis, the presence of the European Cooperative Oncology Group (ECOG) > 2, elevated levels of beta-2 microglobulin, bulky disease, and anemia (hemoglobin < 10 g/dL) had a significant effect on OS. These parameters were considered when computing the prognostic score, which identified three groups with differential survival: Low, intermediate, and high risk of death, with a probability of survival at 60 months of 80.05%, 55.5%, and 29.84%, respectively. This score may select patients to optimize treatment. The presence of high levels of beta-2 microglobulin, bulky disease, and hemoglobin < 10 g/dL, and ECOG > 2 was associated with poor OS in elderly patients with DLBCL.

Abstract No. 615 Performance of MELD score versus MELD-Na in predicting 90-day survival after TIPS placement

The Model for End-Stage Liver Disease (MELD) score was originally developed to assess prognosis after TIPS placement. The addition of sodium to the MELD score (MELD-Na) has been proposed as a more accurate prognostic score for overall survival. We assessed the performance of MELD vs. MELD-Na score in predicting 90-day survival after TIPS placement. Retrospective review of TIPS placements for ascites and hemorrhage at a major academic healthcare network between 1994 and 2014. MELD/MELD-Na scores were assessed for their ability to predict 90-day survival using area under the receiver operative curves (AuROC) and compared using change in AuROC, category free net reclassification index (NRI), and integrated discrimination improvement (IDI). Stratified analysis by TIPS indication was performed. Three hundred seventy seven TIPS placements were analyzed (225 for hemorrhage, 152 for ascites/hydrothorax). 90-day survival was 75% (282/377) for all subjects, 76% (170/225) for the hemorrhage subgroup, and 74% (112/150) for the ascites subgroup. For all subjects, median MELD score was 16 [IQR 11, 21] with AuROC of 0.77. Median MELD-Na was 19 [IQR 14, 23] with AuROC of 0.77. MELD and MELD-Na were highly correlated (r = 0.94; p < 0.001). MELD AuROC was 0.82 for the bleeding subgroup and 0.70 for the ascites subgroup. Addition of Na to the MELD score did not improve its performance by change in AuROC, NRI, or IDI for all patients or when stratified by TIPS indication, except for NRI in the bleeding subgroup (see Table). MELD and MELD-Na performed similarly when predicting 90-day survival after TIPS. MELD-Na score performs better in TIPS placed for hemorrhage compared to TIPS placed for ascites. Further study is required to improve predictive scores in this population.Tabled 1All TIPSn = 377Hemorrhagen = 225Ascitesn = 152MELDMELD-NaP ValueMELDMELD-NaP-valueMELDMELD-NaP ValueAuROC0.770.770.620.820.830.510.700.700.26Category-free NRI0.050.680.330.050.210.26IDI0.00040.530.010.20-0.000020.98 Open table in a new tab

Development of a novel prognostic score for breast cancer patients using mRNA expression of CHAC1.

To develop a prognostic score for primary breast cancer patients integrating conventional predictors and the novel biomarker CHAC1 to aid adjuvant chemotherapy decisions. A prognostic score for overall survival was developed using: conventional predictors from a dataset of 1777 patients and the weight of CHAC1 mRNA expression from an independent dataset of 106 patients using multivariate Cox regression. The new score includes: CHAC1 mRNA expression, age, tumor size, HER2 neu status, lymph node status and degree of malignancy. Using a cut-off value of11 score points, 10-year survival was 82% in low-risk (n=34) and 43% in high-risk patients (n=72). The addition of CHAC1 resulted in 16% reclassification. Including CHAC1 in prognostic prediction may aid (and change) personalized treatment selection.

Overall survival prognosis of patients in immuno-oncology phase I trials: The Gustave Roussy score.

3029 Background: The evaluation of patient’s life expectancy is crucial to select patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on 3 objective variables (number of metastatic sites, LDH and serum albumin) was validated in patients treated with cytotoxic and targeted therapies. We aimed to determine if those factors were applicable to immunotherapy (IT) phase I trials. Methods: A retrospective analysis for risk factors of survival was conducted in a discovery cohort of 155 patients enrolled into IT phase I trials at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in IT phase I trials was used to prospectively re-validate this score. Results: 155 patients receiving an experimental IT between March 2012 and January 2016 were included in the discovery cohort. A MVA assessing the RMH Score variables showed that albumin &lt; 35 g/dL (HR 1.73, 95% CI 1.05-2.86) and LDH &gt; upper normal limit (1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. As opposed to the RMH score, number of metastases was not associated with a poorer outcome for this IT cohort (0.83 95% CI 0.51-1.35). Interestingly, a neutrophil to lymphocyte ratio (N/L) &gt; 6 (1.75, 95% CI 1.04-2.95) was associated with a worse OS. A risk analysis based on the results of the MVA showed that patients presenting a high score (2-3) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0-1) (68.9 weeks; 95% CI 50-83.7) (HR = 2.9 95% CI 1.87-4.64). In the validation cohort of 113 patients, the patients presenting a high score showed an inferior OS (HR = 6.3, 95% CI 2.7-14.8). Conclusions: In phase I trials of IT, traditional prognostic variables included in the RMH Score are suboptimal to determine patient’s prognosis. In this context, the N/L ratio, which reflects the immune contexture, is a significant prognostic variable. The new Gustave Roussy Score, based on albumin, LDH and N/L ratio allows to better select patients for IT phase I trials.

Design and Validation of the GI-NEC Score to Prognosticate Overall Survival in Patients With High-Grade Gastrointestinal Neuroendocrine Carcinomas.

Prognostic markers for risk stratification of patients with gastrointestinal high-grade neuroendocrine carcinomas (GI-NECs) are lacking; we designed and validated a prognostic score for overall survival (OS). Consecutive patients diagnosed in five neuroendocrine specialist European centers were included. Patients were divided into three cohorts: a training cohort (TC), an external validation cohort (EVC), and a prospective validation cohort (PVC). Prognostic factors were identified by log-rank test, Cox-regression, and logistic regression analyses. The derived score was internally and externally validated. All statistical tests were two-sided. Of 395 patients screened, 313 were eligible (TC = 109 patients, EVC = 184 patients, and PVC = 20 patients). The derived prognostic score included five variables: presence of liver metastases, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS), and Ki67. In multivariable analysis, the score was prognostic for OS (hazard ratio [HR] = 1.86, 95% confidence interval [CI] = 1.47 to 2.35, P < .001) and had good discrimination (C-index = 0.76) and calibration (mean error = 0.021, 90th percentile = 0.037) in the TC. These results were validated in the EVC and PVC, in which our score was able to prognosticate for OS when adjusted for other prognostic variables in the multivariable analysis (HR = 1.85, 95% CI = 1.27 to 2.71, P = .001; and HR = 4.51, 95% CI = 1.87 to 10.87, P = .001, respectively). The score classified patients into two groups with incremental risk of death: group A (0-2 points, 181 patients [63.9%], median OS = 19.4 months, 95% CI = 16.1 to 25.1) and group B (3-6 points, 102 patients [36.1%], median OS = 5.2 months, 95% CI = 3.6 to 6.9). The GI-NEC score identifies two distinct patient cohorts; it provides a tool for clinicians when making treatment decisions and may be used as a stratification factor in future clinical trials.

Identification of microRNA-based signatures for response and survival for non-small cell lung cancer treated with cisplatin-vinorelbine A ELCWP prospective study

Clinical variables, like stage and performance status (PS), have predictive and prognostic values in advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy, not allowing adequate individual prediction. MicroRNA (miRNA) are non-coding RNAs regulating gene expression. In a prospective study, we assessed the predictive value for response and survival of tumour miRNA in NSCLC patients treated by 1st line cisplatin and vinorelbine. miRNA expression was analysed on a biopsy obtained during the diagnostic bronchoscopy, using TaqMan Low Density Arrays. The signature for response was derived using logistic regression with stepwise variable selection. The associations between overall survival and miRNA expression levels were estimated by using the Kaplan–Meier method, log-rank test, and Cox proportional hazard regression models to estimate the hazard ratios. In total, 38 patients with adequate tumour biopsies, treated with cisplatin-vinorelbine were included: male (n=27), 80–100 Karnofsky PS (n=27), adenocarcinoma (n=20), stage IV (n=30). One patient was considered not assessable for response but remained included in the survival analyses. Out of the 37 patients assessable for response, 16 partial responses (43%) were observed. A two miRNA signature (miR-149 and miR-375) was found predictive for response and was also associated to progression-free survival (p=0.05). Using a linear combination of the miR CT values with Cox's regression coefficients as weights, we constructed a prognostic score for overall survival including four miRNA (miR-200c, miR-424, miR-29c and miR-124). The signature distinguished patients with good (n=18) and poor (n=20) prognosis with respective median survival times of 47.3 months (95% CI 29.8–52.4) and 15.5 months (95% CI 9.1–22.8) (p<0.001; hazard ratio 21.1, 95% CI 4.7–94.9). ConclusionsmiRNA signature allows predicting response and is of prognostic value for survival in patients with NSCLC treated with first line cisplatin and vinorelbine.

Reirradiation in progressive high-grade gliomas: outcome, role of concurrent chemotherapy, prognostic factors and validation of a new prognostic score with an independent patient cohort

PurposesFirst, to evaluate outcome, the benefit of concurrent chemotherapy and prognostic factors in a cohort of sixty-four high-grade glioma patients who underwent a second course of radiation therapy at progression. Second, to validate a new prognostic score for overall survival after reirradiation of progressive gliomas with an independent patient cohort.Patients and methodsAll patients underwent fractionated reirradiation with a median physical dose of 36 Gy. Median planned target volume was 110.4 ml. Thirty-six patients received concurrent chemotherapy consisting in 24/36 cases (67%) of carboplatin and etoposide and in 12/36 cases (33%) of temozolomide. We used the Kaplan Meier method, log rank test and proportional hazards regression analysis for statistical assessment.ResultsMedian overall survival from the start of reirradiation was 7.7 ± 0.7 months. Overall survival rates at 6 and 12 months were 60 ± 6% and 24 ± 6%, respectively. Despite relatively large target volumes we did not observe any major acute toxicity. Concurrent chemotherapy did not appear to improve outcome. In contrast, female gender, young age, WHO grade III histology, favorable Karnofsky performance score and complete resection of the tumor prior to reirradiation were identified as positive prognostic factors for overall survival. We finally validated a recent suggestion for a prognostic score with our independent but small patient cohort. Our preliminary findings suggest that its ability to discriminate between different prognostic groups is limited.ConclusionsOutcome of our patients was comparable to previous studies. Even in case of large target volumes reirradiation seems to be feasible without observing major toxicity. The benefit of concurrent chemotherapy is still elusive. A reassessment of the prognostic score, tested in this study, using a larger patient cohort is needed.

Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia

Several prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables. We genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model. ASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×10(9)/L, platelet count less than 100 ×10(9)/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001). A new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.

Fractionated radiosurgery for painful spinal metastases: DOSIS - a phase II trial

BackgroundOne third of all cancer patients will develop bone metastases and the vertebral column is involved in approximately 70% of these patients. Conventional radiotherapy with of 1–10 fractions and total doses of 8-30 Gy is the current standard for painful vertebral metastases; however, the median pain response is short with 3–6 months and local tumor control is limited with these rather low irradiation doses. Recent advances in radiotherapy technology – intensity modulated radiotherapy for generation of highly conformal dose distributions and image-guidance for precise treatment delivery – have made dose-escalated radiosurgery of spinal metastases possible and early results of pain and local tumor control are promising. The current study will investigate efficacy and safety of radiosurgery for painful vertebral metastases and three characteristics will distinguish this study. 1) A prognostic score for overall survival will be used for selection of patients with longer life expectancy to allow for analysis of long-term efficacy and safety. 2) Fractionated radiosurgery will be performed with the number of treatment fractions adjusted to either good (10 fractions) or intermediate (5 fractions) life expectancy. Fractionation will allow inclusion of tumors immediately abutting the spinal cord due to higher biological effective doses at the tumor - spinal cord interface compared to single fraction treatment. 3) Dose intensification will be performed in the involved parts of the vertebrae only, while uninvolved parts are treated with conventional doses using the simultaneous integrated boost concept.Methods / DesignIt is the study hypothesis that hypo-fractionated image-guided radiosurgery significantly improves pain relief compared to historic data of conventionally fractionated radiotherapy. Primary endpoint is pain response 3 months after radiosurgery, which is defined as pain reduction of ≥ 2 points at the treated vertebral site on the 0 to 10 Visual Analogue Scale. 60 patients will be included into this two-centre phase II trial.ConclusionsResults of this study will refine the methods of patient selection, target volume definition, treatment planning and delivery as well as quality assurance for radiosurgery. It is the intention of this study to form the basis for a future randomized controlled trial comparing conventional radiotherapy with fractionated radiosurgery for palliation of painful vertebral metastases.Trial registrationClinicalTrials.gov Identifier: NCT01594892

A Prognostic Score for Overall Survival (OS) with Azacitidine (AZA) In Higher Risk MDS Based on 282 Patients (pts), and Validated In 175 Pts From the AZA 001 Trial

AbstractAbstract 3996 Background:AZA significantly improves OS in higher-risk MDS (including RAEB-t/AML) compared to conventional treatments (AZA 001 trial, Lancet Onc, 2009), but prognostic factors of response and OS to AZA remain largely unknown. We designed a prognostic score for OS in a cohort of AZA treated higher-risk MDS in a patient-named compassionate program (French ATU), and validated it in patients from the AZA 001 trial. Methods:Between Sept 2004 and Jan 2009, prior to AZA approval in Europe, IPSS int-2/high risk MDS (including RAEB-t) not previously treated with intensive chemotherapy (IC), allo SCT, or a hypomethylating agent were included in a compassionate program (ATU), and received AZA (planned schedule 75 mg/m2/d ×7 d every 28 d for ≥4 cycles). Independent prognostic factors of OS were individualized in a Cox model. A prognostic score was then developed based on those factors. After validation of the score as a continuous variable, pts were grouped in three distinct risk categories. We subsequently tried to validate this score in the 175 higher risk MDS pts treated with AZA at the same schedule in AZA 001 trial (4 of the 179 pts randomized to AZA in that trial did not start AZA). Results:The ATU cohort included 282 pts with de novo (74%) or therapy related (t) (26%) higher-risk MDS (IPSS int-2 in 54% high in 43%, at least int-2 in 2%). ECOG PS ≥2, RBC transfusion dependence ≥4 units/8 weeks and circulating blasts were present in 21%, 46% and 46% of pts respectively (resp). Cytogenetic risk was good, int, and poor in 31%, 17% and 47% (unknown in 5%). 10% pts had previously been treated with LD araC for their MDS. Multivariate analysis of survival retained PS ≥2 (HR= 2.0 [95% CI: 1.4–2.9]), RBC transfusion dependence ≥4 units/8 weeks (HR=1.9 [1.4-2.6]), presence of circulating blasts (HR=2.0 [1.5-2.7]), and IPSS cytogenetic risk (intermediate: HR=1.4 [0.8-2.3], poor: HR=3.0 [2.0-4.3]) as independent prognostic factors (all p<10-4). We designed a simple prognostic score attributing 1 and 2 points for intermediate and poor risk cytogenetics, resp, and 1 point for each other adverse prognostic factor. As a continuous variable, an increasing score was associated to poorer OS (HR=1.9 [1.6-2.1], p<10-4). Patients were grouped as “low risk” (score=0), intermediate risk (score=1-3) and high risk (score=4-5). Due to missing values, a prognostic group could be attributed to 269 of the 282 pts: 30 (11%), 191 (71%), and 48 (18%) pts were considered low, intermediate and high risk resp. With a median follow-up of 26 months, median OS were not reached, 15.0 and 6.1 months in patients with low, intermediate, and high risk score respectively (p<10-4).The validation cohort included 175 pts of the AZA-001 trial with higher-risk MDS. Apart from the presence of 5 (3%) int-1 pts in AZA-001 cohort (their removal did not affect conclusions), IPSS (int-2 in 42% high in 46%, at least int-2 in 9% vs 54%, 43%, 2% resp., p=0.15) was comparable to the ATU cohort, as well as RBC transfusion dependence ≥4 units/8 weeks (46 vs 45%, p=0.8), presence of circulating blasts (51 vs 45%, p=0.4), whereas all AZA-001 pts were de novo (vs 74% in the ATU cohort), had not been pretreated (vs 10% pretreated by LD AraC in the ATU cohort), had better PS (7% PS ≥2 vs 21% in the ATU cohort, p<10-4) and better cytogenetics (47%, 21% and 27% 5%, good, int, poor, unknown cytogenetics vs 31%, 17%, 47%, 5% resp., p<10-4). The score was validated as a continuous variable on OS (HR=1.4 [1.2-1.7], p=0.0005). Due to missing values, a prognostic group could be attributed to 166 (95%) of pts of the AZA 001 cohort: 27 (16%), 123 (74%), and 16 (10%) pts were classified in the low, intermediate and high risk respectively. Median follow-up was 21 months. Median OS were not reached, 21.4 and 14.3 months respectively in patients with low, intermediate, and high risk score (p=0.004). Conclusion:Our compassionate cohort scoring system based on conventional prognostic factors (ECOG PS, RBC transfusion requirement, circulating blasts and karyotype) was prognostic for survival. Additionally, it was successfully validated in a more selected cohort of higher-risk MDS from a prospective multicenter trial. Prognostic factors of outcome with AZA based on more refined biological studies (including gene methylation status) will probably emerge. In particular, we found in a more recent patient cohort (Itzykson, abstract also submitted to ASH 2010), that TET2 mutations may predict better response to AZA in higher risk MDS. [Display omitted] Disclosures:Beach:Celgene: Employment. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.

Comparison of five prognostic scoring systems, the French–American–British (FAB) and World Health Organization (WHO) classifications in patients with myelodysplastic syndromes: results of a single-center analysis

We retrospectively studied 89 consecutive patients diagnosed with primary myelodysplastic syndrome (MDS) over a period of 10 years to (1) identify prognostic factors for overall survival (OS) and leukemia-free survival (LFS); (2) to assess and compare the Bournemouth-, Spanish-, Düsseldorf-, Lille-, and the International prognostic scoring systems (IPSS); and to (3) compare the French-American-British (FAB) and World Health Organization (WHO) classifications. The median age of patients was 63 years (range, 26-85). Karyotype analyses were done in 85 patients (96%). Median OS was 3 years; 67 patients (75%) have died, and 28 (31%) had progression to acute myeloid leukemia (AML). Major independent prognostic variables for both OS and LFS (multivariate analysis) were percentage of bone marrow (BM) blasts (P < 0.0001), and in patients with cytogenetic data available, cytogenetic risk groups by Lille-score (OS, P = 0.031/LFS, P = 0.002) and IPSS (OS, P = 0.024). All five prognostic scoring systems successfully discriminated risk groups as regards OS and LFS, but in patients with cytogenetic data available, the major independent prognostic score for OS (P < 0.0001) and LFS (P = 0.006) was the IPSS. The FAB and WHO classifications also successfully discriminated between risk groups. The new WHO subgroups [refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without ringed sideroblasts] showed a significantly (P = 0.0454) different prognosis for OS, but not for LFS (P = 0.0839), in comparison to the subgroups having erythroid dysplasia only (RA/RARS). Risk stratification into refractory anemia with excess blast-I (RAEB-I) and RAEB-II tended to yield different prognoses for OS and LFS. The 5q-minus syndrome strongly predicted for a good prognosis. In patients treated with the demethylating agent decitabine (n = 24), IPSS "poor risk" cytogenetics were unable to predict for the expected worse prognosis when compared to "intermediate-risk" cytogenetics. In conclusion, we confirm in a single-center patient cohort that the use of the WHO classification improves the predictive value of the FAB classification and that, in patients with cytogenetic data available, the IPSS can be used for clinical decision-making.