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Halabi S.,Duke University | Lin C.-Y.,Duke University | Small E.J.,University of California at San Francisco | Armstrong A.J.,Duke Prostate Center and the Duke Cancer Institute | And 7 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy. Methods Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively. Conclusions A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed. © The Author 2013.


PubMed | Regina Elena Cancer Institute, Ospedale Niguarda Ca Grande, Marche Polytechnic University, Ospedale Belcolle and 14 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

470 Background: Outcomes of pts treated with three TTs for mRCC have not been well characterized. Survival data as well as existing prognostic criteria in this population were evaluated.Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was send to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type, and length of first-, second-, and third-lines were collected. Values of serum Hb, PLT, neutrophils, LDH and Ca, ECOG-PS, previous RT and number of metastatic sites >2 before the start of third-line were evaluated. Cleveland Clinic, French, Heng, and MSKCC scores and relative survival were calculated.Following the screening of 1,905 pts, 252 (13%) with 3 TTs were identified. The median age was 60 yrs (range 52-68), 73% were male, 96% had nephrectomy and 38% were metastatic at diagnosis. At first-line, the Motzer class was good, intermediate, and poor in 48%, 47%, and 5% of pts, respectively. The median OS from the start of third-line was 14.3 mos (95%CI, 10.1-18.6). Rate and survival by prognostic group according to each classification are reported in table below. When prognostic factors were considered separately, at the univariate analysis ECOG-PS2, Hb1.5ULN, Ca>ULN; PLT>ULN; Neu>ULN, and sites of disease >2 had negative prognostic role. Multivariate analysis shows an independent prognostic role only for ECOG-PS2 (HR: 1.8; 95%CI: 1.1-2.8), HbULN (HR: 2.1; 95%CI: 1.2-3.8). Pts were stratified in 3 groups according to the presence of none, 1 or 2 prognostic factors. The median OS was 20.3, 13.6 and 7.8 months, respectively (p<0.001).Current nomograms are able to predict survival in patients with mRCC before the third-line with TT. Neutrophils, hemoglobin and ECOG-PS were the most important prognostic factors. [Table: see text].


PubMed | University of California at San Francisco, Hopital Europeen Georges Pompidou, Sanofi S.A., San Camillo and Forlanini Hospital and 4 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

24 Background: Several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy nave mCRPC. The primary objective was to develop and validate a prognostic model that can be used to predict OS in men who have failed first-line chemotherapy.Data was used from a phase III trial of 755 mCRPC men who had developed progressive disease following first-line chemotherapy and were randomized to cabazitaxel plus prednisone or mitoxantrone plus prednisone (TROPIC trial). The data was randomly split into training (n=507) and testing (n=248) sets. A separate data, consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone, was used as the validation set (SPARC trial). Penalized regression method was used to identify important prognostic factors. Adaptive Lasso selected nine variables of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.29) and high (>= -1.29) risk groups in the testing datasets. The model was assessed for its predictive accuracy using time dependent area under the curve (AUC) on the testing sets (TROPIC and SPARC trials).The final selected model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. In the TROPIC testing set, the median OS in high and low risk groups were 11 and 17 months, respectively, with a hazard ratio (HR)=2.47 (p-value<0.0001). Using the SPARC set, the median OS were 11 and 20 months in the high and low risk groups, respectively, with a HR=1.94 (p<0.0001). The time dependent AUC were 0.73 and 0.70 on the testing sets.A prognostic model of OS in the post-docetaxel mCRPC setting was developed and validated and risk groups were identified. This model can be used to select patients based on their prognosis to participate in clinical trials. Prospective validation is needed.


PubMed | British Columbia Cancer Agency, Dana-Farber Cancer Institute, Medivation Inc., University Paris - Sud and 4 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes.Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for 1 day on study.On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively.In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself.NCT00974311. [Table: see text].


Arcangeli S.,San Camillo and Forlanini Hospital | Ramella S.,Biomedical University of Rome | De Bari B.,University of Lausanne | Franco P.,University of Turin | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2016

Objective: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02. Methods and materials: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART). Results: With regard to the inclusion criteria: (1) Population: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) Interventions: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) Comparators: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1. ng/mL, a level that would be now deemed inappropriate; (4) Outcomes: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification. Conclusions: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process. © 2015 Elsevier Ireland Ltd.


PubMed | University of the Sea, Dana-Farber Cancer Institute, Princess Margaret Hospital, Heinrich Heine University Düsseldorf and 8 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

301 Background: PFS6 was identified to be a robust intermediate endpoint in the setting of second-line therapy for advanced UC (Sonpavde, ESMO Congress, 2012) We studied the impact of second-line prognostic factors (Sonpavde, ESMO Congress 2012) (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] 1, time from prior chemotherapy [TFPC]) on PFS6 and response rate (RR) to enable comparison of outcomes across phase II trials.Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method.Data regarding progression, Hb, LM, PS and TFPC were available in 570 patients, who were considered evaluable. The mean age was 65.1 years, 45.3% had ECOG-PS 1, 30.2% had LM, 14.6% had anemia and TFPC was <6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). PFS6 and RR varied significantly according to risk group (Table). For every unit increase in risk group, the hazard of progression in 6 mo increased by 41% and the odds of response decreased by 48%.PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. These data facilitate comparison of outcomes across phase II trials enrolling heterogeneous populations. [Table: see text].


PubMed | Regina Elena Cancer Institute, Oncology, Marche Polytechnic University, University of Udine and 15 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

431 Background: In recent years, TTs have improved the prognosis of mRCC patients (pts). Despite a non-negligible number of pts received 3 TTs in clinical practice, no TTs have been evaluated as third-line. Aim of this study is to investigate the clinical outcome in pts who received 3 TTs.Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was sent to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type and length of first-, second- and third-line were collected; MSKCC risk class was calculated before starting the first-line. Sequences were evaluated by class (TKI-TKI-mTOR vs. TKI-mTOR-TKI) or by drug (Su-So-Ev vs. Su-Ev-So). Median PFS, OS and Time to Strategy Failure (TTSF: from start of first- to end of thrid-line) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. Cox model was used to explore predictors of TTSF and OS. The study had the ethical approval.2,065 pts were screened and 281 pts (13%) were treated with 3 TTs. No differences were found between TKI-TKI-mTOR and TKI-mTOR-TKI groups. The TTSF was 36.5 (30.5-42.6) mos vs. 29.3 (23.6-34.9) mos (p=0.059), and the OS was 50.7 (40.6-60.8) vs. 37.8 (34.2-41.5) mos (p=0.004), for TKI-TKI-mTOR and and TKI-mTOR-TKI, respectively. TTSF for Su-So-Ev was 32.1 vs. 30.4 mos for Su-Ev-So (p=0.006). The median OS was not reached in the group treated with Su-So-Ev compared to 35.6 (95%CI, 31.6-39.6) mos in the group treated with Su-Ev-So (p<0.001). The univariate and multivariable Cox analyses for TTSF and OS showed that the only predictive factor is the primary resistance to 1st line (HR: 3.15, 95%CI, 1.98-4.99; p<0.001). The Prognostic factors are the initial MSKCC group (HR: 2.07, 95% CI, 1.41 -3.05; p<0.001), the sequence of therapy (HR: 2.59, 95% CI, 1.59-4.22; p<0.001) and the primary resistance to first line (HR: 2.20, 95% CI, 1.16-4.11; p<0.001).We report as the sequential treatment with two antiangiogenic inhibitors followed by an mTOR inhibitor could increase survival and the control disease in metastatic renal cell carcinoma.


PubMed | Aarhus University Hospital, San Camillo and Forlanini Hospital, EORTC Headquarters, Radboud University Nijmegen and Herlev Hospital
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

252 Background: Lapatinib (Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor approved for the treatment of breast cancer. GC is a standard chemotherapy regimen for advanced/metastatic bladder cancer and there are preclinical and clinical data suggesting the role of EGFR and HER2 in urothelial carcinoma. This phase I study examined the safety of lapatinib in combination with GC in patients (pts) with bladder cancer.The primary phase I objective was to determine the maximum tolerated dose of lapatinib 750-1,250 mg that could be administered safely with GC in bladder cancer pts. A 3+3 dose escalation was used with lapatinib 750 mg, 1000 mg and then 1250 mg. Lapatinib was dosed daily and G (1000 mg/m days 1, 8, 15) + C (70 mg/m day 2) every 28 days.18 pts with median age 63 yrs (range 50-77) and ECOG PS 0/1 (66.7% with WHO-PS 0 and 33.3% with WHO-PS 1) were included. 3/6, 3/5 and 6/7 pts completed at least one cycle according to the protocol and received lapatinib 750 mg, 1000 mg and 1250 mg + GC, in cohorts 1, 2 and 3, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 or 2 (3 pts each); in cohort 3 (2 x 3 pts), 1 of 6 pts had DLT (Gr4 related febrile neutropenia and renal failure). One discontinued due to pt decision after 1 cycle. Ten pts received 6 cycles and one 7 cycles. The response rate among the 11/12 eligible patients was 73% (1 CR, 7 PR, 3 SD and 1 not assessable). Further toxicity data together with responses in relation to EGFR and HER2 status will be presented.Within the limits of a phase I study, lapatinib 750-1,250 mg + GC appears safe and tolerable with considerable activity at the maximum planned dose in bladder cancer.NCT00623064.


PubMed | Novartis, Dana-Farber Cancer Institute, St Jamess Institute Of Oncology, LBI ACR VIEnna and ACR ITR VIEnna and 4 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

255 Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression.Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simons 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if 2 responses seen in stage 1).A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups.Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment.NCT00790426.


PubMed | San Camillo and Forlanini Hospital, Sloan Kettering Cancer Center and Glaxosmithkline
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

380 Background: PAZ, an oral multikinase inhibitor, demonstrated significant improvement in PFS over placebo in patients with aRCC in a randomized, phase III trial (J Clin Oncol 2009:29; 475). The purpose of this study was to develop and internally validate a prognostic nomogram based on the outcome data from phase III trial for predicting the probability of 12-month OS for treatment-nave and cytokine-pretreated aRCC patients who received PAZ.Statistical modeling was performed on a dataset consisting of 281 patients from the PAZ arm of the phase III trial. Missing values were first imputed using multiple imputation with chained equations. A Cox proportional hazards regression model was fit using routinely available predictors thought to be prognostic based on clinical judgment. These predictors included the neutrophil count relative to ULN, platelet count relative to ULN, LDH relative to ULN, alkaline phosphatase relative to ULN, corrected calcium, albumin, hemoglobin, ECOG performance status, months from diagnosis to treatment, number of metastatic sites, and presence of lung, liver and bone metastases. Bootstrap-corrected estimates of discrimination and calibration in the small were calculated following 1,000 resamples. The Cox model was plotted as a nomogram.A prognostic nomogram was developed and internally validated for predicting the probability of 12-month OS in aRCC patients based on a Cox regression model using 13 predictor variables. Calibration plots suggested reasonable correspondence between predicted probabilities and actual proportions of OS. The bootstrap-corrected concordance index, a measure of discrimination, was 0.70. When examining the nomogram, albumin appeared to have the greatest potential influence on predicted OS. Months from diagnosis to treatment and corrected calcium level seemed to be the next most potentially influential predictors.The nomogram predicts with reasonable accuracy and should facilitate treatment decision making for patients with advanced renal cell carcinoma. Validation in a separate dataset is planned.

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