A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5011-5011
Author(s):  
Susan Halabi ◽  
Chen-Yen Lin ◽  
Eric Jay Small ◽  
Andrew J. Armstrong ◽  
Ellen B. Kaplan ◽  
...  

5011 Background: Although several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC, this work sought to develop and validate a prognostic model to predict OS in men who had progressed following first-line chemotherapy, and were receiving second line chemotherapy. Methods: Data from a phase III trial of cabazitaxel plus prednisone compared to mitoxantrone plus prednisone in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC data was randomly split into training (n=507) and testing (n=248) sets. A separate data set consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone (SPARC trial), was used as a second testing set for external validation. Adaptive Lasso selected nine baseline prognostic factors of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.25) and high (≥-1.25) risk groups in the two testing sets. The model was assessed on the testing sets for its predictive accuracy using area under the curve (AUC). Results: The 9 prognostic variables in the final 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. The median OS in the TROPIC testing set were 11 and 16 months in the high and low risks, respectively, with a hazard ratio (HR) 2.3 (p-value<0.0001). The median OS in SPARC were 11 and 20 months in the high and low risk groups, respectively (HR=2.0, p<0.0001). The AUC for this model was 0.73 (95 CI 0.68-0.72) and 0.70 (95 CI 0.72-0.74) on the two testing sets (TROPIC, and SPARC), respectively. Conclusions: A prognostic model of OS in the post-docetaxel second line chemotherapy mCRPC setting was developed and externally validated. This model can be used to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 24-24
Author(s):  
Susan Halabi ◽  
Chen-Yen Lin ◽  
Eric Jay Small ◽  
Andrew J. Armstrong ◽  
Ellen B. Kaplan ◽  
...  

24 Background: Several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve 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. Methods: 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). Results: 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. Conclusions: 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.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4515-4515 ◽  
Author(s):  
Susan Halabi ◽  
Andrew J. Armstrong ◽  
A. Oliver Sartor ◽  
Johann Sebastian De Bono ◽  
Ellen B Kaplan ◽  
...  

4515 Background: PSA kinetics, and more specifically a 30% decline in PSA following initiation of first-line chemotherapy with docetaxel, has been reported to be a surrogate endpoint for OS in mCRPC pts. The objective of this analysis was to evaluate PSA kinetics as surrogate endpoints for overall survival (OS) in patients who were receiving second line chemotherapy following progression after docetaxel front line therapy. Methods: Data from a phase III trial of 755 mCRPC pts randomized to treatment with cabazitaxel in combination with prednisone (C+P) every 3 weeks or mitoxantrone in combination with prednisone (M+P) were used. All pts were previously treated with a docetaxel-containing regimen. PSA decline (≥30% and ≥50% ) and PSA velocity within the first three months of treatment were evaluated as potential surrogate endpoints for OS. The proportional hazards (PH) model was used to test for Prentice’s criteria and the proportion of treatment explained (PTE) was computed as a second test of surrogacy. PTE was defined as one minus the ratio of the treatment coefficient in the adjusted PH model (includes PSA decline or velocity) to the treatment coefficient in the unadjusted PH model. Results: Of 755 men, 654 had sufficient PSA data to be included in the analysis. Treatment arm (C+P vs. M+P) was prognostic of OS with a hazard ratio (HR) of 0.65 (95% CI=0.54-0.79, p<0.001). A 30% PSA decline within three months of treatment was associated with a HR of 0.46 (95% CI 0.37-0.57, p-value<0.001) for OS. After adjusting for treatment effect, the HR for 30% PSA decline was 0.50 (95% CI= 0.40-0.62, p<0.001) but treatment arm remained statistically significant thus failing Prentice’s third criterion. The PTE for ≥30% decline in PSA within three months was 0.39 (95% CI= 0.36-0.42) indicating a lack of surrogacy for OS. Similar results were observed for pts who experienced ≥50% decline in PSA and PSA velocity. Conclusions: Neither PSA decline (≥30% and ≥50%) nor PSA velocity within the first three months of therapy are surrogate endpoints for OS in pts receiving second line chemotherapy.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16036-e16036
Author(s):  
Jerome Fayette ◽  
Valentine Polivka ◽  
Sylvie Chabaud ◽  
Bertrand Favier ◽  
Severine Racadot ◽  
...  

e16036 Background: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Methods: With the standard first line association platinum 5FU and cetuximab, median overall survival (OS) for RMHNSCC was 10.1 months (95% CI [8.6 – 11.2]) (N Engl J Med. 359:1116). Due to the toxicity of this treatment we often offer alternative therapy to our pts. This work aimed to evaluate impact of different 1st line treatment on OS. Results: At initiation of palliative chemotherapy, median age was 62 [29-87]; PS was 0, 1, 2, 3 in 13%, 59%, 16% and 11% of pts, respectively. First line chemotherapy consists in combination cisplatin+taxanes (CIST) 24%, caboplatin+taxanes (CART) 33%, cisplatin or carboplatin without taxanes (NOT) 15% or others (OTH) 28%. Median OS was estimated to 9.6 months CI95%=[8.1-11.4], with 39% of pts; CI95%=[32-47] still alive at 1-year. Second line of treatment has been initiated in 61% of pts. Some of them have even been able to have up to 3, 4 or more than 4 lines of treatment in 19%, 11% and 4% of pts, respectively. In the subgroup analysis, which represents a population similar to those included in [ref1], first line chemotherapy was CIST, CART, NOT or OTH in 30%, 30%, 18% and 22%, respectively. Median OS was 13.0 months, CI95%=[11.2-17.7] reaching up to 15.3 months for CIST subgroup. Second line of treatment was initiated in 73% of pts, with 20%, 15% and 5% of pts having a third, a fourth, and a fifth line, respectively. Conclusions: We can reach for unselected pts the best OS published in phase III studies. The use in first line of combination of platinum and taxanes, followed by monotherapies with cetuximab, capecitabine and methotrexate allows reaching OS of 13 months.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15019-e15019 ◽  
Author(s):  
MinYuen Teo ◽  
Raymond S. McDermott

e15019 Background: Many clinicians adopt a nihilistic approach to the management of APC. Delivery of 2L-Ctx is relatively uncommon and no recognized standard exists. We sought to examine the published activity of chemotherapy in the 2nd line setting, and the rate of 2L-Ctx delivery and its influence on reported overall survival in 1st line trials. Methods: 1st and 2L-Ctx randomized trials published between 2000 and 2012 were identified from Pubmed, and manuscripts were obtained for data extraction. Pooled weighted objective response rates (ORR) and disease control rates (DCR) were calculated. For 1st line studies, the percentage of patients who received 2L-Ctx were extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Spearman correlation and linear regression were performed. Results: Sixty nine 2L Ctx studies (77 arms, n=2859) were identified. Majority received prior gemcitabine-based chemotherapy. Pooled ORR was 6.6% (95% CI 5.6 – 7.6%) and DCR was 36.7% (34.5 – 38.0%). When only prospective studies were evaluated (42 studies, 48 arms, n=1546), ORR was 5.0% (3.8 – 6.2%) and DCR was 33.9% (31.0 – 36.9%). Exploratory analysis suggested that intensification of gemcitabine-based therapy (ORR: 10.0%; DCR: 54.7%) might be marginally more active than fluoropyrimidine (7.6%; 32.2%) or taxane based 2L-Ctx (5.2%; 33.6%). 28/52 identified 1st line studies (54%) reported the percentage of patients treated with second-line chemotherapy (11 phase II, 28 arms, n=1450; 17 phase III, 33 arms, n=5051). Percentage of 2L-Ctx delivery ranged from 14 – 68% and correlated with OS (r=.49 [.26 – .67], p<.01) and PPS (r=.57 [.36 – .72], p<.01). When phase II studies were excluded, correlation was improved for OS (r=.63 [.35 – .81], p<.01) and PPS (r=.79 [.59 – .89], p<.01). Percentage of locally advanced disease did not correlate with OS/PPS nor affect prior analysis. Conclusions: Whilst awaiting further advancement in the 1st line setting, increased delivery of 2L-Ctx to patients with APC and maintained performance status may offer a survival benefit.


2014 ◽  
Vol 32 (7) ◽  
pp. 671-677 ◽  
Author(s):  
Susan Halabi ◽  
Chen-Yen Lin ◽  
W. Kevin Kelly ◽  
Karim S. Fizazi ◽  
Judd W. Moul ◽  
...  

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.


2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 138-138
Author(s):  
Andrew J. Armstrong ◽  
Ping Lin ◽  
Celestia S. Higano ◽  
Cora N. Sternberg ◽  
Guru Sonpavde ◽  
...  

138 Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naïve men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times.


2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 449-449 ◽  
Author(s):  
Gen Kimura ◽  
Hideaki Takahashi ◽  
Kumiko Umemoto ◽  
Kazuo Watanabe ◽  
Mitsuhito Sasaki ◽  
...  

449 Background: Recently, gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) has been frequently used as a first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer (mPC) in Japan. Nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (MM-398 plus 5FU/LV) has not yet been approved in Japan. Under these circumstances, a modified FOLFIRINOX (mFFX) regimen or S-1 is commonly used as a second-line chemotherapy regimen for patients with mPC after GEM plus nab-PTX has failed. Methods: Between December 2014 and March 2016, 45 patients with mPC received second-line chemotherapy after the failure of GEM plus nab-PTX (standard dose regimen) at the National Cancer Center Hospital East. Twenty-two patients received mFFX (irinotecan, 150 mg/m2; bolus of 5FU was eliminated), 19 received S-1 (80 mg/m2/d; d1-28, q6w or d1-14, q3w), and 4 received other chemotherapy regimens. The clinical records of the patients were reviewed retrospectively. Results: At baseline, S-1 group had a more severe disease status than the mFFX group (performance status of 0: 21% vs. 68%, P = 0.003; median CA19-9 level: 1832 vs. 577 U/mL, P = 0.30). No significant difference in the response rate (S-1, 5.3% vs. mFFX, 9.1%, P = 0.56) or the disease control rate (S-1, 42% vs. mFFX, 36%, P = 0.71) was seen between the two groups. The progression free survival (PFS) (median: S-1 vs. mFFX: 2.7 vs. 2.4 months (m), P = 0.77), the overall survival (OS) from the second-line treatment (median: 6.1 vs. 6.4m, P = 0.87) and the OS from the first-line treatment (median: 10.9 vs. 12.4m, P = 0.77) were not significantly different between the two groups. These results were similar to those observed for MM-398 plus 5FU/LV (PFS, 3.1m; OS, 6.1m) in a pivotal Phase III study (NAPOLI-1). The incidences of peripheral neuropathy (5.3% vs. 32%, P = 0.04), fatigue (11% vs. 50%, P = 0.007), and neutropenia (11% vs. 64%, P = 0.001) were significantly lower in the S-1 group. Conclusions: S-1 was less toxic than mFFX and exerted a similar anti-tumor effect in the present study. S-1 could be a treatment option for patients with mPC refractory to GEM plus nab-PTX.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 296-296 ◽  
Author(s):  
Adnan Nagrial ◽  
Venessa T. Chin ◽  
Katrin Sjoquist ◽  
Lorraine A. Chantrill ◽  
Desmond Yip

296 Background: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. Very few randomised studies have been performed in this setting. The aim of this analysis was to compare the different therapeutic approaches in this setting, and the rate of second line treatment delivery and its influence on reported overall survival. Methods: We carried out a systematic analysis of studies in advanced pancreatic cancer. 1st and 2nd line chemotherapy trials were identified from MEDLINE, EMBASE & CENTRAL using the COCHRANE sensitive search strategy. Objective response rates (ORR) and survival (PFS & OS) were extracted and compared amongst groups using the Mann-Whitney U test. For 1st line studies, the percentage of patients who received 2nd line chemotherapy was also extracted and plotted against reported median overall survival (OS) and post-progression survival (PPS), defined as arithmetic difference between median OS and progression-free survival. Linear regression was used to explore the relationship between overall survival and second-line chemotherapy. Results: 20 first line clinical trials with 42 treatment arms met the inclusion criteria treating an aggregate total of 5,768 patients. Overall survival was positively correlated with use of second-line chemotherapy (r=0.65; p=0.012). 61 second-line studies were identified treating an aggregate total of 2,562 patients in 66 treatment arms. Combination treatment was associated with an improved response rate (p=0.045) and PFS (p=0.024) when compared to single agent therapy. Conclusions: In this exploratory analysis, these data suggest that there is a small benefit of second-line chemotherapy in pancreatic cancer. In first-line chemotherapy studies, the use of subsequent treatment correlates with improved overall survival. In second line studies, combination chemotherapy is associated with higher response rates and survival.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14680-e14680
Author(s):  
Milton Jose B. Silva ◽  
Joyce Maria L. Maia ◽  
Adriana Regina G. Ribeiro ◽  
Ludmilla T. D. Chinen ◽  
Tadeu Ferreira Paiva Jr ◽  
...  

e14680 Background: Despite the lack of high-quality clinical trial data suggesting that second-line chemotherapy (SLC) may affect survival on metastatic pancreatic cancer (mPC), most of centers utilizes them after the failure of initial treatment in patients who maintain a good performance status. The aim of the present study was to review our institutional experience with SLC and estimate its role in overall survival (OS). Methods: We performed a retrospective matched case-control analysis based on search of medical records in 106 consecutive patients with mPC at our institution. Patients received first line chemotherapy (FLC) and SLC (n = 49) or FLC only (n =57) from September 2005 to December 2010. Case matching was performed with respect to age (< 60y versus ≥ 60y), topography (head of the pancreas versus body or tail), sites of metastasis. Overall survival was analyzed by Kaplan-Meier method. Results: Median age was 63 (32-86) and 60 (38-85) for SLC group and FLC group respectively. There was no significant difference between the two groups regarding topography, TNM stage at diagnosis, and sites of metastasis. The main site of metastasis was the liver (24,4%), followed by peritoneum (2,8%).Median follow-up of both groups was 8.4 months (0.23m-54.93m). First line treatment consisted of Gemcitabine (55.1% x 49.1%) and gemcitabine + cisplatin (18.4%x14%) in SLC and FLC group respectively. The most used second line treatment was Capecitabine (32.7%), followed by Folfox (16.3%), and Fluoracil (10.2%). The Kaplan-Meier estimate of the overall median survival, 1-year and 2-years survival rate was 15.72 months versus 7.2 months (p:0.021), and 60% vs. 32%, and 30% vs. 19% in SLC and FLC group, respectively. Conclusions: Our result suggests that second-line chemotherapy may be beneficial to improve overall survival in patients with advanced pancreatic cancer. It’s important that new and ongoing clinical trials clarify which is the best chemotherapy scheme in this setting.


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