Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.

2017 ◽  
Vol 35 (18_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
Qian Shi ◽  
Alberto F. Sobrero ◽  
Anthony Frank Shields ◽  
Takayuki Yoshino ◽  
James Paul ◽  
...  
Keyword(s):  
Cox Model ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Stage Iii ◽  
Differential Outcomes ◽  
Phase Iii Trials ◽  
Stratified Cox Model

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4011-4011
Author(s):  
D. J. Sargent ◽  
G. Yothers ◽  
E. Van Cutsem ◽  
J. Cassidy ◽  
L. Saltz ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Weighted Least Squares ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Stage Iii ◽  
Hazard Ratios ◽  
Phase Iii Trials ◽  
Prediction Limits ◽  
Control Association

4011 Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint. [Table: see text] [Table: see text]

End Points for Colon Cancer Adjuvant Trials: Observations and Recommendations Based on Individual Patient Data From 20,898 Patients Enrolled Onto 18 Randomized Trials From the ACCENT Group

2007 ◽  
Vol 25 (29) ◽  
pp. 4569-4574 ◽  
Author(s):  
Daniel J. Sargent ◽  
Smitha Patiyil ◽  
Greg Yothers ◽  
Daniel G. Haller ◽  
Richard Gray ◽  
...  
Keyword(s):  
Individual Patient Data ◽  
Strong Predictor ◽  
Disease Free Survival ◽  
Patient Data ◽  
Phase Iii ◽  
Stage Iii ◽  
End Points ◽  
End Point ◽  
Phase Iii Trials

Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3501-3501 ◽  
Author(s):  
Timothy Iveson ◽  
Alberto F. Sobrero ◽  
Takayuki Yoshino ◽  
Ioannis Sougklakos ◽  
Fang-Shu Ou ◽  
...  
Keyword(s):  
High Risk ◽  
Cox Model ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
Stage Ii ◽  
Phase Iii ◽  
Stage Iii ◽  
Primary Analysis ◽  
Nodal Harvest

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.

scholarly journals Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer

2011 ◽  
Vol 29 (34) ◽  
pp. 4491-4497 ◽  
Author(s):  
Edith A. Perez ◽  
Vera J. Suman ◽  
Nancy E. Davidson ◽  
Julie R. Gralow ◽  
Peter A. Kaufman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
P Value ◽  
Sequential Administration ◽  
Taxane Chemotherapy

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen.

Gemcitabine-based polychemotherapy for advanced pancreatic cancer (APC): Is it ready for prime time? A pooled analysis of 3,682 patients (pts) enrolled in 12 phase III trials

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4118-4118 ◽  
Author(s):  
M. Milella ◽  
P. Carlini ◽  
A. Gelibter ◽  
E. Ruggeri ◽  
A. Ceribelli ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Random Effect ◽  
Single Agent ◽  
Random Effect Model ◽  
Advanced Pancreatic Cancer ◽  
Standard Of Care ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Combination Regimens

4118 Background: Since the introduction of gemcitabine (G), attempts have been made to develop G-based combination regimens to improve the dismal outcome of APC pts. Results of randomized trials, however, have been conflicting and single-agent G presently remains the standard of care for such pts. Methods: All prospective phase III trials comparing single-agent G with G-based polychemotherapy regimens (poly-G) were considered eligible. A pooled analysis was performed and event-based relative risk ratios (RR) with 95% CI were derived through both a fixed- and a random-effect model approach, exploring OS as the primary outcome and PFS and ORR as secondary outcomes. Heterogeneity between different trials was also taken into account. Results: Twelve trials involving 3682 pts were identified. The analysis was conducted considering three different subgroups: 1) overall population (3682 patients, 12 trials), 2) platinum-containing poly-G (PG) vs G (768 pts, 5 trials), and 3) fluoropyrimidine-containing poly-G (FG) vs G (1640 pts, 4 trials). As shown in the table, no significant differences in the primary outcome (OS) were observed in any of the three groups analyzed. Conversely, a significant advantage for poly-G was evident with regard to both PFS and ORR in the overall population as well as in the PG vs G subgroup, although with some heterogeneity. A heterogeneous non-significant trend towards a better PFS and ORR outcome was also observed in the FG vs G subgroup. Conclusions: Single-agent G remains the treatment of choice in APC pts. However, the addition of platinum compounds to G appears to significantly improve PFS and ORR, possibly justifying the use of platinum-based poly-G in younger and fit patients. [Table: see text] No significant financial relationships to disclose.

Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 407-407 ◽  
Author(s):  
Alison Jane Birtle ◽  
John David Chester ◽  
Robert Jones Jones ◽  
Mark Johnson ◽  
Michaela Hill ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Randomised Trial ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Stopping Rules ◽  
Phase Iii ◽  
Early Stopping ◽  
Cross Sectional ◽  
Free Survival

407 Background: The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC. Methods: Pts (max n = 345) ≤90 days post NU were randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p < 0.001) early stopping rules for efficacy & inefficacy. Secondary endpoints included metastasis-free survival (PFS), overall survival (OS), toxicity & quality of life. Results: Between May 2012 & Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 05/09/2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Pts had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0;. Grade ≥3 toxicities were reported in 60% chemotherapy pts & 24% surveillance pts. 47/123 (surveillance) & 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favour of chemotherapy (log-rank p = 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). PFS favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003). Conclusions: Adjuvant chemotherapy improved PFS in UTUC. POUT is the largest randomised trial in this pt population; the trial was terminated early because of efficacy favouring the chemotherapy arm. Whilst follow up for OS continues, this should be considered a new standard of care in these patients. Clinical trial information: ISRCTN98387754.

Prognostic value of tumor deposits for disease free survival in patients with stage III colon cancer: A post hoc analysis of IDEA France phase III trial (PRODIGE-GERCOR).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3519-3519
Author(s):  
Jean Francois Delattre ◽  
Romain Cohen ◽  
Julie Henriques ◽  
Antoine Falcoz ◽  
Jean-François Emile ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cox Model ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Tnm Staging ◽  
Phase Iii ◽  
Stage Iii ◽  
Free Survival ◽  
Stage Iii Colon Cancer ◽  
Disease Free

3519 Background: Tumor deposits (TDs) are isolated tumor foci in the pericolic, perirectal or mesocolic fat without residual lymph node (LN) tissue. TDs seem to impact the prognosis of stage III colon cancer (CC) patients (pts) but are only considered in TNM staging in the absence of LN metastases (LNM). We aimed at evaluating the prognosis value for disease free survival (DFS)of TDs in International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France phase III study (NCT00958737) that compared 3 versus 6 months of adjuvant FOLFOX or CAPOX for stage III CC pts. Methods: All pathological reports of pts included in IDEA France trial were retrospectively analyzed. DFS according to the presence or absence of TDs was evaluated using Kaplan-Meier estimator. Multivariable Cox model analysis was performed to evaluate the association between TDs and DFS. This analysis did not included immunohistochemical biomarkers. Results: Among the 2022 pts included in IDEA France study, 1942 (96%) were analyzed. 80 pts were excluded: no pathological report (n = 68), pts without treatment (n = 12). TDs were found in 184 pts (9.47%), of whom 74 with N1a/b (40%), 55 with N1c (30%) and 55 with N2 LN stage (30%). All characteristics were similar according to the presence of TDs, except for tumor/node (TN) stage (T4 and/or N2 are more frequent in pts with TDs; p = .0046). The 3-year DFS rates were 65.59% [95% confidence interval (95%CI) 58.04-72.12] and 74.71% [95%CI 72.57-76.71] for pts with and without TDs, respectively (p = 0.0079). In multivariable analysis, TDs were associated with higher risk of recurrence or death (hazard ratio (HR) = 1.36, 95%CI 1.05-1.75, p = .0201), as well as T4 and/or N2 (HR = 2.21, 95%CI 1.03-1.59, p < .001), 3 months of adjuvant treatment (HR = 1.29, 95%CI 1.09-1.52, p = .0029), obstruction (HR = 1.28, 95%CI 1.03-1.59, p = .0233) and male (HR = 1.24, 95%CI 1.04-1.46, p = .0151). Adding TDs count to the LNM count, 35 out of 1454 N1a/b/c CC pts (2.4%) were reclassified as N2 and experienced worse 3 years DFS than confirmed N1 CC pts (p = .0151). Conclusions: TD is an independent and valuable prognostic factor for DFSin stage III CC pts and should be considered whatever the LNM status.

Prolongation of the average survival time in pancreatic cancer (a new measure of effect): Pooled analysis of adjuvant chemotherapy trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16723-e16723
Author(s):  
Eduardo Ceballos Barbancho ◽  
Galo Sánchez Robles
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Treatment ◽  
Area Under The Curve ◽  
Pooled Analysis ◽  
National Institutes Of Health ◽  
Phase Iii ◽  
Processing Application ◽  
Average Survival ◽  
Phase Iii Trials

e16723 Background: With the aim of improving the prognosis of the disease, in recent years attempts have been made to optimize the adjuvant treatment of pancreatic cancer, having demonstrated the usefulness of chemotherapy in several phase III trials: CONKO-001, JASPAC-01, ESPAC -4 and PRODIGE. Methods: The method to measure the Area Under the Curve (AUC) is universally known. When the curve is not homogeneous, the AUC is calculated using the traditional method of breaking down the total area into a sum of many polygons. We have calculated the AUC through pixel counting using Image J, which is an image processing application, programmed in Java, developed in the National Institutes of Health and free to access. To estimate the consistency between the pixels and the sum of polygons, we have performed several curves with linear edges to measure the AUC through the sums of the polygons, and then by counting pixels with the Image J application. We have verified that the results are similar, so the pixel count can be used to replace the sum of polygons, especially when the curves are not homogeneous. Entering the areas obtained with Image J in the worksheet, made for this purpose, and available for free at evalmed.es, the measures of the effect are automatically obtained: prolongation of the average surival time (PtS), prolongation of the average event free time (PtSLEv) and time lived without an event (PtvSEV). Results: The median follow-up in all studies was 60 months, with the exception of CONKO-001, for which we have data at an average follow-up time of 136 months, however for our comparative purpose we cite the results in the first 60 months. -CONKO-001: PtS was 5.1 months (24.2 observation vs 29.3 gemcitabine). PtSLEv was 9.6 months (13 observation vs 22.6 gemcitabine). PtvSEv was 22.57 months. -JASPAC-01: PtS was 9.04 months (32.4 gemcitabine vs 41.5 gemcitabine + S1). PtSLEv was 9.75 months (21.6 gemcitabine vs 31.4 gemcitabine + S1). PtvSEv was 31.38 months. -ESPAC-4: PtS was 3.2 months (34 gemcitabine vs 37.2 gemcitabine + capecitabine). PtSLEv was 2.7 months (25.6 gemcitabine + 28.3 gemcitabine + capecitabine). PtvSEv was 24.92 months. -PRODIGE: PtS was 6 months (37 gemcitabine vs 43 FOLFIRINOX). PtSLEv was 8.9 months (22.4 gemcitabine vs 31.2 FOLFIRINOX). PtvSEv was 31.23 months. Conclusions: In the adjuvant treatment with chemotherapy in pancreatic cancer, the transit from observation to gemcitabine, and from here to the most intensive schedules, has meant or contributed an important advance for patients in terms of PtS, PtSLEv and PtvSEv.

Three-year disease-free survival (DFS) as surrogate end-point for predicting five-year overall survival (OS) benefit in adjuvant taxane-based chemotherapy for breast cancer (BC): Analysis of 10 randomized clinical trials (RCTs)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 584-584
Author(s):  
D. Giannarelli ◽  
E. Bria ◽  
F. Cuppone ◽  
M. Ciccarese ◽  
C. Nisticò ◽  
...  
Keyword(s):  
Sample Size ◽  
Randomized Clinical Trials ◽  
Data Transfer ◽  
Disease Free Survival ◽  
New Drugs ◽  
Phase Iii ◽  
End Point ◽  
Early Results ◽  
Phase Iii Trials

584 Background: The issue regarding the eventual correlation between DFS at earlier follow-up (i.e. 3-yrs) with 5-yrs OS has not actually been explored in trials addressing the role of taxanes in BC. All RCTs in which patients were randomized to receive a standard or a taxane-based regimen for early BC were analyzed to evaluate this topic. Methods: All phase III trials with at least 60 month follow-up were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (DFS/OS) for all arms (extracted by curves), their differences, and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following 2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2) correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was estimated according to Pearson (r) and R2 coefficients (parametric) and Spearman (Rho) coefficient (non- parametric). A model to calculate the target sample size to determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well. Results: Ten RCTs (17,067 patients) with available data for outcomes were gathered. For 5-yrs DFS/OS, a linear correlation was found between rates (r=0.74, R2=0.55; p<0.0001; Rho=0.83; p<0.0001), and HRs (r=0.90, R2=0.81; p<0.0001; Rho=0.91; p<0.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81, R2=0.66; p<0.0001; Rho=0.92; p<0.0001), and RRs (r=0.84, R2=0.71; p=0.002; Rho=0.85; p=0.002). Three-yrs DFS and 5-yrs OS absolute differences strongly correlate (r=0.86, R2=0.74; p=0.001; Rho=0.84; p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculates 2,733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively. Conclusions: By these data, 3-yrs DFS is a reliable surrogate end-point for OS when testing new drugs in early BC, and is able to predict a late survival benefit. Thanks to the smaller patient sample size, RCTs with this design will provide early results in a shorter time period, allowing a faster data transfer to clinical practice. No significant financial relationships to disclose.

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