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.

Does progression-free-survival (PFS) correlate with overall- and cancer-specific survival (OS/CSS) in randomized clinical trials (RCTs) exploring the addition of hormonal therapy (HT) to radiotherapy (RT) for early prostate cancer (EPC)? Analysis of six RCTs

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5056-5056
Author(s):  
E. M. Ruggeri ◽  
E. Bria ◽  
P. Carlini ◽  
F. Cuppone ◽  
M. Milella ◽  
...  
Keyword(s):  
Sample Size ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Outcome Data ◽  
Phase Iii ◽  
Cancer Specific Survival ◽  
End Point ◽  
Target Sample Size ◽  
Phase Iii Trials ◽  
Beta Coefficient

5056 Background: Although PFS is considered the standard primary end-point in EPC, the correlation with OS has never been explored in RCTs randomizing patients (pts) to HT plus radiotherapy (RT) versus RT. Given the relatively long prognosis in this disease setting, the correlation between PFS and CSS should be investigated as well. Methods: All phase III trials reporting all outcome’ data were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (PFS, OS and CSS rates) for all arms, and each reported Hazard Ratio (HRs). The correlation was estimated according to both the Pearson- (r) and R2-coefficient (parametric) and the Spearman coefficient (Rho, non-parametric). A sensitivity analysis in 2 subgroups (long- and short-term HT) to test for effect robustness has been accomplished as well. A model to determine the target sample size to determine CSS benefit of 3%, 4%, 6% and 7% months, respectively, was calculated as well. Results: Six RCTs (4,212 pts) were collected (follow-up range: 4.5–7.6 years). In the overall population, when considering the crude rates, a linear stronger correlation was found between PFS and CSS (r=0.71, R2=0.51, p=0.003; Rho=0.75, p=0.005), rather than with OS (r=0.55, R2=0.30, p=0.06; Rho=0.78, p=0.11). Again, when considering HRs, a linear stronger correlation was found between PFS and CSS (r=0.87, R2=0.76, p=0.02; Rho=0.94, p=0.005), rather than with OS (r=0.75, R2=0.56, p=0.08; Rho=0.77, p=0.07). Similar correlations were found whatever subgroups was explored. The sample size model (on the basis of the beta-coefficient=0.71), calculate 4,575, 2,006, 1,115 and 700 pts to improve PFS of 4%, 6%, 8%, and 10% months, which means to improve CSS of 2.8%, 4.3%, 5.7% and 7.1%, respectively. Conclusions: The correlation between PFS and CSS in RCTs exploring the benefit of adding HT to RT for EPC is significant, and suggests its further investigation as surrogate end-point. The natural history of the disease clearly explains the stronger correlation of PFS with CSS rather than with OS. No significant financial relationships to disclose.

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.

scholarly journals Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

2016 ◽  
Vol 34 (3) ◽  
pp. 280-285 ◽  
Author(s):  
Maha Hussain ◽  
Catherine Tangen ◽  
Celestia Higano ◽  
Nicholas Vogelzang ◽  
Ian Thompson
Keyword(s):  
Prostate Cancer ◽  
Statistical Power ◽  
Progression Free Survival ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
End Point ◽  
Phase Iii Clinical Trials ◽  
Noninferiority Trials ◽  
Phase Iii Trials

Purpose Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Patients and Methods Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Results Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. Conclusion No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non–prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials.

Elective versus therapeutic neck dissection in the clinically node negative early oral cancer: A randomised control trial (RCT).

2015 ◽  
Vol 33 (18_suppl) ◽  
pp. LBA3-LBA3 ◽  
Author(s):  
Anil D'Cruz ◽  
Mitali Dandekar ◽  
Richa Vaish ◽  
Supreeta Arya ◽  
Gouri Pantvaidya ◽  
...  
Keyword(s):  
Neck Dissection ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Squamous Carcinoma ◽  
Phase Iii ◽  
Randomised Control Trial ◽  
Elective Neck Dissection ◽  
Clinical Equipoise ◽  
End Point

LBA3 Background: Management of the neck in early oral cancers has been a matter of debate with clinical equipoise between elective (END) or therapeutic neck dissection (TND). Methods: This is a prospective phase III RCT (NCT00193765) to test the superiority of END at the time of primary surgery over TND (neck dissection at the time of nodal relapse) in patients with lateralized T1 or T2 squamous carcinoma of oral cavity, amenable to peroral excision. Patients were stratified based on size, site, sex and preoperative neck ultrasound. The primary end point was overall survival (OS) and secondary end point was disease-free survival (DFS). The trial was planned to demonstrate a 10% superiority (1-sided α = 0.05 and β = 0.2) in OS for END vs. TND, assuming 60% 5-year OS in TND arm, with a planned sample size of 710. Results: This trial was terminated after 596 patients were randomized between January 2004 and June 2014. An interim intent-to-treat analysis of initial 500 patients (255 in TND, 245 END) with a minimum follow-up of 9 months was performed as mandated by Data and Safety Monitoring Committee based on the number of observed deaths in each arm. Both arms were balanced for site and stage. There were 427 tongue, 68 buccal mucosa and 5 floor of mouth tumors; 221 were TI and 279 T2. At a median follow-up of 39 months there were 146 recurrences in TND and 81 in END arms respectively. The 3-year OS was significantly higher in END compared to TND arm (80.0% vs. 67.5%, HR = 0.63, 95%CI 0.44-0.89, p = 0.01) as was 3-year DFS (69.5% vs. 45.9%, HR = 0.44, 95%CI 0.34-0.58, p < 0.001). After adjusting for stratification factors in Cox regression, END continued to be significantly superior to TND for both OS and DFS. Conclusions: There were 8 excess deaths for every 15 excess recurrences in the TND arm. Elective neck dissection in patients with early oral SCC results in 37% reduction in mortality and should be considered the standard of care. Clinical trial information: NCT00193765.

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.

Cancer chemoprevention.

1994 ◽  
Vol 12 (4) ◽  
pp. 851-873 ◽  
Author(s):  
S M Lippman ◽  
S E Benner ◽  
W K Hong
Keyword(s):  
Clinical Trials ◽  
Cancer Incidence ◽  
Randomized Clinical Trials ◽  
Alpha Tocopherol ◽  
Phase Iii ◽  
Significant Activity ◽  
Chemopreventive Agents ◽  
Primary Tumors ◽  
End Point ◽  
Phase Iii Trials

PURPOSE To review the most important recent advances in clinical trials and biologic studies within the growing field of chemoprevention. METHODS The most critical methods issue concerns the definitive end point of phase III trials, which is now cancer incidence. This end point usually needs thousands of subjects monitored for 5 to 10 or more years to determine efficacy. Biologic markers of potential intermediate end points are under intensive study and may one day replace cancer incidence. Validated intermediate end point biomarkers could greatly reduce phase III trial populations, durations, and costs. RESULTS Randomized clinical trials over the last 5 years have produced significant activity in reversing oral, skin, colon, and cervical premalignancy; in preventing primary skin and stomach cancer; and in preventing second primary tumors associated with head and neck and lung cancer. These clinical advances have been paralleled at the basic science level by elegant molecular studies of premalignant carcinogenesis and of chemopreventive agents' mechanisms of action. One major laboratory advance is the discovery of nuclear retinoic acid receptors and strong evidence of their roles both in carcinogenic progression and in its response to retinoids. CONCLUSION Chemoprevention has matured greatly in recent years with the significant reversal or suppression of premalignancy by chemopreventive agents in several sites. The future of chemoprevention will be determined largely by several ongoing phase III trials, including trials of retinoids, beta-carotene, and alpha-tocopherol in the aerodigestive tract, of tamoxifen and fenretinide in the breast, and of finasteride in the prostate.

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]

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

2005 ◽  
Vol 23 (34) ◽  
pp. 8664-8670 ◽  
Author(s):  
Daniel J. Sargent ◽  
Harry S. Wieand ◽  
Daniel G. Haller ◽  
Richard Gray ◽  
Jacqueline K. Benedetti ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Clinical Trials ◽  
Individual Patient Data ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
End Point ◽  
Disease Free

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

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.

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