Primary Endpoint Of Disease-free Survival Research Articles

414P Long-term follow-up of the randomized trial of the conventional technique versus the no-touch isolation technique for primary tumor resection in patients with colon cancer ( JCOG1006)

The no-touch isolation technique (No Touch) aims to reduce cancer cells from the primary tumor site to the liver and other organs by preceding ligation of blood vessels that feed the primary tumor. We conducted a phase III trial (JCOG1006) to confirm the superiority of No Touch in patients with cT3/T4 colon cancer, with a primary endpoint of disease-free survival (DFS). The planned primary analysis at 3 years after the last patient-in failed to confirm the superiority of No Touch compared with conventional technique (Conventional). The present study aimed to compare No Touch and Conventional using long-term follow-up data with 6 years after the last patient-in. Eligibility criteria included histologically proven colon cancer; tumor located in the cecum, ascending, transverse, descending, sigmoid or rectosigmoid colon; clinical T3 or T4, N0-2, M0; patients aged 20-80 years. Patients were randomized preoperatively to either Conventional arm or No Touch arm. Operation was performed by open surgery. Patients with pathological stage III received adjuvant chemotherapy with capecitabine. Planned sample size was 850 to detect a hazard ratio (HR) of 0.732 in DFS with one-sided alpha of 5% and power of 80%. A total of 853 patients were randomized (Conventional: 427, No Touch: 426) between January 2011 and November 2015. The 6-year DFS were 70.3% and 69.4% in the Conventional arm and No Touch arm, respectively. The HR was 1.030(95% CI 0.813-1.304); therefore, the superiority of No Touch was not confirmed (p=0.60). The 6-year overall survival (OS), 6-year relapse-free survival (RFS) and 6-year liver-relapse-free survival (LRFS) are shown in the table.Table: 414PConventional (95% CI)No touch (95% CI)HR (95% CI)6-year DFS70.3% (65.7-74.4%)69.4% (64.8-73.6%)1.030 (0.813-1.304)6-year OS89.4% (86.0-92.0%)86.6% (82.9-89.5%)1.276 (0.902-1.807)6-year RFS78.9% (74.7-82.5%)75.0% (70.6-78.8%)1.209 (0.920-1.589)6-year LRFS85.1% (81.2-88.2%)80.2% (76.0-83.8%)1.311 (0.961-1.787) Open table in a new tab Long-term follow-up data did not support superiority of No Touch compared with Conventional in the patents with stage II and III colon cancer.

PLLBA-01 PEMBROLIZUMAB (PEMBRO) VS PLACEBO AS POST NEPHRECTOMY ADJUVANT THERAPY FOR PATIENTS (pts) WITH RENAL CELL CARCINOMA (RCC): RANDOMIZED, DOUBLE-BLIND, PHASE 3 KEYNOTE-564 STUDY

PLLBA-01 PEMBROLIZUMAB (PEMBRO) VS PLACEBO AS POST NEPHRECTOMY ADJUVANT THERAPY FOR PATIENTS (pts) WITH RENAL CELL CARCINOMA (RCC): RANDOMIZED, DOUBLE-BLIND, PHASE 3 KEYNOTE-564 STUDY

653O Pembrolizumab (pembro) vs placebo as adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): Patient-reported outcomes (PRO) in KEYNOTE-564

The randomized, double-blind, phase III KEYNOTE-564 (NCT03142334) study met its primary endpoint of disease-free survival with adjuvant pembro vs placebo following surgery in pts with RCC. We present PRO findings for adjuvant pembro vs placebo in KEYNOTE-564.

Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study.

LBA5 Background: Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC. Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts. Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred. Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334.

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma (MIUC).

5000 Background: Radical surgery ± cisplatin-based neoadjuvant chemo (NAC) is the mainstay treatment (tx) for MIUC, with no conclusive level 1 evidence for adjuvant chemo (AC). Here we present the primary analysis from IMvigor010, a global, open-label, multicenter, randomized trial of adjuvant atezo (anti–PD-L1; approved in metastatic UC [mUC] settings) in pts with MIUC at high risk of recurrence following primary resection. Methods: Pts with MIUC (bladder, upper tract [UT]), ECOG PS 0-2 and resected tissue for PD-L1 testing on immune cells (IC; VENTANA SP142 assay) were enrolled ≤ 14 wks after radical cystectomy/nephroureterectomy with lymph node (LN) dissection. Pathologic stage: 1) ypT2-4a or ypN+ if pts had NAC or 2) pT3-4a or pN+ if pts did not have NAC. No postsurgical radiation or AC was allowed; if no NAC was given, pts must have been ineligible for or declined cisplatin-based AC. Pts were randomized 1:1 to atezo 1200 mg IV q3w or obs for 16 cycles or 1 y (stratification factors: no. of LNs resected, pathologic nodal status, pathologic tumor stage, PD-L1 status, prior NAC). Disease-free survival (DFS) was the primary endpoint (EP). Final DFS, first interim overall survival (OS; secondary EP) and safety are reported. Results: The ITT population included 809 pts (median follow-up, 21.9 mo). In the atezo and obs arms, respectively, 48% and 47% had NAC; 7% and 6% had UTUC as primary disease; 48% each had LN+ disease. DFS and OS are in Table. Baseline prognostic/clinical factors did not influence DFS tx benefit; stratified HR was 0.81 (95% CI: 0.63, 1.05) in IC0/1 pts (PD-L1 < 5%; n = 417) and 1.01 (0.75, 1.35) in IC2/3 pts (PD-L1 ≥ 5%; n = 392). 16% of atezo-treated pts had a tx-related G3-4 AE. Skin and gastrointestinal toxicities most commonly led to tx discontinuation. Conclusions: IMvigor010, the first phase 3 adjuvant study of a checkpoint inhibitor in MIUC, did not meet its primary EP of DFS. More tx discontinuation due to AEs was seen vs mUC studies. Safety was generally consistent with previous studies. Clinical trial information: NCT02450331 . [Table: see text]

Abstract A43: Spatial organization of pancreatic ductal adenocarcinoma (PDAC)–associated immune cells from the Adjuvant Pancreatic Adenocarcinoma Clinical Trial (APACT) study

Abstract Introduction: It is strikingly difficult to develop successful treatments for PDAC; even with curative resection, most patients die from early occult metastases. Prior studies identified the presence of tumor-infiltrating lymphocytes (TILs) in primary PDAC tumors as having prognostic significance in the PDAC adjuvant setting, sharpening the questions of what fraction of patients have immune-infiltrated tumors and what therapeutic strategies should be pursued in these patients vs. the non-infiltrated group. The phase 3 APACT trial evaluated the use of adjuvant nab-paclitaxel plus gemcitabine vs. gemcitabine in 866 patients with PDAC who had undergone primary tumor resection, with the primary endpoint of disease-free survival evaluated by independent review. We extended studies of the tumor microenvironment of PDAC to a large set of resected APACT primary tumors in an effort to further refine features of tumor or immune infiltrate that influence disease progression and to determine if chemotherapy regimen–specific predictive signatures are identifiable. Tissue analyses for a large subset of APACT samples included RNA-seq, DNA-seq, multiplexed immunohistochemistry (IHC), and proteomics. Methods: We imaged and quantified markers for tumor cells, 7 different immune cells, and 2 immune checkpoint markers using bright-field chromogenic multiplexed IHC from pretreatment samples for more than 500 APACT primary tumor samples. We computationally defined the tumor, tumor margin, and distal stromal (> 150 μm from tumor boundary) regions, and quantified densities and distributions of immune cells in these regions. As part of an initial analysis of more than 400 samples, we applied both unsupervised clustering and supervised classification to these IHC measurements to identify patient subgroups with similar spatial arrangements of immune cells relative to tumor regions. Results: The preliminary analysis of normalized cell densities across all 3 tissue regions revealed 3 patient subgroups: one in which immune cells are mixed within the tumor regions; a second where immune cells approach the tumor boundary but are depleted within the tumor; and a third in which immune cells are depleted in both tumor and its margin, remaining at high densities only in the distal stromal regions. Within these latter subgroups, CD20+, CD4+, and CD8+ cells were more prevalently depleted from tumor and/or margin, whereas CD163+ and CD163+CMAF+ cells showed less of this arrangement. Nearly 85% of patients fell in the second or third patient group. Conclusions: We are pursuing analyses of these data in conjunction with upcoming molecular and genetic profiling data to further elucidate the association of the immune cell populations and these subgroups with clinical outcomes. These data will provide an unprecedented opportunity for exploratory analysis and discovery of immune, molecular, and genetic biomarkers for PDAC patient stratification. Citation Format: David J. Reiss, Thomas Lila, Suzana Couto, Sitharthan Kamalakaran, Yan Ren, Doug Bowman, Amber Ortiz, Maria Wang, Clifton Drew, Kao-Tai Tsai, Mathieu Marella, Brian Fox, Garth McGrath, Matthew Trotter, Fadi Towfic, Ian Cushman, Alexander Ratushny, Brian Lu, Daniel Pierce, Jim Cassidy. Spatial organization of pancreatic ductal adenocarcinoma (PDAC)–associated immune cells from the Adjuvant Pancreatic Adenocarcinoma Clinical Trial (APACT) study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A43.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. F Hoffman-La Roche Ltd.

Phase II multicenter study of adjuvant S-1 for colorectal liver metastasis: survival analysis of N-SOG 01 trial

We previously showed that S-1 after curative resection of colorectal liver metastasis had acceptable toxicity and a high rate of completion of therapy in a prospective phase II trial. We here reported the primary endpoint of disease-free survival (DFS). Between October 2008 and August 2010, 60 patients were eligible for this study and received S-1 for 28days followed by a 2-week rest period. Treatment was started within 8weeks after surgery and repeated for eight cycles. Median follow-up was 41months. Among 60 patients, 45 had solitary metastasis, and the median maximum tumor diameter was 2.6cm. The 3-year DFS and overall survival were 47.4 and 80.0%, respectively. Recurrences developed in 31 patients, with the remnant liver the most common site (19 patients). Multivariate analysis showed that positive lymph node metastasis around the primary site (p=0.013) and early liver metastasis (synchronous disease or metachronous disease within 12months) (p=0.041) were independent poor prognostic factors for DFS. Patients having both risk factors had a significantly worse DFS than those without these risk factors (p<0.001). Early liver metastasis was an independent indicator of early recurrence within 1year. S-1 after curative liver resection yielded promising survival in patients with a low tumor burden. Outcome in patients having both positive lymph node metastasis around the primary site and early liver metastasis was much worse than in patients without these conditions; therefore, they might warrant more aggressive therapy.

Abstract S3-02: NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients (pts) with node-negative breast cancer

Abstract Background NSABP B-36 was originally designed as a 2X2 factorial randomized study to compare 6 cycles of FEC-100 with 4 cycles of standard AC with or without celecoxib in pts with node-negative breast cancer. The rationale for the trial was based on observations from other adjuvant trials suggesting that longer duration of anthracycline-based therapy may result in improved outcomes and also on accumulating evidence that prostaglandins may contribute to the malignant phenotype in breast cancer. The trial opened in May 2004 but random assignment to celecoxib v placebo was terminated in December 2004 (after 327 pts were enrolled) because of concerns for increased risk of cardiovascular disease with the use of COX-2 inhibitors. The trial continued as a two-arm study and completed accrual in July 2008. The primary endpoint of disease-free survival (DFS), and secondary endpoints of overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), and adverse events comparing FEC-100 and AC are reported here. Analyses of quality of life indicators will be reported separately. Methods 2,722 pts with T1-3, pN0 breast cancer were randomly assigned to either adriamycin 60 mg/m2 and cyclophosphamide 600mg/m2 every 21 days for 4 cycles (n=1361) or 5-FU 500mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days for 6 cycles (n=1361). Hormone- receptor positive pts were to receive physician's choice of hormonal therapy for a minimum of 5 yrs. Trastuzumab for HER2-positive pts was at investigator's discretion but was not to begin for &amp;gt;3 weeks after the last dose of chemotherapy. All women treated with lumpectomy were to receive breast radiotherapy; post-mastectomy chest wall radiotherapy was at physician's discretion. The differences in DFS (OS, RFI, and DRFI) between two treatment arms were assessed by log-rank test stratified by hormone receptor status and type of surgery. Results Median follow-up is 82.8 months. Pt and tumor characteristics were equally distributed between the two groups (&amp;lt;50 years old: 40%, lumpectomy: 68%, and hormone positivity: 65 %). Overall, Grade 3 and 4 expected toxicities were more frequent in the FEC arm. Combined Grade 3/4 toxicities reaching statistical significance with a difference of 3% or more between AC and FEC arms included fatigue 3.55% v 8.45%, febrile neutropenia 3.70% v 9.42%, and thrombocytopenia 0.74% v 4.41%, respectively. While on treatment, Grade 3 left ventricular systolic dysfunction occurred in one pt in each arm. There were 2 toxicity deaths on AC and 5 on the FEC arm. Primary and secondary endpoint analyses at 8 ys did not reveal any significant differences in DFS, OS, RFI, or DRFI. EndpointAC (%)FEC (%)HRCIp-valueDFS83.082.81.040.85,1.260.70OS91.292.00.940.71,1.240.65RFI90.090.40.970.76,1.260.84DRFI92.393.00.890.66,1.200.43 Conclusions Six cycles of the FEC-100 regimen did not result in any efficacy advantage over 4 cycles of standard AC in node-negative breast cancer pts. As anticipated, the FEC-100 regimen resulted in greater toxicity. Support NCI: U10-CA-12027, -37377, -69974, -69651, -44066-26; Pharmacia &amp; Upjohn Co. Citation Format: Jacobs A Samuel, John W Wilson, Hanna Bandos, Richard M Elledge, André Robidoux, Louis Fehrenbacher, Patrick J Ward, Johnathan Polikoff, Adam M Brufsky, Louise Provencher, Alexander HG Paterson, John T Hamm, Robert L Carolla, Luis Baez-Diaz, Priya Rastogi, Thomas B Julian, D Lawrence Wickerham, Sandra M Swain, Charles E Geyer Jr, Eleftherios P Mamounas, Norman Wolmark. NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients (pts) with node-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-02.

Abstract P3-12-01: Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide

Abstract Background NSABP B-36 compares 6 cycles of FEC-100 with 4 cycles of standard AC in pts with node-negative breast cancer. As reported separately, no significant differences between the two treatment arms were observed in the primary endpoint of disease-free survival or in the secondary endpoints of overall survival, recurrence-free, or distant recurrence-free intervals. Greater toxicity was reported in pts who received FEC compared to AC. We present here the results of the QOL and MH studies obtained prospectively in conjunction with the treatment study. We hypothesized that pts on FEC would experience greater treatment toxicity in the first 12 months of the study, and would have greater rates of amenorrhea at 18 months compared to pts on AC. Methods Among the 1,357 pts enrolled in the QOL study, 1,332 (675 AC, 657 FEC) submitted the baseline form and had QOL follow-up (fup) information. Pts completed: 1) the FACT-B instrument; 2) a symptom checklist; and 3) the SF-36 Vitality Scale, all at baseline, day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months after random assignment. FACT-B Trial Outcome Index (TOI), symptom severity, and vitality scores were compared between the two treatment arms using a mixed model for repeated measures analysis with adjustment for the baseline scores, type of surgery, and hormone receptor status, examining the first 12 months and the later time points separately. Menstrual status was collected at baseline for all enrolled pts, with subsequent assessments on day 1 of cycle 4, and at 6, 12, 18, 24, 30, and 36 months for pts with menstrual bleeding within 12 months prior to random assignment and not having had a hysterectomy and/or bilateral oophorectomy (1, 096 pts). Post-chemotherapy amenorrhea was defined as the lack of menstrual periods during the 12 months preceding the 18-month fup evaluation. Data from 921 pts (475 AC, 446 FEC) were available for analysis. Logistic regression, adjusted for type of surgery and hormone receptor status, was used to test for association of amenorrhea status and treatment. Results Both TOI and vitality scores were worse for pts on FEC compared to those on AC at 6 months (p&amp;lt;0.01) with no significant difference at 12 months and beyond. No significant differences in symptom severity between the two treatment arms were observed. The rates of post-chemotherapy amenorrhea were significantly different between FEC and AC (66.8% vs. 58.7%, p=0.01) with positive hormone receptor status as an independent risk factor (p=0.03). Conclusions Women receiving FEC had diminished QOL at 6 months after random assignment, but no difference at 12 months or later. Premenopausal women receiving FEC experienced a higher rate of post-chemotherapy amenorrhea than women receiving AC. Support NCI grants U10-CA-12027, -37377, -69974, -69651 and -44066-26, and Pharmacia &amp; Upjohn Company, a subsidiary of Pfizer, Inc. Citation Format: Patricia A Ganz, John W Wilson, Hanna Bandos, André Robidoux, Alexander HG Paterson, Johnathan Polikoff, Luis Baez-Diaz, Adam M Brufsky, Louis Fehrenbacher, Aroop Mangalik, Patrick J Ward, Louise Provencher, John T Hamm, Philip J Stella, Robert L Carolla, Richard G Margolese, Henry R Shibata, Edith A Perez, Norman Wolmark. Impact of treatment on quality of life (QOL) and menstrual history (MH) in the NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-01.

The Prognostic Significance of Postchemoradiotherapy High-resolution MRI and Histopathology Detected Extramural Venous Invasion in Rectal Cancer

This study aimed to determine the prognostic significance of extramural venous invasion (EMVI) after chemoradiotherapy (CRT) by both magnetic resonance imaging (MRI) (ymrEMVI) and histopathology (ypEMVI). EMVI is a prognostic factor in rectal cancer but whether this remains so after CRT preoperative is unknown. Histopathological definitions of EMVI are variable and lead to underreporting particularly after CRT. All consecutive patients staged on initial MRI as EMVI-positive undergoing preoperative CRT and curative surgery between Jan 2006 and Jan 2012 were included. Posttreatment EMVI status (yEMVI) was reevaluated for both MRI and pathology. The primary endpoint of disease-free survival (DFS) for ymrEMVI and ypEMVI was calculated using the Kaplan-Meier product limit and compared with a Mantel-Cox log-rank test. A P < 0.05 was considered significant. Hazard ratios (HRs) for disease recurrence were generated using Cox proportional hazard regression for MRI and histopathology tumor characteristics. A total of 188 patients who had evidence of EMVI on initial baseline MRI staging were included. MRI detected significantly more patients with persistent EMVI than histopathology (53% vs 19%) but both were prognostic for worse survival-ymrEMVI (HR 1.97) and ypEMVI (HR 2.39). Patients with persistent ymrEMVI-positivity had significantly worse DFS at 3 years (42.7%) compared with ymrEMVI-negative tumors (79.8%); DFS for was 36.9% versus 65.9% positive and negative ypEMVI, respectively. Detection of EMVI post-CRT is prognostically significant whether detected by MRI or histopathology. EMVI status after treatment may be used to counsel patients regarding ongoing risks of metastatic disease, implications for surveillance, and systemic chemotherapy.

Abstract 5102: Telomeres and survival in stage III colon cancers: Findings from NCCTG N0147 (Alliance) study

Abstract Introduction: Peripheral blood leukocyte (PBL) telomere length is associated with colon cancer (CC) risk, but the relationship of PBL telomere length to survival in CC patients receiving chemotherapy is unknown. Methods: We measured relative telomere length (RTL) by qPCR of PBL DNA from 2,748 cases (53% male, 85% white, median age 58 yrs) in the North American Phase III Intergroup Trial N0147 that compared disease-free survival (DFS) among completely resected Stage III CC treated with mFOLFOX6 +/- cetuximab. Tumor markers were assessed, and 12% were BRAF mutant; 35% Kras mutant, and 12% deficient mismatch repair (dMMR). Linear and non-linear prognostic associations of PBL RTL to the primary endpoint of DFS were assessed by Cox models. Optimal categories of RTL were developed using cumulative martingale residual plots, designated from shortest to longest RTL (Table 1). Results: Never smokers had longer PBL RTL (p = 0.0006) than past or current smokers. Those with diabetes mellitus (DM) had longer PBL RTL than those without DM (p = 0.0165). PBL RTL was not associated with any tumor markers (MMR status; p = 0.7174; BRAF mutant vs wild-type (wt); p =0.4039; Kras mutant vs wt; p= 0.1149). PBL RTL was significantly associated with DFS in a non-linear form (p = 0.0389). Cases in the longer RTL category had more favorable DFS than those with shorter or longest RTL, (Table), which remained after adjusting for age, sex , T/N stage, grade, tumor markers, and treatment (p = 0.0230). We observed no significant interaction (p = 0.1490) between RTL categories and treatment. Conclusion: We observed a non-linear association between RTL and DFS in stage III CC, suggesting that an optimal range telomere length can influence tumor behavior in CC patients. Future studies of telomere maintenance mechanisms may help to explain the association of RTL with improved DFS. RTL is associated with smoking and DM in CC cases but further studies are needed to determine if either tobacco use or DM affect survival from CC by modulating PBL telomere length. Citation Format: Nivedita Basu, Ruth A. Johnson, Qian Shi, Garth D. Nelson, Julie M. Cunningham, Richard M. Goldberg, Frank A. Sinicrope, Daniel J. Sargent, Steven R. Alberts, Gloria M. Petersen, Stephen N. Thibodeau, Halcyon G. Skinner, Kristin Litzelman, Songwon Seo, Russell J. Vanderboom, Ronald E. Gangnon, Corinne D. Engelman, David N. Rider, Lisa A. Boardman. Telomeres and survival in stage III colon cancers: Findings from NCCTG N0147 (Alliance) study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5102. doi:10.1158/1538-7445.AM2014-5102

Abstract P6-09-01: Central Ki67 analysis as a predictor for adjuvant capecitabine efficacy in early breast cancer (EBC) subtypes in US oncology trial 01062

Abstract Background: USON 01062 (O’Shaughnessy J, et al. Proc SABCS, 2010, abst S4-2) showed no improvement in the primary endpoint of disease-free survival (DFS) (median FU 5 yrs: HR 0.84, 95% CI: 0.67-1.05; p = 0.125) with the addition of capecitabine (X) to standard adjuvant chemotherapy, but showed improvement in OS (HR 0.68, 95% CI: 0.51-0.92; p = 0.011). Exploratory analysis of local pathology-assessed Ki67 suggested benefit from adjuvant X in pts with more highly proliferative cancers with Ki67 ≥ 10% (Pippen J et al. Proc ASCO, 2011, abst 500). The objective of this study is to determine whether centrally-performed Ki67 IHC results corroborate or refute this finding. Methods: 2610 pts with resected high risk EBC were randomized to receive 4 cycles of AC (doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2) IV every 3 wks for 4 cycles followed by either docetaxel 100mg/m2 IV or docetaxel 75mg/m2 IV plus X 825mg/m2 PO bid for 14 days every 3 wks for 4 cycles. Archival primary breast cancer tissue was collected on 2000 pts for predictive biomarker analyses. Central Ki67 IHC was performed using the anti-Ki67 monoclonal antibody SP6 and was read by one pathologist (HK) according to published recommendations (Dowsett M, et al. JNCI 103:1-9, 2011). Results: Central Ki67 IHC has been performed on 1440 pts who had centrally-validated informed consents. The distribution of% Ki67-positive cells by locally-assessed ER/HER2 subtype is shown below. 45% of HR+ HER2- BCs had a Ki67 ≤ 10%, while 24% had a Ki67 11% to 20%, and 31% had a Ki67 &amp;gt; 20%. The concordance between the local vs central Ki67 results was low at 46% for Ki67 &amp;lt;10%, 49% for Ki67 10%-20%, and 76% for Ki67 &amp;gt; 20%. The central Ki67 results tended to be higher than the local testing results. Central mRNA classifiers were developed for ER, PR, HER2 and Ki67 using Fluidigm Microfluidics Dynamic Arrays and correlate highly with central IHC assessment of these markers. Conclusions: HR+ HER2- EBC is enriched for cancers with a low proliferative rate, a group of pts unlikely to benefit from the cell cycle-specific cytotoxic agent, capecitabine. Analyses of the impact of adjuvant X added to AC/T in EBC pts according to ER status, and according to Ki67 (analyzed as a binary and continuous variable) will be performed prior to SABCS, 2013. Number of Patients% Ki67 Pos CellsTotal *HR+TNHER2+/HR+HER2+/ HR-0-104163622222711-151391066151016-20126871615821-3018411539201031-1005751403423555Total144081042510790*Totals do not equal sum of subtype categories due to missing HER2 information Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-01.

Preoperative Chemotherapy for Localized Squamous Cell Carcinoma of the Esophagus? We Should Go Back to the Drawing Board!

Squamous cell carcinoma is rampant in certain parts of the world and it is the most common histologic subtype of esophageal cancer globally. Compared to adenocarcinoma, where obesity, gastroesophageal reflux, and Barrett esophagus seem to play a role, tumorigenesis of squamous cell carcinoma of the esophagus is associated with smoking, alcohol consumption, and poor nutrition (or nutritional deficiencies). Recent molecular studies have identified a subgroup of tumor initiating cells for squamous cell carcinoma with TGF-b and integrin/focal adhesion kinase (FAK) signaling and a cancer stem cell signature has been correlated with a number of self-renewal genes orchestrated by Bmi1, Hmaga2, and Sox2. Genome-wide association studies have also identified three susceptibility loci related to tobacco and alcohol. Further molecular studies are needed to develop better risk stratification and therapeutics for squamous cell carcinoma patients. For patients with localized squamous cell carcinoma, surgery as primary therapy is commonly used in many regions of the world, but results are uniformly poor. We recommend surgery for patients with T1b cancer, but patients with tumors higher that T1b should be considered for combined modality therapy. Preoperative chemoradiation seems to provide the strongest level 1 evidence based on the Dutch trial of preoperative chemoradiation versus surgery. In this issue, Ando et al. discuss their results of a phase III trial comparing preoperative cisplatin/fluorouracil with postoperative cisplatin/fluorouracil in patients with localized squamous cell carcinoma of the esophagus. A total of 330 patients were randomized, and the authors found that the overall survival (OS) of patients who received preoperative chemotherapy was superior to that for patients who received postoperative chemotherapy. The authors claim that preoperative chemotherapy should therefore be regarded as standard treatment. We acknowledge that the conception and execution of a phase III trial requires mobilization of many resources, including commitment of many dedicated investigators, time, cost, and labor. However, a phase III trial, if properly conceived and completed, provides the best tool to sort out the true contributions of a therapy or approach of interest. Let us examine the trial being published by Ando et al. The current trial was based on their previous experience with JCOG9204, which randomized 242 patients with squamous cell carcinoma to surgery alone or postoperative cisplatin/fluorouracil. The primary end point of diseasefree survival (DFS) was increased in the postoperative chemotherapy arm (P = 0.037) but the overall survival was not different for the two groups (P = 0.13). A subgroup analysis of JCOG9204 showed that patients with node-negative cancer did not benefit from postoperative chemotherapy. The current trial randomized localized squamous cell carcinoma patients to receive either postoperative chemotherapy or preoperative chemotherapy with the primary end point of DFS. Unfortunately, the trial design of this study had a major flaw that precludes any meaningful conclusions to be drawn. In the postoperative treatment arm, patients with node negative cancer did not receive chemotherapy because JCOG 9204 did not find a benefit for adjuvant chemotherapy in a subset analysis of node-negative patients. Because of this design, 140 patients receive preoperative chemotherapy, while only 81 patients Society of Surgical Oncology 2011

10-year analysis of the ATAC trial: wrong conclusion? – Authors' reply

Ian Tannock's opinions are not supported by the published data. In the ATAC trial, 1 Cuzick J Sestak I Baum M et al. for the ATAC/LATTE investigatorsEffect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010; 11: 1135-1141 Summary Full Text Full Text PDF PubMed Scopus (670) Google Scholar more women receiving tamoxifen had serious adverse events, treatment-related adverse or serious adverse events, or an adverse or serious adverse event leading to withdrawal than did those receiving anastrozole. 2 The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' GroupComprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol. 2006; 7: 633-643 Summary Full Text Full Text PDF PubMed Scopus (313) Google Scholar These events included a much higher incidence of gynaecological complications, and a four-times increase in endometrial cancer. Furthermore, there were more venous thromboembolic events and strokes, which are now known to be tamoxifen related. 3 Braithwaite RS Chlebowski RT Lau J George S Hess R Col NF Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med. 2003; 18: 937-947 Crossref PubMed Scopus (296) Google Scholar ATAC made no provision for managing bone loss, and more recent studies indicate that such loss is largely manageable when monitored using dual-energy x-ray absorptiometry scans and bisphosphonate treatment as necessary. Musculoskeletal symptoms are a real side-effect of anastrozole, but these and other endocrine symptoms are the result of reduced oestrogen stimulation of end organs, and are associated with increased effectiveness against recurrence. We accept that in some cases side-effects can be severe, and here, tamoxifen might be a better choice than anastrozole. However, aches and pains are common in postmenopausal women—even in the absence of aromatase-inhibitor use—and are often incorrectly attributed to aromatase inhibitors in uncontrolled situations. The situation is reminiscent of the widely held belief that tamoxifen is associated with weight gain; however, placebo-controlled trials have now shown that weight gain is just as great with placebo. 10-year analysis of the ATAC trial: wrong conclusion?The 10-year analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial1 continues to show a difference in its primary endpoint of disease-free survival, which favours anastrozole as adjuvant treatment for postmenopausal women with hormone-responsive breast cancer. Ultimately, however, clinical trials have two aims: either to show improvement in survival, or in its quality. Anastrozole has failed to meet these criteria when compared with tamoxifen. Full-Text PDF

Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial

The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83-0·99; p=0·04), time to recurrence (0·84, 0·75-0·93; p=0·001), and time to distant recurrence (0·87, 0·77-0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78-0·95; p=0·003), time to recurrence (0·79, 0·70-0·89; p=0·0002), and time to distant recurrence (0·85, 0·73-0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67-0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74-1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84-1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15-1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74-1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48-0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60-1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

Comparing doxorubicin plus cyclophosphamide (four courses) and CMF (three more courses) with doxorubicin plus cyclophosphamide (four courses) and paclitaxel plus epirubicin (three courses) as adjuvant therapy for operable breast cancer

11545 Background: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of paclitaxel (T) in metastatic breast cancer (MBC) showed promise in MBC. This is a retrospective study in which we followed all breast cancer patients who came to our office since 1998 to 2005. Patients came from all parts of Iran; there are 450 patients, 400 of whom were treated by AC (four courses) and CMF (cyclophosphamide, MTX, 5FU) and 50 patients who were treated with AC (four courses) and paclitaxel and epirubicin (three courses) with primary endpoint of disease-free survival (DFS). Methods: Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1998 and December 2005, 450 patients were treated. First 400 patient treated with four cycles of standard-dose AC (60 and 600 mg/m2) and three course CMF (500 and 50 and 500 mg/m2) and the next 50 patients treated with four cycles of standard-dose AC (60 and 600 mg/m2) and three course T (175 mg/m2) and epirubicin (60 mg/m2), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy. Results: Both treatment groups (AC-CMF and AC-TE) were not well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was superior for AC-TE compared with AC-CMF (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = 0.015). Overall survival rates for AC -TE and AC-CMF were 90% and 87%, respectively, (HR = 0.76; 95% CI, 0.52 to 1.1; P = 0.13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the AC-TE arm; more nausea and vomiting occurred on the AC-CMF arm as well as one incident of congestive heart failure. Conclusions: At 5 years, AC-TE was associated with a superior DFS and more toxicity profile compared with AC-CMF. The survival it didn’t change. No significant financial relationships to disclose.