Margot J. Burnell

Randomized Placebo-Controlled Study of Low-Dose Warfarin for the Prevention of Central Venous Catheter–Associated Thrombosis in Patients With Cancer

PURPOSE In this multicenter, randomized, placebo-controlled clinical trial, we studied whether warfarin 1 mg daily reduces the incidence of symptomatic central venous catheter (CVC) -associated thrombosis in patients with cancer. PATIENTS AND METHODS Two hundred fifty-five patients with cancer who required a CVC for at least 7 days were randomly assigned to receive warfarin 1 mg or placebo. RESULTS There were 11 (4.3%) symptomatic CVC-associated thromboses among 255 patients, with no difference in the incidence of symptomatic CVC-associated thrombosis between patients taking warfarin 1 mg daily (six of 130 patients; 4.6%) and patients taking placebo (five of 125 patients; 4.0%; hazard ratio, 1.20; 95% CI, 0.37 to 3.94). Warfarin had no effect on CVC life span (84 days v 63 days in control and warfarin groups, respectively; 95% confidence limit, -16 to 55 days; P = .09), and it did not affect the number of premature CVC removals (23.2% v 25.4% in control and warfarin groups, respectively; 95% confidence limit of difference -8.34 to 12.71; P = .68) or the frequency of major bleeding episodes (2% v 0% in control and warfarin groups, respectively; P = .5, Fishers exact test). CONCLUSION Symptomatic CVC-associated thrombosis in patients with cancer, although significant, is less common than previously reported. In this study, the administration of warfarin 1 mg daily did not reduce the incidence of symptomatic CVC-associated thrombosis in patients with cancer. However, the low rate of symptomatic CVC-associated thrombosis means that a much larger trial is required to address this issue definitively.

Cyclophosphamide, Epirubicin, and Fluorouracil Versus Dose-Dense Epirubicin and Cyclophosphamide Followed by Paclitaxel Versus Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Node-Positive or High-Risk Node-Negative Breast Cancer

PURPOSE Cyclophosphamide, epirubicin, and fluorouracil (CEF) and doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) are commonly used adjuvant regimens in women with early breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of high-dose epirubicin and cyclophosphamide (EC) administered every 2 weeks (dose-dense) was equivalent to 6 months of CEF. We hypothesized that 3 months of paclitaxel after dose-dense EC (EC/T) would be superior to CEF or AC/T. METHODS After lumpectomy or mastectomy, women 60 years of age or younger with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive CEF, EC/T, or AC/T for 6 months. This article reports the interim analysis for recurrence-free survival (RFS), which was planned after 227 recurrences. Results A total of 2,104 patients were enrolled. The median follow-up is 30.4 months. Hazard ratios for recurrence are as follows: AC/T versus CEF, 1.49 (95% CI, 1.12 to 1.99), P = .005; AC/T versus EC/T, 1.68 (95% CI, 1.25 to 2.27), P = .0006; and EC/T versus CEF, 0.89 (95% CI, 0.64 to 1.22), P = .46. Three-year RFS rates for CEF, EC/T, and AC/T are 90.1%, 89.5%, and 85.0%, respectively. There was more febrile neutropenia with CEF (22.3%) and EC/T (16.4%) compared with AC/T (4.8%), but more neuropathy with the last two regimens. CONCLUSION Three-weekly AC/T is significantly inferior to CEF or EC/T in terms of RFS. It is too early to detect any difference between CEF and dose-dense EC/T.

Regorafenib for the Treatment of Advanced Gastric Cancer (INTEGRATE): A Multinational Placebo-Controlled Phase II Trial

PURPOSE We evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma. PATIENTS AND METHODS We conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-to-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014. RESULTS A total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P < .001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-to-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported. CONCLUSION In this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.

Outcome of Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma Referred for Autologous Bone Marrow Transplantation

Fifty-one patients with relapsed or refractory intermediate- or high-grade non-Hodgkins lymphoma were referred for autologous bone marrow transplantation (ABMT). The primary criterion for eligibility was sensitivity to conventional-dose salvage chemotherapy. Of 47 patients who received salvage chemotherapy, 30 demonstrated chemotherapy-sensitive disease. Six eligible patients did not undergo ABMT for various reasons. A total of 24 patients underwent ABMT, with etoposide, melphalan ± total body irradiation as the intensive therapy regimen. There was one early treatment-related death and three non-responders. Of the remaining patients, 9 relapsed, while 11 remain in continuous complete remission (CR) at a median follow-up of 21 months after transplant (range 5-37 months). Two patients with chemosensitive disease and bone marrow involvement underwent allogeneic BMT with marrow from HLA-identical siblings. Both are in continuous CR at 6 and 12 months follow-up. Of the 25 patients who did not undergo ABMT, all have died (median survival 5 months). The results indicate that approximately one-half of relapsed or refractory aggressive histology lymphoma patients referred for ABMT eventually undergo transplantation, if chemotherapy-sensitive relapse is the major criterion for eligibility. Approximately 25% of the referred patients may become long-term disease-free survivors with this approach. Reports of marrow transplant series should include all patients referred for ABMT as the denominator for calculating disease-free survival in order to reduce the bias of patient selection.

Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.

Background We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Methods Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. Results In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Conclusions Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. Clinical Trials numbers CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

Abstract P3-09-02: Association between definitive surgery and times to administration of adjuvant chemotherapy and outcomes in early breast cancer: Analysis of adjuvant studies conducted by NCIC Clinical Trials Group (NCIC CTG)

Background: For early high risk breast cancer, adjuvant chemotherapy following definitive surgery is a current standard of care. However, the optimal time to commencement of therapy has not been well established. We evaluated the association between time to initiation of adjuvant chemotherapy after definitive surgery (sTTC) with survival. Methods: We retrospectively analyzed 4 NCIC CTG-led breast cancer adjuvant clinical trials involving women diagnosed from 1984 and 2005 with stage 1 to 3 breast cancer, who received adjuvant chemotherapy. Patient data were categorized into four time groups: 8-12, >12 weeks after definitive surgery. Outcomes measured were: overall survival (OS) and disease-free survival (DFS). Results: 3837 patients were included in the final analysis. In univariate analysis, an improvement was identified for patients treated between >8 and 12 weeks: However, in multivariate analysis there was no significant association between any sTTC time periods and either outcome (see table below). Covariates which did show a significant association are listed in the table. The fact that the statistical significance of sTTC in univariate analysis was lost when covariates related to DFS and OS were accounted for in a multivariate analysis suggested there might be a relationship between sTTC and the risk of adverse outcomes. A disease risk score analysis was therefore carried out, but there was no indication of an advantage to an earlier sTTC within disease risk categories. Conclusions: Within the context of chemotherapy given within 12 weeks, we were unable to demonstrate an effect on survival based on time to adjuvant chemotherapy in our multivariable analysis. Those treated later did not do significantly worse than those treated earlier. Significant covariates which effected survival were consistent with predictors of poor prognosis (younger age, poorer performance status, increased disease burden and receptor negativity). There is a potential relation of patient risk to time to treatment which requires further study. Citation Format: Ravi Ramjeesingh, Bingshu E Chen, Joseph L Pater, Liting Zhu, Margot Burnell, Vivien H Bramwell, Kathleen I Pritchard, Lois E Shepherd, Wendy R Parulekar. Association between definitive surgery and times to administration of adjuvant chemotherapy and outcomes in early breast cancer: Analysis of adjuvant studies conducted by NCIC Clinical Trials Group (NCIC CTG) [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 P3-09-02.

A four gene signature of chromosome instability (CIN4) predicts for benefit from taxanes in the NCIC-CTG MA21 clinical trial

Recent evidence demonstrated CIN4 as a predictive marker of anthracycline benefit in early breast cancer. An analysis of the NCIC CTG MA.21 clinical trial was performed to test the role of existing CIN gene expression signatures as prognostic and predictive markers in the context of taxane based chemotherapy. RNA was extracted from patients in cyclophosphamide, epirubicin and fluorouracil (CEF) and epirubicin, cyclophosphamide and paclitaxel (EC/T) arms of the NCIC CTG MA.21 trial and analysed using NanoString technology. After multivariate analysis both high CIN25 and CIN70 score was significantly associated with an increased in RFS (HR 1.76, 95%CI 1.07-2.86, p=0.0018 and HR 1.59, 95%CI 1.12-2.25, p=0.0096 respectively). Patients whose tumours had low CIN4 gene expression scores were associated with an increase in RFS (HR: 0.64, 95% CI 0.39-1.03, p=0.06) when treated with EC/T compared to patients treated with CEF. In conclusion we have demonstrated CIN25 and CIN70 as prognostic markers in breast cancer and that CIN4 is a potential predictive maker of benefit from taxane treatment.

Abstract P4-11-06: TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial

Background: TLE3, a nuclear transcriptional repressor downstream of the WNT signaling pathway, has been identified as a candidate predictive biomarker of taxane benefit in early breast cancer. However, robust clinical evidence is required before implementing novel diagnostic biomarkers. We tested the hypothesis that TLE3 predicts for benefit from taxane containing polychemotherapy in the NCIC CTG MA.21 clinical trial. Methods: MA.21 accrued 2104 patients [701 each to cyclophosphamide, epirubicin, and 5 fluorouracil (CEF) and epirubicin and cyclophosphamide with filgrastim and epoetin alfa followed by paclitaxel (EC/T), 702 to doxorubicin and cyclophosphamide followed by paclitaxel (AC/T)] who were followed median 8 years by the final analysis. EC/T and CEF were not significantly different (p= 0.69) while AC/T was inferior to both EC/T and CEF (respectively, p=0.001 and p=0004). Tissue microarrays were constructed from 1097 of the 2104 patients. Patient characteristics were well balanced between those included in the TLE3 analysis and the full trial population. Up to four 0.6 mm tumor cores were stained for TLE3 expression by immunohistochemistry using a previously validated methodology. Continuous visual TLE3 score was the average % positive stain across all cores, while continuous automated score was sum of cells with positive stain/ total cells assessed in all cores. The primary objective used the EC/T (taxane-containing) and CEF (non-taxane; similar dose-density) arms for a test of predictive effect of TLE3 on relapse free survival. TLE3 was positive if >30% of cells stained, the established cut-point, with data available from at least 1 core/tumor. We also examined quartile cut-points, multivariate effects of TLE3, and compared AC/T and CEF. Results: MA.21 patients had 83.2% TLE3+ tumors by visual score and 80.6% TLE3+ by automated image analysis greater than the predicted rate of TLE3 positivity (58.6%) based on prior series and adjusting for clinicopathological features. TLE3 expression was significantly positively associated with ER expression (91.2% of ER+ were TLE3+; p Conclusions: MA.21 patients had a much higher proportion of TLE3+ tumors than anticipated. Multiple assessments of TLE3 cut-points yielded no evidence that it was predictive of taxane benefit. In our trial TLE3 expression was not a biomarker for taxane benefit (EC/T vs CEF) when using either previously established or common quartile cut-offs for expression in breast cancer. Citation Format: John MS Bartlett, Torsten O Nielsen, Dongxia Gao, Karen A Gelmon, Mary Anne Quintayo, Jane Starczynski, Lei Han, Margot J Burnell, Mark N Levine, Lois E Shepherd, Judy-Anne W Chapman. TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial [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 P4-11-06.