Significant Improvement In DFS Research Articles

Smoking Habit and Respiratory Function Predict Patients’ Outcome after Surgery for Lung Cancer, Irrespective of Histotype and Disease Stage

Growing evidence suggests that sublobar resections offer more favorable outcomes than lobectomy in early-stage lung cancer surgery. However, a percentage of cases that cannot be ignored develops disease recurrence irrespective of the surgery performed with curative intent. The goal of this work is thus to compare different surgical approaches, namely, lobectomy and segmentectomy (typical and atypical) to derive prognostic and predictive markers. Here we analyzed a cohort of 153 NSCLC patients in clinical stage TNM I who underwent pulmonary resection surgery with a mediastinal hilar lymphadenectomy from January 2017 to December 2021, with an average follow-up of 25.5 months. Partition analysis was also applied to the dataset to detect outcome predictors. The results of this work showed similar OS between lobectomy and typical and atypical segmentectomy for patients with stage I NSCLC. In contrast, lobectomy was associated with a significant improvement in DFS compared with typical segmentectomy in stage IA, while in stage IB and overall, the two treatments were similar. Atypical segmentectomy showed the worst performance, especially in 3-year DFS. Quite unexpectedly, outcome predictor ranking analysis suggests a prominent role of smoking habits and respiratory function, irrespective of the tumor histotype and the patient's gender. Although the limited follow-up interval cannot allow conclusive remarks about prognosis, the results of this study suggest that both lung volumes and the degree of emphysema-related parenchymal damage are the strongest predictors of poor survival in lung cancer patients. Overall, these data point out that greater attention should be addressed to the therapeutic intervention for co-existing respiratory diseases to obtain optimal control of early lung cancer.

DA-R-EPOCH versus R-CHOP in intermediate and high risk IPI diffuse large B-cell lymphoma, a randomized controlled trial

Background: Diffuse large B-cell lymphoma is a challenging disease in management. Although most patients are cured with the standard R-CHOP, one third of them remains refractory to this regimen. As prognosis of refractory disease is worse than primarily responding one, several trials investigated other more intense frontline regimens tailored based upon risk and biological characteristics. Patients & Methodology: This is a prospective randomized trial investigating the more intensive DA-R-EPOCH regimen as frontline therapy in intermediate and high risk DLBCL patients in comparison to the standard R-CHOP regimen. We compared both regimens in these risk categories as well as undergoing a subgroup analysis according to cell of origin (Germinal center versus activated B cell) and according to BCL2 and C-myc expression (double expressor lymphoma). Toxicities in both arms have been analyzed according to common terminology criteria for adverse events (CTCAE). Results: In spite of being more toxic and complex, there was no significant improvement in DFS or response rate with DA-R-EPOCH. No significant benefit for DA-R-EPOCH over R-CHOP in both germinal center and activated B-cell DLBCL. Conclusion: Tailoring upfront treatment of DLBCL based upon risk classification or BCL2/c-myc expression remains an area of unanswered questions and warrants further investigations.

Minimal Residual Disease (MRD) Assessed By Multi-Parameter Flow Cytometry (MFC) Is Highly Predictive of Outcome in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Purpose - Predicting outcome in patients with ALL has been traditionally based on pre-treatment characteristics such as age, white blood cell count (WBC) and cytogenetics. Minimal residual disease is a surrogate to the complex interaction of disease biology and therapy and its role in assigning risk is well-established. Many prior studies in patients with ALL have used molecular markers of MRD with few studies evaluating the role of multi-parameter flow cytometry (MFC) in the adult population.We investigated the predictive value of MRD assessed by MFC among 340 patients with ALL treated between March 2004 and March 2014 using regimens including the hyperCVAD backbone.Methods - Among 340 patients with B-ALL treated in this period 323 (95%) achieved complete remission (CR) or CR without platelet recovery (CRp) and were included in this study. Median age was 52 (Range, 15-84). Median WBC was 9.35 x109/L (Range, 0.4-658.1 x109/L). Cytogenetics were normal in 62 (18%), Philadelphia+ in 146 (43%), 11q23/rearranged MLL in 14 (4%), aneuploid in 45 (13%), hyperdiploid in 29 (9%), hypodiploid in 13 (4%), insufficient metaphases/ not done in 31 (9%). MRD by MFC was assessed with a sensitivity of 0.01%, using a 15-marker, 4-color panel in the first half of the study and subsequently a 6-color panel. Bone marrow specimens for MRD assessment were obtained at the time of achievement of CR and at approximately 3 month intervals thereafter.Results - 260 patients had available samples at CR and 166 (64%) became MRD negative. Achieving MRD negative status at CR was associated with a statistically significant improvement in disease-free survival (P =0.004) and overall survival (P=0.03). 215 patients were evaluated for MRD at approximately 3 months and 201 (93%) became negative. Achieving MRD negative status at approximately 3 months was also associated with a statistically significant improvement in DFS (P=0.002) and OS (P=0.003). 166 patients were evaluated for MRD at approximately 6 months and 160 (96%) became negative. Achieving MRD negative status at approximately 6 months was also associated with a statistically significant improvement in DFS (P<0.0001) and OS (P<0.0001). Figure below demonstrates the DFS and OS by MRD status at CR (Figure 1a and 1b), at 3 months (Figure 2a and 2b), and at 6 months (Figure 3a and 3b) with patients censored at the time of undergoing an allogeneic stem cell transplant or last follow-up. On multivariate analysis including age, WBC at presentation, cytogenetics (standard vs. high risk), and MRD status at CR, 3 months and 6 months, achieving an MRD negative status at CR was an independent predictor of DFS (P<0.05).Conclusion – Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in patients with ALL [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract P6-09-03: Improved clinical outcomes associated with statin use during adjuvant chemotherapy in patients with HER2+ non-metastatic breast cancer

Abstract Background Statins are established as first line therapy in patients with hypercholesterolemia and are thought to have pleiotropic effects including inhibition of signaling pathways known to drive cell proliferation and survival responses. Numerous preclinical and observational studies have demonstrated activity and improved outcomes in breast cancer patients who received statins, particularly lipophilic statins, as part of their adjuvant therapy. In the Life After Cancer Epidemiology (LACE) Study, 1,945 early-stage breast cancer survivors were shown to have a 33% decreased risk of breast cancer recurrence with post-diagnosis statin use, an effect that was magnified with increasing duration of statin use. We hypothesized that statin use concurrent with trastuzumab based chemotherapy in patients treated for non-metastatic HER2 positive breast cancer would be associated with improved outcomes. Methods We performed a retrospective review of all patients (n = 300) with HER2+ breast cancer who received trastuzumab from 2006-2012 at UM/SCCC. We identified two groups of patients for comparison - those who received statins (ST) during adjuvant chemotherapy (n = 45) or no statins during chemotherapy (NST) during adjuvant chemotherapy (n = 200). Patients with unclear documentation of concurrent statin use, men, patients with de-novo-metastatic breast cancer or prior primary cancer, bilateral breast cancers, and patients without follow-up were excluded. 5-year disease free (DFS) and overall survival (OS) were calculated. A univariate analysis was performed. Multivariate analysis for time-to-event data, using the Cox and extended Cox regression model will be performed and reported. Results The median age at diagnosis was 58 and 48, in the ST and NST groups, respectively. The most commonly used statin was lipophilic simvastatin (34.1%). The average baseline and post chemotherapy total cholesterol level in the ST group was 200.8 and 218.1mg/dL, respectively. Descriptive characteristics of the ST and NST groups respectively are as follows: postmenopausal (77.8% vs. 43.5%) tumor size &amp;lt;2cm (48.9% vs. 41.0%), node-negative disease (40.0% vs. 40.0%), HR+ status (64.4% vs. 60.5%), diabetes mellitus (26.7% vs. 9.0%), baseline BMI &amp;gt;30 (40.0% vs. 27.0%), and concomitant metformin (28.9% vs. 11.5%). The NST group was more likely to have a reduction of greater than 10% in their EF (9.0% vs. 6.7%). At a median follow-up of 32 and 26 months, the estimated 5-year DFS was significantly improved in the ST group (81.8% vs. 51.5%, p = 0.046). Meanwhile, the estimated 5-year OS was not significantly different between both groups (93.4% vs. 91.6%, p = 0.121). Metformin was not associated with a significant improvement in DFS or OS. Conclusion Our study demonstrated that statin use concurrent with trastuzumab-based chemotherapy for non-metastatic HER2 breast cancer was associated with improved estimated 5-year DFS, but not OS. The retrospective nature of our study does not allow for a definitive answer but further research needs to be done to define the role of statins in HER2+ breast cancer treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-03.

Assessing the impact of CMF/FEC/FEC-DOC/ETC (dose-dense) adjuvant chemotherapy in dependency of positive axillary lymph nodes on survival: A retrospective multicenter cohort study of 4,526 breast cancer patients receiving adjuvant chemotherapy.

1074 Background: Adjuvant chemotherapy has changed dramatically in the last decades. Anthracycline-/taxane-based and dose-dense chemotherapy regimens improved survival in node positive breast cancer. This study tries to answer the following questions: (1) Are there differences in survival dependent on chemotherapy regimens in 0/0-3/4-10/&lt;10 positive lymph nodes? (2) Is it possible to define a cut-off of positive lymph nodes for the use of Taxane-based and dose dense chemotherapy? Methods: This German is a multi-center [17 participating hospitals all are certified as breast cancer centers] retrospective cohort study. We included CMF (1.385), FEC (1.170), FEC-DOC (1.723), and dose-dense ETC (248) into the analysis. Results: In case of 0 LN CMF/FEC/FEC-DOC did not show significant differences in DFS, but OAS was significantly impaired by the use of FEC-DOC in 0 LN [p=0.024; HR=2.02 (95% CI: 1.10-3.73)] (no ETC use in 0 LN). In case of 1-3 positive LN CMF/FEC/FEC-DOC/ETC did not differ significantly in survival parameters. But in 4-10 LN FEC-DOC [p=0.049; HR=0.67 (95% CI: 0.44-0.99)] and ETC [p=0.024; HR=0.56 (95% CI: 0.34-0.93)] demonstrated a significant benefit in DFS and a strong trend in OAS. Dose-dense ETC showed a significant improvement in DFS [p=0.003; HR=0.35 (95% CI: 0.17-0.69)] and OAS [p=0.009; HR=0.35 (95% CI: 0.16-0.77)] in patients with &gt;10 positive LN. Conclusions: Our data confirms that Taxane-based chemotherapy does not improve DFS in LN negative breast cancer, but rather demonstrated an inferior OAS. But in LN positive breast cancer we can demonstrate a benefit by the use of Taxane-based chemotherapy regimens. Furthermore, dose-dense ETC demonstrated a significant benefit in survival in &gt;10 positive LN.

Abstract S5-2: HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up

Abstract Background: One year (yr) of trastuzumab (T) significantly improves disease-free (DFS) and overall survival (OS) in patients with HER2-positive early breast cancer (EBC) and is considered the standard of care. HERA is the only randomized trial investigating whether longer duration of T can further improve efficacy outcome. Materials and Methods: HERA (BIG 01–01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive EBC. Pts were randomized, after completion of primary therapy [surgery, chemotherapy and radiotherapy as indicated], to T every 3 weeks for 1 yr, 2 years (yrs), or observation. This landmark efficacy analysis compares the outcome of pts randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr after randomization (N = 1553 for 2 yrs, and N=1552 for 1 yr). The primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Updated efficacy analyses of the T arms vs. observation at 8-yrs of median follow-up (FU) are also presented. Results: On 12 April 2012 HERA reached the target number of 725 DFS events needed for 80% power to detect a true hazard ratio (HR) of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85–1.14; p = 0.86). OS in the two arms was comparable [HR=1.05 (95% CI 0.86–1.28; p = 0.63)]. TTDR results were similar. The primary cardiac endpoint* was comparable (1.0% vs. 0.8% for 2-yr and 1-yr arms, respectively), but the secondary cardiac endpoint** was higher in the 2-yr arm (7.2% vs. 4.1%). Importantly, the durable benefit in DFS and OS for both 1 yr and 2 yrs of T compared with observation remains stable at 8 yrs of median FU. Subgroup analyses including by hormone receptor status will be available for the meeting. Conclusions: These results confirm that 1 yr of adjuvant T remains the standard of care for HER2-positive EBC pts. It is also reassuring that the significant improvement in DFS and OS persists over time and that the incidence of cardiac endpoints remains low at a median FU of 8 yrs. * NYHA class III or IV, confirmed by a cardiologist, and LVEF &amp;lt; 50% and ≥ 10% below baseline, OR cardiac death. ** LVEF &amp;lt; 50% and ≥ 10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-2.

LBA6_PR - Hera Trial: 2 Years Versus 1 Year of Trastuzumab After Adjuvant Chemotherapy in Women with Her2-Positive Early Breast Cancer at 8 Years of Median Follow up

ABSTRACT Background One year (yr) of trastuzumab (T) significantly improves disease-free (DFS) and overall survival (OS) in patients with HER2-positive early breast cancer (EBC) and is considered the standard of care. HERA is the only randomized trial investigating whether longer duration of T can further improve efficacy outcome. Materials and methods HERA (BIG 01-01) is an international, multicenter, phase III randomized trial involving 5102 women with HER2-positive EBC. Pts were randomized, after completion of primary therapy [surgery, chemotherapy and radiotherapy as indicated], to T every 3 weeks for 1 yr, 2 years (yrs), or observation. This landmark efficacy analysis compares the outcome of pts randomized to either 2 yrs or 1 yr of T who were disease-free at 1 yr after randomization (N = 1553 for 2 yrs, and N = 1552 for 1 yr). The primary endpoint is DFS and secondary endpoints are OS and time to distant recurrence (TTDR). Updated efficacy analyses of the T arms vs. observation at 8-yrs of median follow-up (FU) are also presented. Results On 12 April 2012 HERA reached the target number of 725 DFS events needed for 80% power to detect a true hazard ratio (HR) of 0.80 for the comparison of 2 yrs vs. 1 yr of T. The unadjusted HR for an event in the 2-yr vs. 1-yr T arms was 0.99 (95% CI 0.85-1.14; P = 0.8588). OS in the two arms was comparable [HR = 1.05 (95% CI 0.86-1.28; P = 0.6333)]. TTDR results were similar. The primary cardiac endpoint* was comparable (0.96% vs. 0.83% for 2-yr and 1-yr arms, respectively), but the secondary cardiac endpoint** was higher in the 2-yr arm (7.17% vs. 4.10%). Importantly, the durable benefit in DFS and OS for both 1 yr and 2 yrs of T compared with observation remains stable at 8 yrs of median FU. Conclusions These results confirm that 1 yr of adjuvant T remains the standard of care for HER2-positive EBC pts. It is also reassuring that the significant improvement in DFS and OS persists over time and that the incidence of cardiac endpoints remains low at a median FU of 8 yrs. *Cardiac death or severe CHF (NYHA class III or IV, confirmed by a cardiologist, and a significant LVEF decrease) ** An absolute decline ≥10% points from baseline LVEF and to Disclosure M. Piccart: Roche - Genentech: Consultancy, honoraria M. Procter: Marion Procter's institution has received funding in relation to the HERA trial E. De Azambuja: I have received travel grant form Roche. I have received honoraria from Roche. H. Weber: Stock options from Roche, Employment from Roche I.E. Smith: Honoraria from Roche L. Gianni: Roche: Advisory board, GSK: Advisory board C. Jackisch: Speakers Bureau Roche & GlaxoSmithKline D. Cameron: Personal and institutional reimbursement from Roche for advisory boards, consultancy and grants. M. Dowsett: Roche: Grant, advisory board, lecture fees J. Baselga: Advisory board memberships of Roche and GlaxoSmithKline. All other authors have declared no conflicts of interest.

Randomized phase III study of adjuvant chemotherapy for high-risk, node-negative breast cancer (BC) comparing FAC with FAC followed by weekly paclitaxel: First efficacy analysis of the GEICAM/2003-02 trial.

1001 Background: Adjuvant weekly paclitaxel (wP) sequential to anthracyclines improves the outcome of operable node-positive BC patients (pts) [Sparano NEJM 2008, Martin BCRT 2009]; however, most BC pts are currently node-negative at diagnosis. The role of wP in these pts is not well established yet. Methods: Pts aged 18-70, with T1-T3/N0 operable BC and at least one high-risk St Gallen 1998 criteria (size &gt;2 cm, hormone-receptor [HR] negative, grade 2/3, age &lt;35 years,) were eligible. HER2+ pts were allowed, after 792 entered the trial, the study was amended to exclude them. Pts were stratified by site, menopausal status, nodal status diagnostic method (sentinel-node biopsy versus lymphadenectomy) and HR status and randomized to receive FAC x6 (500/50/500 mg/m2 every 3w) or FAC x4→wP x8 (paclitaxel 100 mg/m2 weekly). The primary endpoint was DFS. The trial was designed to detect an absolute 5-y DFS increase of 5% (80% FAC, 85% FAC→wP); a sample size of 1812 evaluable patients (906 per arm) was required to detect this difference (α=0.05, β= 80%). Assuming a drop-out rate of 6%, 1929 pts were required. The first analysis of DFS was planned when a median follow-up of 5 years was reached. Results: Between September 2003 and October 2008, 1925 pts (FAC 974, FAC→wP 951) were randomized. Patient characteristics were well balanced between arms, median age was 50, 73% of pts were HR positive and 9% HER2 positive. 97% of pts with FAC and 85% of pts with FAC→wP completed all treatment as planned. The median dose intensity was 98% with FACx6, 99% with FACx4 and 98% with wP. The most frequent grade 3-4 toxicities (&gt;3% in either arm) with FAC vs FAC→wP were neutropenia (25% vs 22%) with 4% vs 3% of febrile neutropenia, fatigue (3% vs 8%), sensory neuropathy (0 vs 5%), and vomiting (4% in each arm). After a median follow-up of 5.3 years, the proportion of patients disease free is 93% and 90% with FAC→wP and FAC (HR for relapse 0.732, 95% CI: 0.542 to 0.990; log-rank p-value=0.0423). Conclusions: For pts with high-risk node-negative BC, adjuvant FAC→wP was associated with a small but significant improvement in DFS compared with FAC, with manageable toxicity.

Observational study to evaluate the pattern of trastuzumab (T) use and survival outcomes in HER2-positive (HER2+) early breast cancer (EBC): Regional Southern Italy experience.

e11043 Background: HER-2 have shown to be over-expressed in 20-25 % of primary breast cancer, and is associated with poor prognosis. Several large, randomized studies have reported a significant reduction in the risk of recurrence when trastuzumab is administered with chemotherapy in EBC HER2+ cancer. The aim of this study is to identify the pattern of use of T and survival outcomes in HER2+ EBC in Sicily. Methods: This observational, multicenter, retrospective study was conducted in 11 oncology centers in Sicily during 2006-2010. Inclusion criteria: age ≥18 years, surgery for early breast cancer, diagnosis of invasive disease, HER2-positivity as defined by current guidelines, and treatment with T. Results: 569 patients (pts) were included. Surgical outcomes: quadrantectomy 58.1%, mastectomy 33.7% and tumorectomy 8.2%. Tumor stage: T1 50.6%, T2 37.9% and T3 11.5%. Histology: invasive ductal carcinoma 94.7%. Histological Grade: G3 55.6%. Node status: N0 52.6%, N1 27.3%, N2 12.5%, N3 6.7% and Nx 0.9%. Hormonal status: estrogen receptor positive 60.1% and progesterone receptor positive 47.3%. Proliferation: Ki67 ≥10% in 82.4%. Neoadjuvant and adjuvant T was administered in 11.9% and 93.4% pts, respectively. Sequential administration of T after adjuvant chemotherapy was the most common schedule. Cytotoxic agents used: anthracyclines 76.04%, taxanes 33.02% and both agents in combination 26.8%. Relapses were observed in 5.6% pts. The main metastatic sites were: liver 18.75%, bone 12.5%, lung 12.75%, brain 12.75%, locoregional and contralateral 12.5% and lymph nodes 9.4%. N positivity and hormone receptor negativity are significantly associated to relapse. Cardiac toxicity (LVEF reduction >10%) was observed in 3.5% pts. DFS at 25 months of FU was similar to that of HERA DFS at 23.5 months of FU. Conclusions: Our study confirms the efficacy and safety of T in early HER2+ breast cancer, although includes a better prognostic population. These data indicate a satisfactory level of adherence to the international guidelines in the management in HER-2 positive EBC, showing a significant improvement in DFS when T was added to adjuvant chemotherapy.

Abstract P4-11-04: The Influence of Radiation on Survival in Patients with Triple Negative Stage II Breast Cancer

Abstract Background: Prospective trials of locally advanced breast cancer patients treated with adjuvant radiation (RT) have demonstrated a survival advantage; however, use of postmastectomy RT in stage II patients is controversial. This study explores the possibility that patients with aggressive variant molecular subtypes [triple receptor negative (TN)] treated with modern chemotherapy, may experience a survival benefit from adjuvant RT. Methods: Billing codes for all breast cancer patients treated with chemotherapy between 1/1998 and 5/2005 at the University of Alabama at Birmingham were reviewed to comprehensively capture all Stage II and III patients with intact data. Patient, tumor, and treatment related variables were recorded and patients were divided into 3 molecular subtypes based on receptor status: hormone receptor (HR) positive, Her2 negative; HR+/− , Her2+; and TN. Kaplan Meier curves to assess survival were performed by dividing the TN group into 2 groups: those who did or did not receive adjuvant RT. Results: 409 patients with stage II-III disease with were identified. Out of this group, 81 patients had TN breast cancer (60 Stage II and 21 Stage III). RT data was known in 79 of these patients. Median age was 49 years. Median follow-up was 72 months. Thirty-seven stage II and 18 stage III patients received adjuvant RT. Of the stage II patients who received radiation, 25 underwent lumpectomy and 11 underwent mastectomy. Stage II patients who received adjuvant RT had a statistically significant improvement in DFS (p=0.03), and had a trend towards improvement in OS (p=0.07) when compared with those who did not receive adjuvant RT. There was no significant difference in survival for the stage III patients with use of RT, however numbers in this group were small. Conclusion: Adjuvant RT was associated with an improvement in DFS and a trend towards improvement in OS in patients with Stage II, TN breast cancers treated with modern chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-04.

Cardiac toxicity and adjuvant trastuzumab for breast cancer – the Cancer Centre of Southeastern Ontario experience.

Abstract Abstract #3158 Background: In May 2005 several large randomized trials reported a significant improvement in DFS following the addition of trastuzumab (T) to adjuvant chemotherapy (CT) in early stage breast cancer (BC) such that in the summer of 2005 adjuvant T became standard of care for patients (pts) whose tumors over-expressed her2. Cardiotoxicity had been reported as the main toxicity suffered by pts exposed to T. As the generalizability of clinical trial results to the 'real world' is under increasing scrutiny from the oncology community, we undertook this study to identify and follow the population of interest and to characterize cardiac toxicity related to adjuvant T as practice changed.&amp;#x2028; Methods: We conducted a retrospective review of electronic and paper records of all pts prescribed adjuvant T for early stage BC at the Cancer Centre of Southeastern Ontario from June 2005 through January 2007; collecting demographic, disease-related, and treatment-related variables, along with serial left ventricular ejection fraction (LVEF) measurements for each pt.&amp;#x2028; Results: 54 pts prescribed adjuvant T were identified in this time period, nearly half of which were still on T at the time of this analysis. Mean age was 54.4 ± 9.5 years, 38.9% had N0 disease, and 40.7% had left sided tumors, with 42.6% being ER+ and 50% being PR+. Most pts received anthracycline based CT (53.7%) and 39% received an anthracycline/taxane combination. T was concurrently with CT in 14.8% of pts, concurrently with radiotherapy in 33.3% and sequentially in the remainder. T was initiated at a mean of 91.2 days from completion of chemotherapy (range 19-365). Our local protocol mandated LVEF assessments at baseline pre CT, upon completion of CT and/or prior to initiation of T for all pts, and while on T all pts underwent LVEF assessments at 12, 24, 36, 48 and 52 weeks, and in response to any symptoms suggesting cardiac dysfunction. Mean LVEF pre CT and post CT was 64% and 62% respectively. We saw no change in LVEF post CT and pre T. We noted a significant decline in LVEF after 12 weeks on T, from 60.5 ± 6.2% to 56.5 ± 9.5% respectively (p = 0.003), with LVEF values remaining stable thereafter. However, at the time of this analysis only approximately half the pts had completed the full year of therapy. Twelve pts (22.2%) interrupted their T therapy due to a drop in LVEF of &amp;gt;10%, only one pt experienced symptomatic cardiotoxicity requiring treatment. Of these twelve, only two pts restarted T at a later date. Follow-up of those patients still on trastuzumab is ongoing.&amp;#x2028; Discussion: Adjuvant trastuzumab in general clinical practice is associated with significant decreases in LVEF that are associated with premature discontinuation of therapy. A better understanding of factors associated with LVEF decline and the trends in LVEF over time may allow for targeted interventions for pts at risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3158.

Reducing the Risk for Breast Cancer Recurrence After Completion of Tamoxifen Treatment in Postmenopausal Women

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence ( P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported. Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment. Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]). Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status ( P < 0.001), and there was a significant (39%) improvement in as in node-positive patients ( P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS ( P < 0.001), a 72% improvement in distant DFS ( P = 0.002), and a 47% improvement in as ( P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy. Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.

1106: Randomized Trial of Conventional Fractionated RT (CFRT) vs. Concomitant Chemo Radiotherapy (CTRT) and Accelerated Radiotherapy (ACRT) in Patients With Advanced, Non Nasopharyngeal, Squamous Cell Cancers of the Head and Neck Region

Randomized trial comparing efficacy and sequelae of conventional fractionated RT (CFRT) vs. concomitant chemo radiotherapy (CTRT) vs. accelerated fractionated radiotherapy (ACRT) in patients with advanced HNSCC. Between April 2000 and Dec 2004, 150 untreated patients with Stage III and IV non nasopharyngeal, squamous cancers of the head and neck region were included in this 3 arm trial. Arms A: CFRT (66-70Gy in 6-7wks @ 5 fractions per week), Arm B: CTRT (66-70Gy in 6-7wks @ 5 fractions per week + concomitant weekly Inj. Cisplatin 30mg/m2), Arm C: ACRT (66-70Gy in 6.5wks @ 6 fractions per week). The sixth fraction was delivered using the reduced fields. For randomization patients were stratified by site and stage. The analysis was on an intention to treat basis. Response and toxicity were documented according to the WHO response assessment and RTOG criteria, respectively. Results were analysed after a median follow-up of 17 months (Range: 0-68months). Median age of patients was 53.6 years (range 20-70). Majority were males (95%) with a male: female ratio of 17:1. Oropharynx was the most commonly involved sub site (56%), followed by larynx (23.3%) and hypo pharynx (18%). Treatment was completed as per protocol in 94%, 90 % and 86% of patients in arms A, B and C respectively. The median duration of treatment was 49(31-68), 51(32-63), and 40(1-55) days for arms A, B, and C respectively. The median RT dose was 70Gy in each arm. In the CTRT arm the median weekly dose of Cisplatin was 45mg (range: 30-50mg). Seventy four percent received more than 5 cycles of Cisplatin. The overall CR rates were 43%, 53% and 31% in the three arms respectively. The 2yr DFS were 38%, 55% and 31% (p=0.07) for arms A, B, and C respectively and the 2yr OS were 44%, 58% and 44% (p=0.35). For each arm univariate analysis of all known prognostic factors was done to assess their impact on DFS and OS. There was a significant improvement in DFS for pts in the CTRT arm with oropharyngeal tumours (p=0.01). CTRT also resulted in improved DFS compared to CFRT and ACRT in pts with stage III disease (p=0.04) although it did not translate into a significant difference in OS, although the CTRT arm did better (p =0.09). When the DFS was analysed according to the T-stage, the benefit with chemotherapy was seen in patients with low primary tumor volume (T1-T2) which was statistically significant (p= 0.02). On further analysing patients in T1-2 subgroup, the results were in favour of the CTRT arm in the presence of nodal disease (p= 0.03), especially in patients with higher nodal involvement i.e. N2c (p = 0.03). These results did not translate into a benefit in OS. For larger tumours (T3-T4) with N0 status the DFS in the three arms was 71%, 58.9% and 39%, respectively (p= 0.12).The incidence of grade II skin reactions was higher in the accelerated arm (p = 0.482). Seventeen percent, 28%, 28.6% of patients on arm A, B and C respectively experienced grade III mucosal toxicity. CTRT resulted in superior DFS in pts. with advanced disease compared to CFRT & ACRT, especially for oropharyngeal tumors. This improvement did not translate into an improved OS and was associated with acceptable toxicity and compliance. The toxicity of CTRT is acceptable with a marginal increase in hospital support.

Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633

7007 Background: In 2004, preliminary results of CALGB 9633 demonstrated statistically significant evidence that adjuvant chemotherapy with paclitaxel and carboplatin (PC) improved disease-free (DFS) and overall survival (OS) in resected stage IB NSCLC. Indeed, the study was closed early by the DSMB after a planned interim analysis demonstrated a p value for OS less than a prespecified stopping boundary. However, two larger trials, NCIC-JBR10 and ANITA, have shown significant OS advantages with adjuvant chemo, but failed to demonstrate improved survival in the stage IB subset. This report provides more mature data from CALGB 9633. Methods: InCALGB 9633, stage IB patients (pts) were randomized following resection to paclitaxel 200 mg/m2 and carboplatin AUC 6 q3wks ×4 cycles or to observation. While initially planned to accrue 500 pts, the accrual rate was &lt;50% of expected. Because slow accrual allowed longer observation times for each pt, the accrual target was reduced to 384 pts. OS is the primary endpoint. The redesigned study had 80% power to detect a hazard ratio (HR) of 0.67 after 150 observed deaths using a 1-tailed logrank test conducted at the 0.05 level of significance. Results: Between 9/15/96 and 11/26/03, 344 pts were randomized. Median follow-up is 54 mo. Demographics and toxicity has been previously reported (JCO Sup, 22:621a, 2004). The current intent-to-treat analysis shows a significant improvement in DFS favoring adjuvant chemo (HR=0.74; 90% 2-sided CI: 0.57–0.96; p=0.027). There is a trend toward improvement in OS that is not significant (HR=0.80; 90% CI: 0.60–1.07; p=0.10). There is, however, a significant advantage in 3-yr survival (79% vs. 70%; p=0.045). Five-yr survival is not different (60% vs. 57%; p=0.32), although median follow-up is &lt;5 yrs and CIs are wide. Continued follow-up is planned since only 131 of 150 deaths required for final analysis have been observed. Conclusions: This updated but “preliminary” analysis no longer shows a significant OS advantage for adjuvant chemotherapy in stage IB NSCLC. However, the re-designed study does not have adequate power to detect small differences in OS that may be clinically significant. Advantages in DFS and 3-yr survival support continued consideration of adjuvant PC in stage IB NSCLC. [Table: see text]

Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer

10622 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy either pre- or postoperatively; OS and DSF rates at 9 years were identical. Importantly, pathologic complete response (pCR) was directly proportional to DFS and OS. Recently, dose dense adjuvant chemotherapy has shown a statistically significant improvement in DFS and OS. However, no data is available for the use of dose dense preoperative chemotherapy at this time. Methods: Women enrolled in the I-SPY correlative trial with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were evaluated to assess response rates and safety to dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m2 IV Q2 wks × 4, paclitaxel 175 mg/m2 IV Q2 wks × 4, and cyclophosphamide 600 mg/m2 IV Q2 wks × 4). Results: Since 02/2003, 43 pts have been treated with dose dense neoadjuvant chemotherapy on the I-SPY trial at UAB (mean age 47.9). 47% of the pts were ER+, 37% were PR+ and 5% were Her2+ by FISH. 2 pts dropped out for personal reasons and 9 pts are actively undergoing treatment. Overall, 32 pts received dose dense chemotherapy and proceeded to surgery. Of those, 31 received dose dense sequential ATC and 1 received dose dense concurrent AC followed by T. 34% had a pCR (breast &amp; nodes) while an additional 10% had a pCR in the breast but residual disease in lymph nodes; 41% had a PR; 9% had SD; and 6% had PD. Hematologic toxicity consisted of grade 3 anemia in 2 pts, febrile neutropenia in 2 pts and no grade 4 thrombocytopenia. Non-hematologic grade 3–4 toxicity consisted of mediport-associated thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and disseminated varicella in 1 pt. Conclusion: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast &amp; nodes) in about 1/3 of patients (34%) with tolerable toxicity. No significant financial relationships to disclose.

Bowel resection at the time of primary cytoreduction improves disease-free survival in epithelial ovarian cancer patients and is associated with acceptable morbidity

Abstract Introduction: To determine the morbidity, disease-free (DFS) and overall survival (OS) associated with bowel resection at the time of primary cytoreductive surgery for advanced epithelial ovarian cancer (EOC) in the era of platinum/taxane chemotherapy. Methods: A computerized database identified 37 women who underwent a bowel resection at the time of primary cytoreduction for advanced EOC and subsequently received platinum/taxane chemotherapy from 1996 to 2000. Data was collected on demographics, stage, histology, debulking status, surgical morbidity, recurrence, and survival. Survival analysis and comparisons were performed using the Kaplan Meier method and log-rank test. Results: Of 37 patients with Stage III/IV EOC, 20 patients (54%) were optimally debulked to less than 1 cm residual disease. Four-year OS was 78% in the optimally debulked group versus 53% in the suboptimally debulked group (p = 0.20). Four-year DFS in the optimally debulked group was 46% versus 0% in the suboptimally debulked group (p = 0.004). The primary indication for bowel resection was tumor debulking in 86% of patients. Five patients (14%) experienced a major postoperative complication including stroke, small bowel obstruction, colon obstruction, entercutaneous fistula, and pelvic abscess. Other perioperative morbidity included pneumonia (3 patients), ileus (6 patients), and wound infection and/or seroma (3 patients). Mean estimated blood loss was 700 ml; mean hospital stay was 7 days (range 3–15). Conclusions: Patients with advanced EOC who undergo bowel resection and are optimally debulked have a significant improvement in DFS. Bowel resection at the time of primary cytoreductive surgery has acceptable perioperative morbidity.

Assessment of medication unblinding in the multicenter diltiazem post-infarction trial: Mary W. Brown, Arthur J. Moss and Eric Carleen University of Rochester, Rochester. New York(P33)

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence (P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported.Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment.Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]).Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status (P < 0.001), and there was a significant (39%) improvement in as in node-positive patients (P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS (P < 0.001), a 72% improvement in distant DFS (P = 0.002), and a 47% improvement in as (P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy.Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.

Adjuvant Chemotherapy for Early Breast Cancer

Adjuvant Chemotherapy for Early Breast Cancer