Treatment Overall Survival Research Articles

Meta-analysis of 59 gene expression based biomarker candidates predicting survival after tamoxifen treatment in breast cancer.

e11564 Background: To date, three molecular markers (ER, PR and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment by evaluating these in a meta-analysis of available microarray datasets with known treatment and follow-up. Methods: Biomarker candidates were identified in Pubmed 2007-2012 and in the 2010-2012 ASCO and SABCS abstracts. Breast cancer microarray datasets were downloaded from GEO and EGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. In the transcriptomic datasets, only patients with tamoxifen treatment for relapse-free survival and endocrine treatment for overall survival were eligible. The raw microarray data was re-processed and integrated into two databases. Relapse free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO datasets. In the EGA dataset, Kaplan-Meier analysis was performed for overall survival (OS). Statistical significance was set at p<0.01. Results: The transcriptomic datasets included 667 GEO-based and 1208 EGA-based patient samples. All together 59 biomarker candidates were identified. Of these, the best performing genes were PGR (AUC=0.64, p=2.3E-07), MAPT (AUC=0.62, p=7.8E-05), SLC7A5 (AUC=0.62, p=9.2E-05) and TP53 (AUC=0.60, p=1.2E-03). Further genes significantly correlated to relapse-free survival include BTG2, HOXB7, DRG1, CXCL10, BCL2, TPM4, IGF1R and SMC3. Correlation to overall survival was significant for PGR (HR=0.67, p=1.7E-04), MAPT (HR=0.7, p=7.2E-04) and SLC7A5 (HR=1.6, p=1.6E-05). None of the remaining genes including ESR1 reached statistical significance for relapse-free survival. Conclusions: We validated two genes (MAPT and SLC7A5) as being capable to select those patients most likely benefit from tamoxifen treatment.

Assessment of the association of the VeriStrat test with outcomes in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (G) with or without erlotinib (E) in the NCIC CTG PA.3 phase III trial.

4061 Background: VeriStrat is a mass spectrometry based assay performed on serum or plasma that has been shown to be prognostic in several tumor types, and may predict differential drug benefit in several settings. We investigated the association of VeriStrat with outcomes in the NCIC CTG PA.3 randomized phase III trial of G and E vs. G and placebo (P) in pts with advanced PC. Methods: Pre-treatment plasma samples were available for 499/569 (87.7%) enrolled pts. VeriStrat testing was performed in a CLIA-certified laboratory; pts were classified as either Good, Poor, or indeterminate. The relationship between VeriStrat results and overall survival (OS) and progression free survival (PFS) was assessed by Kaplan-Meier curves and log-rank test in univariate analysis and Cox model adjusting for gender, age [>60 vs. ≤60], race [Caucasian vs. other], ECOG [0-1 vs. 2], and pain intensity at baseline [≤20 vs. >20] in multivariate analysis. The predictive effect was assessed by interaction test. All statistical analyses were performed by the NCIC CTG. Results: Of the 499 samples, 11 were hemolyzed and 4 had acquisition failures. VeriStrat was performed on 484 samples, 9 failed quality control, 22 had indeterminate results. Of the remaining 452, 353 (78%) were classified as Good and 99 (22%) as Poor. In the G and P arm, median OS was 7.16 months (ms) for VeriStrat Good vs. 3.78ms for VeriStrat Poor (p<0.0001); Adjusted Hazard Ratio (AHR) 0.59 (0.43-0.82), p=0.002. In the G and E arm, median OS was 7.33ms for VeriStrat Good vs. 4.50ms for VeriStrat Poor p<0.0001; AHR 0.47 (0.32-0.70), p=0.001. A similar relationship was seen for PFS (G and P arm: median PFS 3.91 vs. 2.07ms (p=0.001); AHR 0.67 [0.49-0.92], p=0.01); G and E arm: median PFS 4.24 vs. 2.86ms (p=0.0004); AHR 0.54 [0.37-0.80], p=0.002). Tests of interaction of VeriStrat status and treatment for OS and PFS were not significant: AHR 0.78 (0.48-1.25), p=0.30 and AHR 0.80 (0.50-1.30), p=0.37 respectively. Conclusions: VeriStrat results were significantly associated with OS and PFS for both regimens in this study. VeriStrat was not predictive of benefit from the addition of E to G.

A retrospective assessment of outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I–IV uterine carcinosarcoma (UCS) with rhabdomyosarcoma (RMS) differentiation.

5595 Background: UCS with RMS differentiation are aggressive cancers with poor survival, and without an established standard treatment (txt). We aimed to determine the progression-free survival (PFS) and overall survival (OS) in patients (pts) who received either platinum-based chemo with or w/o radiation therapy (pelvic or IVRT), or RT alone (pelvic or IVRT). Methods: MSKCC EMR from 1990 to 2012 was reviewed for pt age, diag. date, primary surgery, residual disease at completion of primary surgery, FIGO stage, txt details, dates of progression, death, site(s) of first recurrence. Univariate analysis for PFS/OS utilized Kaplan Meier method. Differences between PFS/OS and categorical variables of stage + txt type were assessed using log-rank test. All analyses utilized SAS version 9.2. Pts who received chemo with or w/o RT or RT alone were included in the analysis. Results: 53 pts met study criteria. 41/53 (77.4%) pts received chemo: 30/41 (73.2%) paclitaxel-carboplatin (TC); 3/41 (7.3%) ifosfamide (I)-platinum; 3/41 (7.3%) weekly cisplatin followed by TC; 2/41 (4.9%) other platinum-doublets; 3/41 (7.3%) IT. 34% of the chemo pts also received pelvic or IVRT. 12/53 (22.6%) pts received only pelvic RT+/-IVRT. FIGO stage: I =16 (30%); II =5 (9%); III =14 (26%); IV =18 (34%). Median PFS for the entire cohort: 11.7 mos (95% CI 6.4, 14.1). Median OS for the entire cohort: 21.8 mos (95% CI 14.9, 31.8). Median PFS by stage: 14.3 mos for early stage (stages I and II) vs 9.9 mos for late stage (stages III and IV), p=0.0217. Median OS by stage: not reached in the early stage cohort. Median OS for the late stage: 19.9 mos, p=0.0106. Median PFS by txt: 10.7 mos for the Pelvic RT+/- IVRT group vs 13.5 mos for chemo+/-Pelvic RT+/- IVRT group, p=0.5126. Median OS treatment: 23.9 mos for the chemo+/-Pelvic RT+/- IVRT group vs 17.4 mos for the Pelvic RT+/- IVRT group, p = 0.5191. Conclusions: PFS and OS outcomes in our cohort of pts with UCS with RMS differentiation were similar to survival outcomes among pts treated with platinum-based chemo on GOG 150 and GOG232B. The role of adjuvant RT in addition to chemo warrants further investigation.

Bevacizumab for the Treatment of Glioblastoma

Glioblastoma (GBM) or grade IV glioma is the most common primary brain tumor in adults. Standard treatment median overall survival (OS) is only 14–15 months and less than 10% of patients will survive 5 years after diagnosis. There is no standard treatment in recurrent GBM and OS ranges from 3 to 9 months. GBM is 1 of the most vascularized human tumors and GBM cells produce vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, has demonstrated activity in vitro and in phase II trials in relapse, as well as in 1 phase III trial as first line therapy. Bevacizumab also improves quality of life for patients suffering GBM. This paper reviews the mechanism of action of bevacizumab, its metabolism and pharmacokinetic profile. It summarizes the clinical studies in recurrent and newly diagnosed GBM, its potential side effects and complications and its place in therapy.

SY9-5 - Optimization of Anti-Angiogenic Therapy for Gastrointestinal Cancer

ABSTRACT Bevacizumab (BV) was associated with a survival benefit when combined with chemotherapy in metastatic colorectal cancer (mCRC). Patients who received BV plus standard chemotherapy (FOLFOX/XELOX or FOLFIRI/XELIRI) as the initial treatment of mCRC and were then continued on BV with a different chemotherapy regimen as a second-line agent after their cancer progressed lived significantly longer than patients who received chemotherapy alone in the second-line setting, based on the recent results of the ML18147 study. This is the first trial to confirm the efficacy of continuing on a BV-based regimen after disease progression and to prove the necessity of BV continuation for blocking VEGF. Aflibercept, which is a soluble fusion protein consisting of the extracellular domains of human VEGFR-1,2 linked to a human IgG1 Fc portion, binds all VEGF-A isoforms, VEGF-B, and PlGF. Regorafenib is an oral multi-kinase inhibitor that targets VEGFR, PDGFR and KIT kinases. Both drugs showed survival benefit in other phase III trials. Understanding the underlying mechanisms of resistance to anti-angiogenic therapy will facilitate the optimization of the use of these three active agents in the treatment of mCRC. The global phase III AVAGAST trial did not demonstrate a survival benefit of BV when it was administered with a chemotherapy regimen of capecitabine plus cisplatin (XP) for metastatic gastric cancer. Low tumor neuropilin-1 expression was associated with shorter overall survival (OS) in placebo-treated patients. The addition of BV seems to produce a survival benefit; patients with low tumor neuropilin-1 expression had OS treatment hazard ratio values that were better than those with high neuropilin-1 expression. A similar effect was observed in the NO16966 mCRC study (FOLFOX/XELOX ± BV). In addition, lower baseline plasma VEGF-A was correlated with longer OS. Additional data from the AVAGAST trial revealed different survival outcomes based on the histological and regional subtype of gastric cancer. Although European patients with diffuse type and distal non-diffuse type gastric cancer had the worst prognosis for survival; these individuals were most likely to benefit from the addition of BV to XP. Different approaches to the development of novel agents for each histologic type of gastric cancer treatment are required.

1018O - Safety and Efficacy of Cisplatin Plus 5-Fu and Cetuximab in HPV-Positive and HPV-Negative Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN): Analysis of the Phase III Extreme Trial

ABSTRACT Background Tumor human papillomavirus (HPV) status is a strong predictor of survival and response to treatment in patients (pts) with early and locally advanced oropharyngeal cancer, but its effects in R/M SCCHN remain to be clarified. This retrospective analysis of data from the EXTREME trial assessed the role of tumor HPV status in pts with R/M SCCHN receiving cisplatin + 5-FU chemotherapy (CT) alone or in combination with cetuximab. Material and methods: Immunohistochemical detection of p16INK4A was used to determine HPV status: p16-positive and p16-negative disease is referred to as HPV-positive (HPV+) and HPV-negative (HPV-) disease, respectively. Results 196/222 (88%) pts in the CT + cetuximab and 185/220 (84%) pts in the CT arm had tissue evaluable for p16. Of these, 91% and 88%, respectively, had HPV- tumors. Among HPV- pts, CT + cetuximab (n = 178) improved overall survival (OS), progression-free survival (PFS) and overall response rate (ORR), compared with CT (n = 162) (Table). A similar pattern was observed among HPV+ pts, between CT + cetuximab (n = 18) and CT (n = 23) for OS, PFS and ORR. Interaction tests between treatment and HPV status for OS and PFS confirmed that the treatment effect of CT + cetuximab vs CT was independent of tumor HPV status (p = 0.482 and p = 0.430, respectively: no significant interaction was noted). Within the CT + cetuximab and CT arms, HPV (p16) expression is associated with a more favorable outcome than HPV- (Table). In the CT + cetuximab arm, the overall incidence of grade 3/4 adverse events was slightly higher among HPV+ than HPV- pts. Conclusions Although the number of HPV+ pts in this analysis was low, the results suggest that in R/M SCCHN pts in the EXTREME trial, the survival benefits ofCT + cetuximab vs CT are independent of tumor HPV status and HPV (p16) expression is associated with a more favorable outcome than HPV-. Table: 1018O: Tumor HPV status: effects on prognosis and efficacy of CT + cetuximab and CT in R/M SCCHN. Population Comparison OS PFS ORR CT + cetuximab vs CT HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17 HR/odds ratio 95% CI p 0.822 (0.647–1.043) 0.1064 0.486 (0.376–0.628) 2.753 (1.655–4.579) HPV+ (n = 41) Median (months)/rate (%) 12.6 9.6 5.6 3.6 50 22 HR/odds ratio 95% CI p 0.628 (0.295–1.338) 0.2241 0.730 (0.363–1.469) 0.3761 3.600 (0.929–13.953) 0.0614 HPV+ vs HPV- CT + cetuximab (n = 196) Median (months)/rate (%) 12.6 9.7 5.6 5.7 50 37 HR/odds ratio 95% CI p 0.592 (0.319–1.098) 0.0925 1.172 (0.685–2.005) 0.5624 1.738 (0.657–4.600) 0.2620 CT (n = 185) Median (months)/rate (%) 9.6 7.3 3.6 3.1 22 17 HR/odds ratio 95% CI p 0.827 (0.504–1.355) 0.4492 0.871 (0.529–1.434) 0.5870 1.329 (0.455–3.880) 0.6025 Data are medians and hazard ratios (HR) for PFS and OS and rates and odds ratios for ORR. p: log-rank test for OS/PFS; Cochran-Mantel-Haenszel test for ORR. Disclosure B. De Blas: The author is an employee of Merck KGaA. I. Celik: The author is an employee of Merck KGaA J.B. Vermorken: I have participated in advisory boards of Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-aventis and have lectured (compensated) for Merck-Serono, Amgen, Bristol-Myers Squibb and Sanofi-aventis All other authors have declared no conflicts of interest.

Long-Term Clinical Outcome of Patients With Recurrent Epithelial Ovarian Carcinoma: Is it the Same for Each Histological Type?

This study was conducted to estimate the long-term clinical outcome of patients with recurrent ovarian carcinoma (ROC). Six hundred three patients with ROC were analyzed in this study. The pathological slides were evaluated under central pathological review. The prognostic significances of clinicopathologic factors were evaluated using both univariate and multivariate analysis. The 5-year overall survival (OS) and postrecurrence survival (PRS) rates were 31.1 and 16.9%, respectively. On stratifying to treatment periods, the PRS has been prolonged over the last decade (year ≥2000) compared with before this period (year ≤1999) (P = 0.0002). In contrast, on stratifying to histological types and treatment periods, in both OS and PRS, the prognosis of patients with the nonmucinous/clear-cell histology, including serous, endometrioid, and other histological types, was significantly improved after 2000 compared with before (year ≤1999) (OS, P = 0.0009; PRS, P < 0.0001). In contrast, that of patients with the mucinous/clear-cell histology did not significantly differ regardless of the treatment period (≥2000 vs ≤1999: OS, P = 0.3887; PRS, P = 0.7617). In multivariate analysis, the stage, period of starting initial treatment, histological type, and the treatment-free interval were independent prognostic factors of a poor OS and PRS (OS/PRS: histological type: mucinous/clear-cell vs nonmucinous/clear-cell: hazard ratio, 1.300/1.498; 95% confidence interval [CI], 1.039-1.626/1.197-1.874). Despite the continuous administration of treatment for ROC, survival is poor, and the extent of therapeutic progress differs according to the histological type.

An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.

Potential clinical applications of halichondrins in breast cancer and other neoplasms.

Halichondrin B is a large polyether macrolide found in a rare Japanese sponge, Halichondria okadai and has been shown to have anticancer activity. Eribulin mesylate is a completely synthetic analog of halichondrin B with a unique mechanism of action relative to other antimicrotubule agents. This new agent has demonstrated activity in preclinical studies, and it is being developed for the treatment of different tumor types. Eribulin has been approved by the United States Food and Drug Administration and the European Medicines Agency as late-line therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. It has demonstrated superiority over other treatments in overall survival (OS) (hazard ratio: 0.81, P = 0.041), leading to its regulatory approbation for clinical practice use. Median OS for the eribulin-treated group was 13.1 months versus 10.6 months in the physician's treatment-of-choice group. Eribulin demonstrated a manageable toxicity profile. Most common adverse events associated with treatment were mild neutropenia and fatigue, mainly of grade 1 or 2. In contrast to other antimicrotubule agents, eribulin has a relatively low incidence of peripheral neuropathy and alopecia. Eribulin has been extensively studied in breast cancer and is currently being developed for treatment of other cancer types. Eribulin has demonstrated activity in Phase II trials in non-small cell lung cancer, pancreatic cancer, urothelial tract cancer, and sarcomas. Further studies in these cancers are ongoing. This article reviews pharmacology, mechanism of action, pharmacokinetics and efficacy of eribulin in breast cancer and other neoplasms.

A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254

Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.

Low-grade lymphoma: Beyond fludarabine-single therapy

Low-grade lymphoma: Beyond fludarabine-single therapy

Adjusting for Selective Crossover in Analyses of Letrozole (Let) Versus Tamoxifen (Tam) in the BIG 1-98 Trial.

Abstract Background: BIG 1-98 is a double-blind randomized trial comparing 5yrs of Let (Letx5), Tam (Tamx5) and sequences of Let and Tam as adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer. Initial results (presented Jan05) demonstrated superiority of Let over Tam in significantly prolonging disease-free survival (DFS) and reducing risk of relapse in distant sites. Following these results, investigators were informed of the treatment allocation for patients (pts) randomized to Tamx5 and 25% of pts selectively crossed over to Let. Selective crossover has occurred in other clinical trials (eg trastuzumab trials).At SABCS 2008 the protocol-specified 8yr update of the monotherapy comparison (Tamx5 vs. Letx5; median follow-up 76 mo) was presented, as randomized (ITT) and with follow-up of the pts who selectively crossed over artificially censored at the time of the crossover. As with the earlier results, Let significantly improved DFS; a trend for improved overall survival (OS) was seen in the ITT, and was significant in the artificially censored analysis (Table). Treatment effect estimates of both analyses are affected by the selective crossover.Methods: The goal of this analysis is to estimate the true magnitude of the Letx5 : Tamx5 treatment effect had pts randomized to Tam not selectively crossed over to Let. Pts assigned Tamx5 who took Let after Jan05 were identified as selective crossover pts (619/2459 pts; 25%); post-crossover follow-up was 7% of the total, and median duration of post-crossover Let was 18 months. 21 DFS and 5 OS events occurred among these 619 pts. Inverse probability of censor weighting (IPCW), to handle induced selection bias by artificial censoring at crossover, is used to estimate the treatment effect. IPCW assigns a weight to each pt who remains on Tam so that she accounts in the analysis not only for herself but also for those with similar characteristics who are artificially censored at crossover to Let.Results: Several baseline factors, including age, prior local therapy, nodal status, ER/PgR status, and tumor grade were associated both with outcome and with selective crossover. Also performance status (PS) over time was associated with OS and crossover. For DFS, the IPCW estimate of treatment effect (HR=0.84) was larger than the ITT and artificially-censored estimates, and more similar to the ITT estimates reported earlier in follow-up. For OS, the IPCW estimate (HR=0.83) was larger than the ITT estimate but suggested the artificially-censored estimate over-estimated the OS treatment effect. HR[Letx5:Tamx5] (95% CI)Analysis (mo/yr presented) [median follow up]DFSOSITT (3/05) [26 months].81 (.70-.93).86 (.70-1.06)ITT (12/08) [76 months].88 (.78-.99).87 (.75-1.02)Artificially censor Tam pts at selective crossover (12/08) [76 months].85 (.75-.96).82 (.70-.96)IPCW (new analysis) [76 months].84 (.75-.95).83 (.71-.97) Conclusion: The selective crossover affects efficacy results of the ITT analysis of the BIG 1-98 monotherapy comparison. Additional IPCW analysis accounting for the selective crossover indicates that the benefit of Let over Tam is greater than that reflected by the ITT estimate. Let for 5yrs is significantly better than Tam for DFS and OS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 16.

Effect of Epoetin Alfa on Survival and Cancer Treatment–Related Anemia and Fatigue in Patients Receiving Radical Radiotherapy With Curative Intent for Head and Neck Cancer

To evaluate the effect of epoetin alfa on local disease-free survival (DFS), overall survival (OS), and cancer treatment-related anemia and fatigue in patients with head and neck cancer receiving radical radiotherapy with curative intent. Patients (N = 301) with hemoglobin (Hb) less than 15 g/dL were randomly assigned in a ratio of 1:1 to receive radiotherapy plus epoetin alfa (10,000 U subcutaneously [SC] three times weekly if baseline Hb was < 12.5 g/dL; 4,000 U SC three times weekly if baseline Hb > or = 12.5 g/dL) or radiotherapy alone. Hb levels were monitored weekly. The primary end point was local DFS, defined as the time from random assignment to local disease recurrence or death. Secondary efficacy end points included OS, local tumor response, and local tumor control. Patients were followed at 1, 4, 8, and 12 weeks postradiotherapy and annually for 5 years. Cancer treatment-related anemia and fatigue were evaluated with the Functional Assessment of Cancer Therapy-Anemia and Functional Assessment of Cancer Therapy-Head and Neck. Adverse events were recorded up to 12 weeks postradiotherapy. Hb levels increased from baseline with epoetin alfa. The median duration of local DFS was not statistically different between groups (observation, 35.42 months; epoetin alfa, 31.47 months; hazard ratio, 1.04; 95% CI, 0.77 to 1.41). Groups did not significantly differ in DFS, OS, tumor outcomes, or cancer treatment-related anemia or fatigue. No new or unexpected adverse events were observed. Addition of epoetin alfa to radical radiotherapy did not affect survival, tumor outcomes, anemia, or fatigue positively or negatively in patients with head and neck cancer.

High-dose chemotherapy with autologous stem-cell support versus standard-dose chemotherapy: meta-analysis of individual patient data from 6 randomized metastatic breast cancer trials.

Abstract Abstract #6113 Background: The role of high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation for metastatic breast cancer has not been well defined. The statistical power of the available trials has limited precision for determining whether HDC has any benefit for this indication, or for any subset of patients.&amp;#x2028; Methods: Individual patient data from the 6 known randomized trials were merged into a single database. The primary endpoint was overall survival (OS): time from randomization to death. The secondary endpoint was progression-free survival (PFS). Cox proportional hazards regression compared the effect of HDC vs standard-dose chemotherapy (SDC) on PFS and OS adjusted for age, trial and hormone receptor (HmR) status (positive if either estrogen (ER) or progesterone (PgR) receptor positive), and other variables. Among the subset analyses considered were by age, HmR status, number metastatic sites, and soft tissue metastases.&amp;#x2028; Results: A total of 846 patients (433 HDC, 413 SDC) had median follow-up of 1.9 years. Median age was 47 years (range 23 to 65). Preliminary analyses show that after adjusting for age and trial, HDC significantly prolonged OS (hazard ratio (HR) 0.86; 95%CI 0.73-1.00; p=0.05) and PFS (HR 0.73; 95%CI 0.63-0.84; p&amp;lt;0.0001). Mean improvement (out to 8 yrs) was 4 months for both OS and PFS. Both age (p=0.023) and soft tissue disease (p=0.0025) had statistically significant interactions with treatment for OS, but neither remain significant after adjusting for multiple comparisons.&amp;#x2028; Conclusions: HDC may have a modest benefit on OS that may be greater in patients younger than 50 years. However, we were not able to draw firm conclusions about age or other subset analyses.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6113.

Phase II Study of UFT with Leucovorin Plus Hepatic Arterial Infusion with Irinotecan, 5-Fluorouracil and Leucovorin for Non-Resectable Liver Metastases of Colorectal Cancer

Background: Compared with systemic therapy, hepatic arterial infusion (HAI) increases the response to fluoropyrimidines. Methods: Thirty-one patients with non-resectable, colorectal cancer (CRC) liver metastases received irinotecan 120 mg/m², followed by leucovorin (LV) 20 mg/m² and 5-fluorouracil (5-FU) 500 mg/m² administered by HAI every 2 weeks, plus UFT (tegafur-uracil) 200 mg/m²/day with LV 30 mg/day on days 1–22, followed by a 6-day rest. Results: The objective response rate was 65% (all 20 patients achieving a partial response). Ten patients (32%) had stable disease. The median time to progression (TTP) and overall survival (OS) were 12 and 36 months. OS was similar in patients with low versus high expression of thymidylate synthase (TS) and/or dihydropyrimidine dehydrogenase (DPD). The regimen was well tolerated. Conclusions: UFT with LV plus HAI irinotecan and 5-FU/LV was a feasible and effective treatment for non-resectable CRC liver metastases, increasing response, TTP and OS. TS and DPD levels in liver metastases did not predict outcome.

Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study

The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037). Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.

Percent positive axillary lymph node metastasis predicts survival in patients with non-metastatic breast cancer

Purpose. We retrospectively evaluated the impact of percent positive axillary nodal involvement on the therapeutic outcomes in patients with non-metastatic breast cancer receiving postmastectomy radiotherapy and chemotherapy. Materials and methods. Between January 1994 and December 2002, the medical records of 939 eligible non metastatic breast carcinoma patients were analyzed. Chest wall radiotherapy was indicated in case of positive surgical margin, tumor size equal or more than 4 cm, skin-fascia invasion. Lymphatic irradiation was applied for more than three metastatic axillary lymph nodes, incomplete axillary dissection (<10 lymph nodes), extracapsular extension or perinodal fat tissue invasion. A total dose of 50 Gy was given to chest wall and lymph node regions with 2 Gy daily fractions. Statistical analyses were performed by Kaplan-Meier method, Log-rank test and Cox's regression analysis. Results. The median follow-up for all patients alive was 62 months. The 5-year overall survival (OS) and disease-free survival (DFS) for entire cohort were 81%, and 65%, respectively. Univariate analysis for OS revealed significance for tumour size (≤5 cm vs. >5cm, p<0.001), metastatic nodal involvement (0 vs. 1–3 vs. >4 LN, p<0.001), percent positive nodal involvement ([metastatic nodes/total nodes removed]×100; 0 vs.≤25% vs. 26–50% vs. >50%, p<0.001), surgical margin status (negative vs. positive, p=0.05), and hormonal treatment (present vs. absent, p=0.03). DFS had similarly significance for age (≤40 years vs. >40 years, p=0.006), tumour size (0.02), metastatic nodal involvement (p<0.001), percent positive nodal involvement (p<0.001), and perinodal invasion (present vs. absent, p=0.01). Multivariate analysis revealed significance for tumour size, percent positive nodal involvement, hormonal treatment, and surgical margin status for OS. Age and percent positive nodal involvement were found to be significant for DFS. Conclusion. Percent positive nodal involvement was found to be a significant prognostic factor for survival in all end-points.

Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5)

533 Background: It has been suggested that Topoisomerase II alpha (TOP2A) status rather than Her-2/neu status may predict response to anthracycline chemotherapy in breast cancer. Methods: In MA.5, 710 premenopausal women with node positive breast cancer were randomized to receive adjuvant CEF (epirubicin 60 mg/m2 &amp; 5-FU 500 mg/m2 both IV, days 1 &amp; 8, and cyclophosphamide 75 mg/m2 p.o. days 1 through 14); vs CMF (methotrexate 40 mg/m2 &amp; 5-FU 600 mg/m2 both IV days 1 &amp; 8 and cyclophosphamide 100 mg/m2 p.o. days 1 through 14), all for six 28-day cycles. Tissue microarrays (TMAs) were constructed from paraffin embedded specimens from 447 (63%) of these patients. TOP2A was measured by fluorescence-in-situ hybridization (FISH), classifying tumors into 3 groups by TOP2A/CEP 17 ratios: amplified (Amp) if ratio ≥2; deleted (Del) if ratio &lt; 0.8; normal (N) if ratio 0.8 to 2. Cox models assessed interaction between treatment and TOP2A, adjusting for age, nodal status, ER, HER-2/neu status, grade, surgery and tumor size. Results: Thirty-one patients (6.9%) had tumours with Del TOP2A; 53 (11.9%) with Amp TOP2A; and 353 (81.2%) with N TOP2A. 5-year disease-free survival (DFS) was 48%, 51%, and 61% for patients with Del, Amp and N TOP2A respectively (p=0.22 adjusted global test). 5-year overall survival (OS) was 55%, 61% &amp; 75% for patients with Del, Amp, and N TOP2A (p=0.67 adjusted global test). HRs for DFS and OS by treatment and TOP2A are presented in the table . Conclusions: TOP2A status was a significant predictive factor for benefit from CEF treatment for OS. Although there was a trend for TOP2A status predicting improved DFS with CEF, the test for interaction was not significant. In adjusted analysis TOP2A did not reach significance as a prognostic factor for DFS or OS. (This study was supported by the Canadian Breast Cancer Research Alliance (CBCRA), the National Cancer Institute of Canada (NCIC) and the Canadian Cancer Society.) [Table: see text] [Table: see text]

Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG

Background: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil + adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm.Patients and methods: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial.Results: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P = 0.87) or OS (hazards ratio: 0.98, P = 0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively.Conclusion: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.

Microgranular Variant (M3V) of Acute Promyelocytic Leukemia (APL) Does Not Have a Worse Prognosis than Classical APL in the Atra Era: A Report of 153 Patients Treated on Intergroup 0129 and Pethema LPA96 and LPA99.

The microgranular variant (M3V) accounts for 15–20% of patients (pts) with acute promyelocytic leukemia (APL). Historically, it has been associated with a higher white blood cell count (WBC) at diagnosis and an inferior outcome compared to classical morphology. Pts with APL treated with ATRA plus chemotherapy strategies have a 3–5 year DFS of 70–80%. The prognosis of pts with M3V treated with ATRA-containing chemotherapy strategies has not been adequately studied. This analysis included 153 patients with M3V entered on the North American Intergroup protocol 0129 (INT0129), a randomized phase III study of either ATRA (INT, ATRA)or daunorubicin/cytarabine for induction (INT, DA) and ATRA maintenance or observation after intensive consolidation or PETHEMA protocols LPA96 and LPA99 in which all pts received ATRA plus idarubicin for induction, intensive consolidation and ATRA plus low-dose chemotherapy for maintenance (PETHEMA, ATRA). The median age was 39 years (range 3–79), the median WBC was 14.5 K/μL (range 0.4–550), and the median platelet count was 25 K/μL (range 1.8 – 207.0). The median follow-up time for pts on INT0129 is 9.7 years, and for pts on PETHEMA LPA96 and LPA99 is 3.2 years. The 3-year disease-free (DFS) and overall survival (OS) analyses are shown in the table below.NMedian (in mo) (95% CI)DFS p-valueNMedian (in mo) (95% CI)OS p-valueINT+PETHEMA, ATRA106NE77% <0.0001*128NE75% <0.0001*INT, ATRA19NE63%24NE71%PETHEMA, ATRA87NE81%104NE76%INT, DA208.3(6.7, 12.6)15%2519.4(10.4, 41.8)32%INT+PETHEMA, ATRA0<WBC<10K47NE89% 0.01**52NE90% 0.07**10K≤WBC<50K37NE78%48NE69%WBC≥50K22NE54%28NE58%INT, DA0<WBC<10K88.4(3.0, 24.6)13% 0.94**1019.5(8.6, 41.8)30% 0.32**10K≤WBC<50K69.2(5.2, 12.6)17%856.6(10.3, NE)50%WBC≥50K67.9(7.4, 15.9)17%713.6(6.8, 22.2)14%*comparison between ATRA (INT+PETHEMA) and DA; **comparison among WBC groups. NE: not estimable or not reached in this analysisIn a Cox regression model, when age, gender, WBC, platelet, Hgb, ATRA treatment (ATRA vs DA), and source of pts (INT vs. PETHEMA) are included, only ATRA induction treatment (HR=0.16, p-value=0.0005) appears to be a significant prognostic factor for DFS, and age, WBC, and ATRA induction treatment (HR=0.38, p-value=0.03) for OS. These data suggest that the outcome for pts with APL M3V is excellent, influenced by the WBC at diagnosis and is not different than that of pts with classical morphology when treated with ATRA-containing strategies.