Time Of Disease Progression Research Articles

Long-Term Follow-Up of IV Busulfan (Bu) with Fludarabine (Flu) vs IV Bu with Cyclophosphamide (Cy) as Pre (Allogeneic) Transplant Conditioning Therapy for AML/MDS.

We previously demonstrated early safety and efficacy of fixed-dose IV BuFlu. Here we compare IV BuFlu and IV BuCy2, with long follow-up in a large number of pts. Since pts were treated on consecutive, not randomized programs, we used pts receiving Flu-Melphalan (M) in a program spanning the time of the IV Bu-based studies to estimate/correct for this non-randomized “period” effect.Methods: 293 pts received Bu 130 mg/m2, Flu 40 mg/m2 (after April 2001; n=148); Bu 0.8 mg/kg × 16, Cy 60 mg/kg × 2 (before April 2001; n=67); Flu 30mg/m2 × 4, M 140–180 mg/m2 (FM; before and after April 2001; n=78). Patients received FM mainly based on higher age and coorbidities. Graft-vs-host dx (GVHD) prophylaxis was tacrolimus-based. Bayesian log-normal regression models were used to assess covariate- and treatment effects on survival, non-relapse mortality (NRM) and time to progressive disease (TPD). Covariates and survival model are shown in the table. The model accounts for the “period” effect, the effects of Bu-vs-FM, and Flu-vs-Cy within IV Bu pts. Patient and treatment characteristics were (BuFlu, BuCy2 and FM): median age 46 (19–66), 39 (13–64) and 54 (22–74) years. At HSCT 47%, 48% and 21% of the patients were in CR1-3. Donors were HLA-identical siblings in 53%, 79% and 41%. 30% of the Bu groups and 47% of FM had poor prognosis cytogenetics. Results: Median follow-up in months (BuFlu, BuCy2 and FM; alive pts): 30 (9–56; n=80; all but 2 pts followed for at least 1 yr), 69 (24–102; n=23) and 48 (17–89, n=25). 100-day NRM for pts in CR at HSCT was 2% and 9% after Bu-Flu and BuCy2, while 1 yr-NRM was 7% and 18%. BuFlu produced significantly better EFS (P=0.04) and overall NRM (P=0.02) than BuCy2, but TPD was similar (P=0.34). 2-yr actuarial survival (CR pts): 75% (BuFlu) vs. 50% (BuCy), P=0.01.Conclusion: After accounting for covariate and treatment period effects, there was a significant benefit to being treated with BuFlu compared to BuCy2 in spite of a higher median age and proportion of MUDs. The benefit was most evident for CR-pts due to a significant reduction in NRM, without loss of antileukemic activity due to exchanging Cy with Flu.Fitted Bayesian log-normal overall survival modelVariableMeanSDPosterior 95% credible interval 2.5% 97.5%*Probability of beneficial effectCytogenetics−0.850.4−1.652−0.0450.017Disease status (CR vs other)1.120.550.0192.150.975Donor (sibling vs other)0.6060.2370.1491.0560.992Age−0.0220.010−0.041−0.0030.017Circulating blasts (0 vs >0)0.9510.2680.4541.4631Platelet count0.0020.0010.0000.0040.967Period effect−0.9140.458−1.7950.0410.029IV Bu (vs FM)−0.5130.481−1.4550.4200.148BuFlu (vs Bucy2)1.4760.5440.4062.5550.995*1=beneficial effect; 0=low likelihood of beneficial effect [Display omitted]

Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer

Sipuleucel-T (APC8015) is an investigational immunotherapy product designed to stimulate T-cell immunity against prostatic acid phosphatase. A phase III study was undertaken to evaluate the safety and efficacy of sipuleucel-T in a placebo-controlled study. A total of 127 patients with asymptomatic metastatic hormone refractory prostate cancer (HRPC) were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks. On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells. Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months. The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (P = .052, log-rank; hazard ratio [HR], 1.45; 95%CI, 0.99 to 2.11). Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (P = .01, log-rank; HR, 1.70; 95%CI, 1.13 to 2.56). Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multivariable regression model (P = .002, Wald test; HR, 2.12; 95%CI, 1.31 to 3.44). The median ratio of T-cell stimulation at 8 weeks to pretreatment was eight-fold higher in sipuleucel-T-treated patients (16.9 v 1.99; P < .001). Sipuleucel-T therapy was well tolerated. While the improvement in the primary end point TTP did not achieve statistical significance, this study suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway.

Phase I-II trial of daily thalidomide in combination with docetaxel in patients with relapsed non-small cell lung cancer: A final analysis

17060 Background: Recent studies have shown that inhibition of vascular endothelium growth factor (VEGF) in combination with chemotherapy can improve the antitumor efficacy of chemotherapy in NSCLC. This study tested the effectivness and toxicity of thalidomide (an inhibitor of VEGF) combined with docetaxel as second-line therapy for progressive NSCLC. Methods: Patients(pts) with recurrent/progressive NSCLC, prior chemotherapy, measurable/evaluable disease, ECOG performance status (PS) 0–2 and adequate hematologic, renal and hepatic function were enrolled. Pts with uncontrolled CNS disease or hypercoagulable state were excluded. Doxetaxel 75 mg/M2 was administered every 3 weeks (maximum of 8 cycles). Thalidomide was administered orally at a starting dose of 50 mg daily escalated by 50 mg every 3 weeks to a maximum dose of 200mg day and continued until disease progression, dose limiting toxicity, or completion of chemotherapy. Primary end-point was overall survival (OS), secondary end points were time to disease progression(TTP) by Kaplan Meyer method and response rate (RECIST criteria). Results: Of 28 enrolled patients, 26 were eligible for treatment and 25 were evaluable for disease progression and survival. For evaluable pts: mean PS = 1, median age 64.5 years, median number of prior chemotherapy regimens + 1.2. Response rate was 19.1% (1 complete response, 4 partial responses). Stable disease was observed in 9 patients (34.6%). TTP was 2.7 months (95% confidence interval [CI] 2.1–5.0+): median OS was 5.4 months (95% CI 3.1–9.3+). One episode each of febrile neutropenia requiring hospitalization and pulmonary embolism was observed. No grade 3–4 neuropathy was shown. Nonhematologic adverse events included constipation, alopecia, nausea and anorexia. Conclusions: These data suggest thalidomide in doses of 200mg/ day may be combined with docetaxel 75 mg/m2 every 3 weeks in the second line treatment of NSCLC. The response rate, TTP and OS compare favorably with previously reported studies with docetaxel in this population. No significant financial relationships to disclose.

Evaluating carcinoembryonic antigen (CEA) and tumor size as predictors of outcome in patients receiving capecitabine (X) plus oxaliplatin for metastatic colorectal cancer (MCRC): findings from a retrospective analysis

13534 Background: The oral fluoropyrimidine X has superior efficacy and improved safety compared with bolus 5-FU/LV in CRC. Twice-daily oral X is replacing 5-FU as the backbone of combination regimens. The combination of X and 3-weekly oxaliplatin (XELOX regimen) has demonstrated similar efficacy to FOLFOX with some safety advantages and enhanced convenience in phase II/III clinical trials. The objective of this retrospective study was to investigate the use of CEA as an early predictor of outcome. Methods: The data used in this analysis came from a previously published large phase II study (n=96) of XELOX as first-line treatment for patients with MCRC [Cassidy et al. J Clin Oncol 2004]. A population-based pharmacodynamic analysis of CEA and tumor size progressions was performed. The resulting data were linked to hazard models for the secondary clinical endpoints: time to disease progression (TTP) and overall survival. As we were interested in early prediction, model-predicted time courses of CEA and tumor size (up to 10 weeks) were examined as covariates in the hazard models. The resulting predictions for TTP and survival based on either measure were tested and compared using stochastic simulations. Results: An indirect effect model provided the best description of CEA progression. For tumor size, a similar indirect effect model with an added resistance term gave the best description. CEA performed marginally better than tumor size in predicting survival and less well in predicting TTP. For survival the misclassification rate decreased from 0.426 to 0.404 when using tumor size and to 0.396 when using CEA as predictors. Conclusions: CEA and tumor size were found to have clinically equivalent power as early phase predictors of clinical outcome. [Table: see text]

EGFR, HER2, and phospho-Akt are not predictive factors for response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)

7111 Background: Response to Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is significantly associated with increased EGFR gene copy number, increased EGFR expression or presence of activating EGFR gene mutations. In presence of EGFR, increased HER2 gene copy number, as well as activation of the anti-apoptotic protein Akt demonstrated to increase EGFR-TKI sensitivity in both clinical and preclinical models. Aim of the present study was to assess whether these biomarkers also associate with response to first-line chemotherapy. Methods: Patients with advanced NSCLC with full clinical data and with tumor tissue available were selected for this analysis. Specimens were evaluated for EGFR and HER2 gene copy number by FISH, EGFR and p-AKT protein expression by immunohistochemistry. RECIST criteria were used to assess response to chemotherapy. Results: A total of 144 NSCLC were included in this analysis. Patient characteristics included: male/female: 95/49; PS 0/1/2: 112/29/3; stage III/IV: 44/100; adenocarcinomas plus bronchioloalveolar/squamous/other: 86/35/23; never/former/current smokers: 26/69/49. The majority of patients were treated with first-line platinum-based chemotherapy (115/79.9%). Response to chemotherapy was not associated with any clinical characteristic. A trend towards better response was observed in non-adenocarcinoma histologies (p = 0.08) and in smokers (p = 0.20). Response and time to disease progression (TTP) were not influenced by EGFR/HER2 FISH status, nor P-Akt/EGFR expression. In EGFR FISH positive response rate was 36.4% and TTP was 6.4 months, versus 28.7% and 7.3 months in EGFR FISH negative (p = 0.4 for both). Conclusions: Biomarkers useful for selection of patients candidate for TKI therapy are not predictive for response to first-line chemotherapy in NSCLC. No significant financial relationships to disclose.

Mature data on capecitabine (X) + fractionated cisplatin (P) as first-line therapy in patients (pts) with advanced gastric carcinoma (AGC)

4075 Background: Gastric cancer is one of the most common malignancies in Asia with an adjusted mortality rate above 20/100,000 population. 5-FU + fractionated P is a standard treatment for AGC in China. In a Korean study by Kim et al., X + P produced a response rate of 55% in pts with previously untreated AGC. Here we present mature efficacy/safety results in Chinese pts with AGC. Methods: 154 pts of a planned population of 120 pts were enrolled between Jun 2002 and Aug 2004. All had measurable AGC (WHO), Karnofsky performance status ≥60, adequate bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was permitted. Pts received × 1000 mg/m2 orally bid on days 1–14 + P 20mg/m2/day i.v. on days 1–5, every 3 weeks for 6 cycles. The primary endpoint was time to disease progression (TTP). Results: Baseline characteristics of the 141 evaluable pts (104 men, 37 women) are: median age 54 years (range 23–80), main sites of metastases: lymph nodes 45%, liver 40%, stomach 18%, skin 6%, other 6%, lung 5%, abdomen 4%. The overall response rate was 36%, including 13 complete responses and 38 partial responses. After a median follow-up period of 12 months, the median TTP is 9 months (95% CI, 9–12 months) and the median overall survival is 12 months (95% CI, 12–15 months). Median treatment duration was 6 cycles (range 3–6). The most common treatment-related clinical adverse events (all grades &gt;5%) were: hand-foot syndrome (HFS) 25%, leucopenia 13%, and SGOT abnormality 12%. The most commongrade 3 adverse events were SGPT abnormality 3%, HFS 2%, and anemia 2%. There were no grade 4 adverse events. Most grade 3 adverse events improved or resolved after treatment or interruption except in 1 pt with anemia who withdrew after 2 cycles. Conclusions: X combined with fractionated P is highly active and very well tolerated as first-line treatment for AGC, with comparable results to 5-FU + P. No significant financial relationships to disclose.

A multicenter randomized study comparing vinorelbine plus gemcitabine versus capecitabine monotherapy as salvage treatment in patients with advanced breast cancer pretreated with taxane and anthracycline chemotherapy: A preliminary report

658 Background: Both Vinorelbine plus Gemcitabine (VG) regimen and Capecitabine (C) monotherapy are active salvage treatments in patients (pts) with advanced breast cancer (ABC). In this multicenter study we compared the efficacy and tolerability of the two regimens as salvage treatment in pts with ABC pretreated with taxane and anthracycline chemotherapy. Methods: Pts were randomized to receive either vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 (VG) both on day 1 in cycles every 2 weeks or capecitabine 1250 mg/m2 (C) twice a day on days 1–14 in cycles every 3 weeks. The primary end point of the study was to compare the time to disease progression (TTP). Results: A total of 114 pts were randomized to VG (n=60) and C (n=54). All pts were evaluable for toxicity and 58 VG and 54 C pts for response. Seven (VG) vs 9 (C) pts had stage IIIB disease and 6 vs 5 pts had PS 2. We observed one complete response on each arm and 14(24%) vs 12(22%) partial responses for an overall response rate of 25.8% vs 24.1% (p=0.8) in VG vs C pts, respectively. The median duration of response was 5 vs 12 months (p=0.02) and the median TTP 3.7 vs 5.8 months (p=0.4) for VG and C pts, respectively. A total of 339 VG and 270 C cycles were administered with no toxic deaths. Both regimens were overall well tolerated; grade 3–4 neutropenia 17% vs 4% (p=0.02), anemia 4% vs 2% (p=0.6), grade 3 thrombocytopenia 2% vs 2%, neurotoxicity 3% vs 2%, grade 2–4 hand-foot syndrome 2% vs 15% (p=0.009) for VG and C pts, respectively. Conclusions: In this preliminary analysis the VG and C regimens showed similar activity but different although rarely severe toxicity. Updated results will be presented at the meeting. No significant financial relationships to disclose.

A phase II study of DJ-927 administered orally once every three weeks as second line therapy to subjects with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of platinum-based non-taxane regimen

17006 Background: For the treatment of NSCLC (1st and 2nd line) effective oral formulations of drugs are currently investigated. DJ-927 is a semi-synthetic novel taxane with in vitro activity against NSCLC cells lines. Phase I studies show active plasma concentrations after oral administration with hematologic dose-limiting toxicity (DLT). This multi-centre phase II study was conducted to evaluate the safety and efficacy of the DJ-927 in patients (pts) with recurrent NSCLC. Methods: Pts with locally advanced or metastatic NSCLC who have received one prior platinum (non-taxane) containing treatment regimen, performance status 0 -2, and adequate organ function were enrolled. Pts received an initial DJ-927 dose of 27 mg/m2 on day 1 of cycle 1, orally, every 3-weeks. If &lt; 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at that dose level. The primary endpoint was to assess the response rate. Pts were also assessed for time to disease progression (TTP), survival and safety. Results: 36 pts were enrolled, male/female 27/9; median age of 57 years (range 33–75); ECOG 0/1/2 7/21/8; stage IIIB/IV 12/24. Histology included adenocarcinoma 5; squamous cell 16; large cell 3; undifferentiated 3; other 7; unknown 2. Thirty-four pts received DJ-927; the median number of cycles was 2 (range 1–8). The optimal dosing level was confirmed at 27 mg/m2 as no dose escalation was performed based on toxicity data from parallel studies. Response in evaluable pts (completed Course 1) included CR 1, PR 1, SD 15, PD 8; for an overall response rate of 7 % and a disease control rate (CR, PR and SD) of 61%. Toxicity, ≥ grade 3, in evaluable pts (n = 32) included neutropenia (15), anaemia (6), thrombocytopenia (2), fatigue (2), nausea (2), anorexia (2), pneumonitis (1). Conclusions: In a 3-weekly setting, an oral dose 27 mg/m2 of DJ-927 shows limited efficacy in 2nd line therapy for NSCLC with neutropenia, gastrointestinal toxicity and fatigue as major side effects. [Table: see text]

Mitoxantrone Plus Gemcitabine in Pretreated Patients with Metastatic Breast Cancer

Gemcitabine and mitoxantrone have both shown significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of this combination as second or third-line treatment in patients with metastatic breast cancer (MBC).Forty-six previously treated patients with MBC were enrolled from June 2000 to November 2002. Mean age was 56 years and ECOG performance status was ≤2. All patients received mitoxantrone 10 mg/m2, D8 and gemcitabine 1000 mg/m2, D1+8 every 21 days for 6 cycles.There were no complete responders. Objective response was observed in 12 patients (26%), 15 (33%) patients had stable disease, 15 (33%) had progressive disease and 4 (9%) were non-evaluable. At median follow-up of 27.8 months, overall survival was 13.3 months (range 0.6-33.8+) and the median time to disease progression (TTP) was 4.4 months (range 0.2-33.8). Toxicities (grade 3-4) were as follows: leukopenia 18 (39%), neutropenia 19 (41%), thrombocytopenia 4 (8.5%), anemia 6 (13%) and alopecia 1 (2%). Febrile neutropenia was recorded in 2 (4%) patients. There were no treatment related deaths.The authors conclude that the combination of mitoxantrone and gemcitabine is an effective regimen in pretreated patients with metastatic breast cancer. Toxicity was manageable.

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non-small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial. One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP). The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, chi(2) test). Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

Maximal COX‐2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma

Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFNalpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial. Patients with untreated, metastatic RCC received IFNalpha 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential. There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3-31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P=0.03). Therapy was well tolerated without cardiac or other notable toxicity. The addition of celecoxib to IFNalpha did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFNalpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.

New aromatase inhibitors as second‐line endocrine therapy in postmenopausal patients with metastatic breast carcinoma

New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC. The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods. No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance. This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.

Nasopharyngeal/nasal type peripheral T-cell lymphomas: Long-term outcomes and prognostic analysis of 112 cases in Southern China

6646 Background: Extranodal peripheral T-cell lymphoma arising in facial midline has unique clinicopathologic features, the optimal treatment and prognostic factors remain unclear. Methods: 112 patients with pathologically confirmed nasopharyngeal/nasal type peripheral T cell lymphomas were included from April, 1994 to Dec, 2003, 39 patients were identified as CD56(+) NK/T cell lymphoma. Median pre-treatment disease history(PTDH) was 4 months, male/female ratio was 3.0:1, with a median age of 46 years. 91.1% of the patients were staged as Ann Arbor I and II diseases. International Prognostic Indices were < 2 scores in 78.8% of the patients. Most patients underwent combined chemo and radiotherapy, 32 patients underwent chemotherapy only. Chemotherapy was mainly in CHOP like regimens(median 5 cycles). High energy photon/electron rays were used for radiotherapy(median curative dose 54Gy). Results: Median follow-up time for survived patients was 42 months. Chemotherapy achieved a CR rate of 34.4% as initial treatment, the CR rate after primary treatment was 65.1%. Median time to disease progression (TTP) was 11 months, local control rate for stage I and II tumors was 50.5%. There were evidences indicating systemic relapse in > 30% of the patients. Radiation therapy showed a positive correlation with local control and TTP. The number of chemo cycles was positively correlated with TTP, but not with local control. Progress-free survival and overall survival rates were 38.8% and 52.4% at 3 years, and 34.9% and 44.8% at 5 years, respectively. In univariate analysis survival favorable factors included PTDH > 2 months, earlier clinical stage, non-NK/T lymphoma diagnoses, no skin invasion, lower risk IPI, CR after initial chemotherapy and radiotherapy. In multivariate analysis, PTDH > 2 months, non-NK/T lymphoma diagnoses, CR after initial chemotherapy, and radiotherapy were survival favorable prognostic factors. Conclusions: CD56(+) NK/T lymphoma can be more aggressive than other nasopharyngeal/nasal type peripheral T-cell lymphomas. Combined chemo and radiotherapy as principal treatments need improvement to increase remission rates so as to improve survival. No significant financial relationships to disclose.

Quality of life as a potential predictor for morbidity and mortality in patients with metastatic hormone-refractory prostate cancer

8095 Background: The relationship between quality of life (QoL) and morbidity and mortality in metastatic hormone-refractory prostate cancer (M+HRPC) remains unclear. The role of QoL as a predictor for morbidity and mortality measures such as survival, time to disease progression (TTP), time to bone pain (TTBP), and prostate specific antigen doubling time (PSADT) of less than 4 months was assessed using data from a phase 3 trial (n=809) of atrasentan (Xinlay) 10 mg in men with M+HRPC. Methods: QoL data were collected using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30). The relationship between the QoL change score from baseline to week 12 for survival, TTP, and TTBP was assessed using Cox proportional hazards methodology. For PSADT, the relationship was explored using a logistic regression. All models included the baseline Karnofsky score; bone alkaline phosphatase, hemoglobin, and lactose dehydrogenase levels; and treatment assignment (ie, atrasentan or placebo) as covariates. Results: The change score of the Prostate Cancer Subscale (PCS) domain of the FACT-P was significantly associated with all of the morbidity and mortality endpoints (P <0.0001 for each). Specifically, the risk ratios were 0.57, 0.57, and 0.49 for TTP, TTBP, and survival, respectively, indicating that a greater decline in PCS values at week 12 significantly increases the risk of disease progression, bone pain, and death. The odds ratio for PSADT was 1.80, which indicates that a greater decline in PCS values at week 12 significantly increases the likelihood of experiencing a PSADT of less than 4 months. Similar results were observed for other FACT-P and EORTC domains. Conclusions: QoL change scores are significantly prognostic of survival, TTP, TTBP, and PSADT. Therapies that provide QoL benefits may have beneficial effects on the morbidity and mortality of M+HRPC patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Abbott Laboratories, Aventis, OSI Abbott Laboratories, AstraZeneca, Lilly Oncology, NCI

Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer

4563 Background: Atrasentan (Xinlay), a selective endothelin-A receptor antagonist, has been studied in 2 randomized placebo controlled studies of men with metastatic hormone-refractory prostate cancer (HRPC) using time to disease progression as the primary endpoint. A meta-analysis of these studies was performed to more precisely define the clinical benefit of atrasentan 10 mg in this patient population. Methods: A meta-analysis using subject-specific data was conducted on the intent-to-treat populations of both studies. Time to disease progression (TTP), time to bone pain (TTBP), as well as time to prostate specific antigen (TTPSA) and bone alkaline phosphatase (TTBALP) progression were analyzed by Kaplan-Meier methodology and by Cox proportional hazards modeling, both stratified by study. Results: 1002 patients were randomized to either atrasentan 10 mg (n=497) or placebo (n=505) in the 2 studies. Atrasentan 10 mg resulted in a statistically significant delay in TTP (log-rank p=0.045), TTBP (log-rank p=0.025), TTPSA (log-rank p=0.002), and TTBALP progression (log-rank p <0.001) compared with placebo. Compared with patients receiving placebo, patients treated with atrasentan 10 mg were 14% less likely to experience disease progression (HR=0.863; 95% CI=0.747, 0.997), had an 18% less likelihood of experiencing bone pain (HR=0.819; 95% CI=0.687, 0.976), had a 22% less chance of experiencing PSA progression (HR=0.775; 95% CI=0.657, 0.914), and were 46% less likely to experience BAP progression (HR=0.537; 95% CI=0.414, 0.695). The relative probability of remaining progression-free was 10% greater at 3 months and 22% greater at 6 months for patients treated with atrasentan 10 mg compared with those treated with placebo, where the probability of remaining progression-free on placebo was 49% and 27% at 3 and 6 months respectively. Conclusions: The results of this analysis demonstrate that atrasentan 10 mg, a novel cytostatic agent, provides significant clinical benefit to patients with metastatic HRPC and indicate that atrasentan would be a valuable addition to the limited treatment options available for these men. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Abbott Laboratories, Aventis, OSI Abbott Laboratories, AstraZeneca, Lilly Oncology, NCI

A phase II study of docetaxel (T) and capecitabine (X) combination chemotherapy as first-line chemotherapy for patients (pts) with metastatic breast cancer (MBC)

889 Background: The addition of X to T extends survival, time to disease progression (TTP) and response rate (RR) in pts with pretreated MBC. This phase II study evaluated the efficacy and safety of TX as a first-line therapy for pts with stage IV or recurrent breast cancer. Methods: Eligible pts had measurable MBC, ECOG PS of 0–2 and had received no prior chemotherapy for metastasis. Pts received T 75mg/m2 i.v. with routine premedication on day 1 and X 1000mg/m2 p.o. bid on days 1–14, q 3 weeks until disease progression or unacceptable toxicity. Results: Of the 38 pts enrolled, 5 are not evaluable (2 ineligible and 3 lost to follow up after 1 cycle). Of the 33 evaluable pts, 21 had recurrent and 12 stage IV disease with median age of 52 yrs (range 28–68). ER+ was 36%, PR+ 30%, HER2 3+ 18%. Disease free interval for recurrent disease was 24 mo (range 5–96). Metastatic site: lymph nodes (76%), breast (52%), bone (36%), liver (33%), lung (27%), and skin (9%). Previous adjuvant chemotherapy: anthracycline-based (29%); CMF (67%). A total of 178 cycles with median 6 (range 2–10) per pt were given. The mean relative dose intensities for T and X were 85% and 75%, respectively. Adverse event: G3/4 neutropenia (82%, febrile 3%), G3 hand-foot syndrome (12%), and G2 nail changes (79%). There was no treatment-related death. The overall RR was 61% (3 CRs and 17 PRs). RR was significantly higher in pts without prior adjuvant chemotherapy (85% vs. 45%; p=0.02). All 3 CRs and 15/17 PRs were observed in anthracycline-naïve pts. Median TTP was 8.4 mo (95% CI, 7.0–10.9) and median response duration was 7.4 mo (95% CI, 6.6–16.5). After a median follow up of 20.0 mo (range 3.3–27.7), 10 pts died and median survival has not been reached. Conclusion: TX is highly active as first-line therapy for pts with MBC, with a durable TTP and high RR, particularly in pts having received no anthracyclines in adjuvant setting. The rate of G3/4 neutropenia was high, but would likely be reduced through appropriate T dose reductions. (Supported in part by Aventis and Roche Korea) No significant financial relationships to disclose.

Fulvestrant (FUL) and goserelin (GOS) in premenopausal women with advanced, hormone-sensitive breast cancer: A pilot study

708 Background: FUL is an estrogen receptor (ER) antagonist for the treatment of postmenopausal women with hormone-dependent advanced breast cancer (ABC). Our pilot study evaluated the efficacy and safety of FUL in premenopausal women with hormone-sensitive ABC rendered postmenopausal with continuous GOS treatment. Methods: This prospective trial included 14 patients (pts) with ER and/or progesterone receptor-positive ABC. 2 pts were human epidermal growth factor receptor 2-positive (HER2+). Pts received at least 3 doses of FUL 250 mg i.m. q 4 weeks and continued to receive GOS 3.6 mg sc q 4 weeks until disease progression or intolerability. Tumor assessment and evaluation of time to disease progression (TTP) occurred every 3 cycles. Results: 14 pts (median age 41 years, range 28–49) were included in this evaluation. 1 pt received GOS + FUL as 1st-line therapy, 7 as 2nd-, 5 as 3rd-, and 1 as 4th-line treatment, respectively. 11 pts (78.6%) had received adjuvant chemotherapy and 8 pts (57.1%) adjuvant endocrine therapy (tamoxifen). Prior palliative chemotherapy had been given to 6 pts (42.9%) and prior palliative endocrine therapy to 13 pts (92.9%) (anastrozole and/or exemestane under GOS treatment). 3 pts (21.4%) had only non-visceral metastases, 1 pt (7.1%) only visceral, and 10 pts (71.4%) both. 11 pts are currently evaluable for response: partial remission (PR) was observed in 1/11 pts, stable disease (SD) >3 months but <6 months in 1/11 pts, SD >6 months in 4/11 pts (36.4%), and progression despite treatment (PD) in 5/11 pts (45.5%). Both pts with HER2+ disease experienced SD >6 months. Median TTP is 5 months (2–12+). No local or systemic side effects were reported. Conclusion: Adding FUL to GOS treatment appears to be effective and well tolerated in premenopausal women with ABC including those with asymptomatic visceral disease and HER2+ disease. These preliminary data indicate a clinical benefit rate (PR+SD >6 mo) of 45.5%. FUL activity in pts with visceral disease and HER2+ tumors, and a TTP of 5 months, compares very favorably with data from similar naturally menopausal women with ABC. Thus, FUL in premenopausal women with iatrogenic menopause should be studied in controlled clinical trials. No significant financial relationships to disclose.

Phase 2 study of ABT-751 in patients with refractory metastatic colorectal carcinoma (CRC)

3537 Background: ABT-751, an oral antimitotic agent that binds to the colchicine site of β-tubulin and prevents microtubule polymerization, has shown antitumor activity in CRC in xenograft models, including HCT-15, a human colon carcinoma-derived cell line in which paclitaxel and vincristine were ineffective. Minor responses to ABT-751, including one partial response, were seen in CRC patients in phase 1 studies. Methods: This phase 2, multi-center study evaluated the safety and efficacy of ABT-751 in patients with metastatic CRC (N = 49) refractory to irinotecan or oxaliplatin [single refractory (SR) arm, n = 14], or irinotecan and oxaliplatin [double refractory (DR) arm, n = 35]. For each cycle, patients received 200 mg ABT-751 orally once daily for 21 days followed by a 7-day break. Time to disease progression (TTP) was analyzed using Kaplan-Meier Methods: CT scans were obtained every 2 cycles. Patient response was evaluated using RECIST. Results: The median duration of therapy was 2 cycles (range 1–8). 57% of patients experienced Grade 3 or 4 toxicities. 18/49 (37%) subjects experienced Grade 3 or 4 toxicities considered probably or possibly related to study drug, including 15/35 in the DR arm and 3/14 in the SR arm [most common = asthenia (12%), anorexia (10%), neuropathy (8%), and constipation (6%)]. Median TTP was 2.1 months (95% CI = 1.9–2.6). Median TTP by study arm was 2.0 months for the DR arm (95% CI = 1.8–2.3) and 3.8 months for the SR arm (95% CI = 2.0–3.9). Three patients remain on study in the SR arm, including 1 patient in Cycle 6. One patient discontinued after exhibiting stable disease through 8 cycles. No complete or partial responses have been observed to date. Conclusions: ABT-751 was well tolerated in CRC patients. Despite preclinical and phase 1 data suggesting activity, ABT-751 was not active as a single-agent in patients with multiple refractory metastatic CRC. Phase 2 studies in patients with renal, breast, and lung carcinoma are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories

Determination of clinically meaningful change (CMC) for functional assessment of cancer therapy-prostate (FACT-P)

8077 Background: Determining CMCs that explore the relationships between clinical measures and Quality of Life (QoL) and establishing the smallest magnitude of change in QoL that would reflect change in clinical parameters facilitates interpretation of QoL results. CMCs for the FACT-P have not been determined. Our objective was to ascertain the CMC for FACT-P using data from a phase 3 trial of atrasentan (Xinlay) 10 mg in men with metastatic hormone-refractory prostate cancer. Methods: Cross section comparison of baseline FACT-P scores and baseline Karnofsky score (Kfsky), bone alkaline phosphatase (BALP), hemoglobin (Hb), and lactate dehydrogenase (LDH) was performed using t-tests. Longitudinal comparison of changes in FACT-P scores from baseline to week 12 and time to disease progression (TTP), time to bone pain (TTBP), prostate specific antigen doubling time (PSADT) and survival was conducted using analysis of covariance. CMC’s and effect size were calculated using these analyses as well as the standard errors of mean QoL scores. Results: FACT-P scores were significantly associated with all clinical variables evaluated (Table). CMC ranges for FACT-P scores were computed and are shown in the table below. CMC’s based on the distribution based criteria fell within the range identified by clinical variables, corroborating the CMC for each FACT-P score (Table). Conclusions: This analysis defines CMC’s for the FACT-P in metastatic HRPC patients. A decrease in QoL score greater than the minimum value of the CMC range represents the Minimally Clinically Important Difference for that score. This data can aid in the interpretation of QoL outcome using the FACT-P. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories Abbott Laboratories, Aventis, OSI Abbott Laboratories, AstraZeneca, Lilly Oncology, NCI

Gemcitabine, Epirubicin, and Paclitaxel Versus Fluorouracil, Epirubicin, and Cyclophosphamide As First-Line Chemotherapy in Metastatic Breast Cancer: A Central European Cooperative Oncology Group International, Multicenter, Prospective, Randomized Phase III Trial

The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.