Risk Factors For Progression-free Survival Research Articles

Prognostic value of ki67 in BCG-treated non-muscle invasive bladder cancer: a meta-analysis and systematic review

ObjectivesThe aim of this study was to explore the prognostic value of ki67 as a marker in patients with non-muscle invasive bladder cancer (NMIBC) treated with BCG.MethodsStudies were systematically retrieved...

Novel prognostic scoring system for diffuse large B-cell lymphoma.

The objective of the present study was to evaluate the prognostic values of platelet count (PLT) and platelet to lymphocyte ratio (PLR) in diffuse large B-cell lymphoma (DLBCL), creating a novel prognostic scoring system. A total of 309 patients with newly diagnosed DLBCL were retrospectively analyzed. Receiver operating characteristic analysis was used to determine the optimal threshold values for PLT and PLR, which were 250×109/l and 170, respectively. The patients with PLT ≥250×109/l and PLR ≥170 experienced significantly decreased overall survival (OS) (P<0.001) and progression-free survival (PFS) times (P=0.003, P<0.001) In multivariate analysis, PLR was a significant prognostic factor for OS (P<0.001) and PFS (P=0.003) time, whereas PLT was not a risk factor for PFS or OS time. According to the results of Cox regression analysis, a novel prognostic scoring system was created that combined PLR and β2-microglobulin level with International Prognostic Index value or age-adjusted International Prognostic Index value and the patients were divided into three groups: i) Low-risk patients with a PLR <170, International Prognostic Index (IPI) <2 scores or age-adjusted International Prognostic Index (aaIPI)=0 and normal β2m; ii) high-risk patients with a PLR ≥170, IPI ≥4 or aaIPI=3 and high level of β2m; and iii) intermediate-risk patients. The novel score predicted 5-year OS rates of 86.4, 54.1 and 21.1% in the low-, intermediate- and high-risk groups, respectively (P<0.001). This novel prognostic scoring system may aid the evaluation of patient prognosis and guide treatment.

Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma.

ObjectiveProgrammed death-ligand 1 (PD-L1) was expressed in various tumors and antibodies targeting its receptor programmed cell death-1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and its correlation with clinicopathologic features and clinical outcomes in ovarian clear cell carcinoma (OCCC).MethodsThe PD-L1 expression was measured by tissue-microarray-based immunohistochemistry from 122 eligible patients diagnosed with OCCC. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model.ResultsOverall, high PD-L1 expression (PD-L1high) was observed in 44.7% (55/123) of OCCC patients, and was strongly associated with advanced stages (p=0.020), positive ascitic fluid (p=0.016), platinum-resistant (PR) disease (p=0.045), and recurrence (p=0.038). Moreover, patients with PD-L1high were associated with poorer OS (hazard ratio [HR]=2.877; p=0.001) and PFS (HR=1.843; p=0.021) than those with low PD-L1 expression (PD-L1low). In subgroup analysis, PD-L1high patients experienced a poorer PFS (HR=1.926; p=0.044) and OS (HR=2.492; p=0.021) than PD-L1low cases among advanced stages (III–IV), but this difference was not observed in stage I–II patients. Meanwhile, PD-L1high was associated with poorer prognosis than PD-L1low in PR patients (OS, HR=2.253; p=0.037; PFS, HR=1.448; p=0.233). Multivariate analysis revealed that PD-L1high and advanced stages (III–IV) were adverse independent prognosticators for both PFS (HRPD-L1=2.0; pPD-L1=0.038; HRstage=10.2; pstage<0.001) and OS (HRPD-L1=3.0; pPD-L1=0.011; HRstage=14.3; pstage<0.001).ConclusionPD-L1high might serve as a risk factor for PFS and OS in patients with OCCC. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCCC.

Comparison of clinical efficacy of gefitinib and erlotinib treating non-small-cell lung cancer with epidermal growth factor receptor mutation in either exon 19 or 21

Objective To compare the clinical outcomes of gefitinib and erlotinib treating non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation in either exon 19 or 21. Methods A total of 242 patients diagnosed as NSCLC with EGFR mutation in either exon 19 or 21 from May 2013 to December 2014 in our hospital were chosen in this study. According to age, sex, smoking history, eastern cooperative oncology group performance status and types of EGFR mutation, all the patients were matched to 121 pairs, and randomly divided into group A and B. Patients in group A received gefitinib treatment, and those in group B received erlotinib treatment. Based on the response evaluation criteria in solid tumors (RECIST), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) were assessed. To assess the independent risk factors for PFS by univariate and multivariate Cox regression analysis. The subgroup analysis was performed for the 63 NSCLC patients using these two drugs as the first-line treatment. To evaluate the adverse drug reactions and quality of life between A and B groups. Results The median PFS of group A and B were 11.6 months and 9.5 months, respectively, with no significant difference (HR=0.39, P>0.05). The ORR and DCR in the two groups were 76.9%, 74.4% (χ2=1.03, P=0.58) and 90.1%, 86.8% (χ2=1.46, P=0.31). The independent risk factors of poor PFS were ECOG PS≥2 (HR=2.60, 95%CI: 1.54-4.43, P=0.001) and non-adenocarcinoma (HR=3.61, 95%CI: 1.54-8.66, P=0.003). For patients receiving these two drugs as the first-line treatment, there was no significant difference between two groups in overall response rates (76.6% vs. 90.2%, χ2=0.83, P=0.12) and median PFS (11.6 months vs. 14.4 months, HR=0.59, P>0.05). The adverse drug reactions were significant differences in emotion function (F=10.27, P=0.03), diarrhea (F=10.24, P=0.03) and pain (F=9.02, P=0.04). After receiving drug treatment, the quality of life scores were improved, and most of the differences were statistically significant between A and B groups(P<0.05). Conclusion As for NSCLC with EGFR mutation in either exon 19 or 21, both gefitinib and erlotinib are well tolerated and have similar clinical effectiveness. Key words: Carcinoma, non-small-cell lung; Receptor, epidermal growth factor; Gefitinib; Erlotinib

Significance of venous thromboembolism in women with cervical cancer

ObjectiveTo characterize risk factors of venous thromboembolism (VTE) and to examine effects of VTE on survival of women with cervical cancer. MethodsThis is a retrospective study examining consecutive stage I–IV cervical cancer cases diagnosed between 2000 and 2014. Cumulative risk of VTE after cervical cancer diagnosis was evaluated by a time-dependent analysis, expressing adjusted-hazard ratio [HR] and 95% confidence interval [CI]. Survival analysis was performed to determine independent risk factors for progression-free survival (PFS) and disease-specific overall survival (OS). ResultsVTE was recorded in 98 (12.3%, 95%CI 11.6–22.8) out of 798 cases with 1-, 2-, and 5-year cumulative incidences after cervical cancer diagnosis being 8.4%, 11.3%, and 18.7%, respectively. On multivariable analysis, advanced-stage disease (2-year cumulative risk, distant metastatic disease 44.8% [HR 4.13, 95%CI 1.06–10.7, P=0.003], and locally-advanced disease 13.4% [HR 2.46, 95%CI 1.17–4.43, P=0.004]) were independently associated with increased risk of VTE compared to early-stage disease (stage IA1–IB1 4.1%). In addition, low albumin level (HR per unit change, 0.59, 95%CI 0.40–0.85, P=0.005) and chemotherapy treatment (HR 2.46, 95%CI 1.30–4.66, P=0.006) remained independent risk factors associated with increased risk of VTE. On univariate analysis, VTE was significantly associated with decreased PFS (5-year rates, 22.3% versus 68.7%, P<0.001) and OS (5-year rates, 55.1% versus 90.0%, P<0.001). On multivariable analysis, VTE remained an independent prognostic factor associated with decreased PFS (HR 1.95, 95%CI 1.43–2.67, P<0.001) and OS (HR 3.54, 95%CI 2.04–6.13, P<0.001). ConclusionVTE represents aggressive tumor behavior and poor patient condition, and is an independent prognostic factor for decreased survival in women with cervical cancer.

Influence of microvascular invasion on progression-free survival in patients with a solitary small he-patocellular carcinoma

Objective To study the influence of microvascular invasion (MVI) on progression-free survival (PFS) in patients with a solitary small hepatocellular carcinoma, and to analyze the risk factors of MVI. Methods 126 patients with a solitary small hepatocellular carcinoma who underwent liver resection at Tianjin Medical University Cancer Hospital from January 2010 to December 2012 were retrospectively stu-died. Their demographic and clinicopathological characteristics including age, gender, HBV infection, HCV infection, alcohol consumption, comorbidity, liver cirrhosis, ascites, tumor size, tumor differentiation, MVI, satellite lesion, AFP, CA19-9, ALT and TBil were analyzed. Results The 1-, 2- and 3-year PFS rates of patients with a solitary small hepatocellular carcinoma were 81.0%, 60.3% and 47.3% after surgical resection, respectively. Univariate analysis revealed that MVI, comorbidity, non-well-differentiated tumor, tumor size >4 cm were risk factors of PFS. Multivariate analysis demonstrated that only MVI and comorbidity were independent factors of PFS. MVI occurred in 43.7% of the patients. The median PFS of patients without MVI was 45 months, and the 1-, 2- and 3-year PFS rates of these patients were 91.5%, 67.6% and 56.0%, respectively. The median PFS of patients with MVI was 30 months, and the 1-, 2- and 3-year PFS rates were 67.3%, 50.9% and 35.4%, respectively. On univariate analysis, AFP >100 μg/L, non-well-differentiated tumor and satellite lesions were significantly associated with MVI. On multivariate analysis only non-well-differentiated tumor was independently associated with MVI. Conclusions MVI was an important factor affecting PFS in patients with a solitary small hepatocellular carcinoma. AFP>100 μg/L, non-well-differentiated tumor and satellite lesions were risk factors of MVI. Key words: Solitary small hepatocellular carcinoma; Progression-free survival; Microvascular invasion; Risk factors

Clinical and prognosis analysis in 78 patients with advanced renal cell carcinoma treated with sunitinib: a report from single center

Objective To discuss and evaluate the clinical efficacy and safety of sunitinib for patients with advanced renal cell carcinoma and further to analyze the associated prognostic factors. Methods A retrospective analysis was performed in 78 cases with advanced renal cell carcinoma, receiving sunitinib therapy from April 2009 to December 2014. Patients consisted of 53 males and 25 females, with median age of 54 years old, ranged from 25-85 years old. Therapeutic regimen was described as following: 52 cases receiving sunitinib 50.0 mg/d 4 weeks on and 2 weeks off (4/2 regimen), 26 cases receiving 50.0 mg/d 2 weeks on and 1 weeks off (2/1 regimen). The dosage and regimen were adjusted according to the severity of side effects. Efficacy evaluation and drug-related toxicity were based on RECIST version 1.1 and CTCAE version 3.0. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards model were used to assess the risk factors of PFS and OS. Results Nineteen cases switched from 4/2 to 2/1 regimen. Attenuated dosage was allowed in 49 cases to ameliorate drug-related toxicities. The most common drug-related toxicities were hand-foot syndrome (HFS) in 63 cases (80.8%), diarrhea in 59 cases (75.6%), fatigue in 59 cases (75.6%) and thrombocytopenia in 6 cases (71.8%). The most common grade Ⅲ-Ⅳ toxicities were HFS in 9 cases (11.5%), thrombocytopenia in 6 cases (7.7%) and hypertension in 5 cases (6.4%). In RECIST evaluation, complete response (CR) was not recorded. 8 cases (10.3%) achieved partial response (PR) , 59 cases (75.6%) kept stable disease (SD) and 11 cases (14.1%) suffered progressive disease (PD). The objective response rate (ORR) was 10.3% and the disease control rate (DCR) was 85.9%. The median PFS was 11.0 months and median OS was 21.8 months. Multivariate Cox proportional hazards model showed two independent risk factors for PFS, including number of metastasis organs≥2 and a high ECOG score. One independent risk factor for OS was number of metastasis organs≥2. Conclusions Sunitinib shows encouraging efficacy and safety for patients with advanced renal cell carcinoma. Patients with multiple metastatic organs and poor performance status seems to be high risky of poor prognosis. Key words: Tyrosine kinase inhibitor; Sunitinib; Advanced renal cell carcinoma; Efficacy; Adverse reactions

Predictive value of bone scan index using computer-aided diagnosis system for bone scans in patients receiving first-line hormone therapy for metastatic hormone-sensitive prostate cancer.

225 Background: Recently, the CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen deprivation therapy (ADT) in men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC). While GETUG-AFU 15 failed to demonstrate a survival benefit of early chemotherapy. New biomarker for select the candidate for early chemotherapy in mHSPC is warranted. The objective of this study is to evaluate the bone scan index (BSI) using computer-aided diagnosis system for bone scans for predictive factor in patients receiving ADT as first-line hormone therapy for mHSPC. Methods: We identified consecutive 85 mHSPC patients treated with maximum androgen blockade (MAB) as first-line hormone therapy. We analyzed the correlations between progression-free survival (PFS) of MAB and clinicopathological characteristics, including patients’ age, initial PSA levels, Gleason scores, clinical TNM stage, hemoglobin (Hb), lactase dehydrogenase (LDH), c-reactive protein (CRP), and bone scan index (BSI). Statistical analyses were assessed using cox proportional hazards regression models. Results: The median patients’ age was 73 and the median follow-up duration was 11.3months. The median initial PSA value was 270 ng/ml. Median BSI was 2.7 % (range: 0.0-14.6). Clinical or PSA progression occurred in 55 (64.7%) patients. The median time to progression was 12.9 months. In multivariate analysis, three significant risk factors for PFS were identified; patients’ age ( &gt; 73 years old vs ≤ 73; HR 0.53, p = 0.038), initial PSA levels ( &gt; 270 ng/mL vs ≤ 270; HR 0.53, p = 0.038), and BSI ( &gt; 2.7 vs ≤ 2.7; HR 3.0, p &lt; 0.000). We stratified the patients into two cohorts with low risk (0-1 risk factor present) and high risk (2-3 risk factors present). We found a significant difference in PFS among risk groups (median PFS 15.3 months vs 8.5, p &lt; 0.000). Conclusions: Patients’ age, initial PSA levels, and bone scan index were the significant predictive factors for MAB as first-line hormone therapy in patients with mHSPC. These findings might support the decision-making of induction of early chemotherapy for mHSPC.

Enhanced cell migration and apoptosis resistance may underlie the association between high SERPINE1 expression and poor outcome in head and neck carcinoma patients.

High SERPINE1 expression is a common event in head and neck squamous cell carcinoma (HNSCC); however, whether it plays a role in determining clinical outcome remains still unknown. We studied SERPINE1 as a prognostic marker in two HNSCC patient cohorts. In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival. In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival. SERPINE1 expression was identified as an independent risk factor for progression-free survival in patients treated with chemo-radiotherapy or radiotherapy (p = 0.043). In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029). The association between SERPINE1 expression and survival was confirmed using the HNSCC cohort included in The Cancer Genome Atlas project (n = 507). Once again, patients showing high expression had a poorer survival (p < 0.001). SERPINE1 over-expression in HNSCC cells reduced cell proliferation and enhanced migration. It also protected cells from cisplatin-induced apoptosis, which was accompanied by PI3K/AKT pathway activation. Downregulation of SERPINE1 expression had the opposite effect. We propose SERPINE1 expression as a prognostic marker that could be used to stratify HNSCC patients according to their risk of recurrence.

Infradiaphragmatic Hodgkin Lymphoma In Patients Treated With State-Of-The-Art Therapies: A Risk Factor Analysis From The German Hodgkin Study Group (GHSG) HD13 and HD14 Trials

IntroductionThe prognostic impact of isolated infradiaphragmatic Hodgkin Lymphoma (HL) is controversial and no large risk factor analysis in patients treated with state-of-the-art therapies exists. Therefore, we performed a risk factor analysis focusing on isolated infradiaphragmatic nodal disease in patients treated within the German Hodgkin Study Group (GHSG) HD13 (2xABVD vs 2xABV, 2xAVD and 2xAV; followed by 30Gy IFRT each) and HD14 (4xABVD vs 2xBEACOPPescalated plus 2xABVD; followed by 30 Gy IFRT each) trials. MethodsThe characteristics and outcomes of patients with isolated infradiaphragmatic nodal disease qualified for and treated within the HD13 and HD14 trials were compared to patients with supradiaphragmatic nodal disease. Patients with extranodal disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared between groups using the log-rank test. The Cox proportional hazards regression model was applied for multivariate analyses. To assess whether the prognostic impact of infradiaphragmatic disease depends on treatment intensity, patients were divided into groups of less intensive (HD13 arms 2xABV/2xAVD/2xAV and HD14 arm 4xABVD) and more intensive (HD13 arm 2xABVD and HD14 arm 2xBEACOPPescalated plus 2xABVD) chemotherapy, and groups were analyzed separately. All Hazard Ratios (HR) reported for these subgroup analyses were obtained from Cox proportional hazards regression models adjusted for age (HRa). Results1500 and 1403 patients with nodal disease from the HD13 and HD14 trials, respectively, qualified for the analysis. Of those, 139 patients from HD13 (9.3%) and 84 patients from HD14 (6.0%) had isolated infradiaphragmatic disease. Compared to patients with supradiaphragmatic disease, these patients were older (median age 47 vs 35 years, p<0.001), had a WHO index >0 more frequently (22.4 vs 15.2%, p<0.01), and had the subtype of nodular sclerosis less frequently (29.7 vs 55.3%, p<0.001). More patients with infradiaphragmatic disease were male (69.5 vs 52.1%, p<0.001). After a median follow-up of 51 months, PFS was significantly worse in patients with infradiaphragmatic disease (5-year PFS 80.1% vs 91.2%, p<0.001). In a multivariate model adjusted for age and sex, infradiaphragmatic HL remained a significant risk factor in terms of PFS (HR 1.6, 95%-CI [1.2-2.3], p<0.01). However, the inferior PFS could only be observed in the group receiving less intensive chemotherapy (HRa 2.1 [1.4-3.0], p<0.001, figure 1A) whereas there was no difference in patients treated within the more intensive arms (HRa 1.1 [0.5-2.3], p=0.8, figure 1B). Similarly, infradiaphragmatic disease was a significant risk factor for OS when analyzed univariately (5-year OS 91.5 vs 97.6%, p<0.001) and in a multivariate model adjusted for age, trial and WHO index (HR 2.2 [1.3-3.7], p=0.002), but this difference was also restricted to the arms with less intensive chemotherapy (HRa 3.0 [1.7-5.5], p<0.001; more intensive chemotherapy: HRa 1.3 [0.5-3.5], p=0.6). To assess if the current GHSG standard for early favorable HL is sufficient to treat patients with infradiaphragmatic disease, 299 patients who received 2xABVD and 20Gy IFRT within the GHSG HD10 trial were additionally analyzed. The rate of infradiaphragmatic disease was 8.4% (25 patients). In this limited number of patients, there was no PFS or OS difference (HRa 1.0 [0.3-3.2], p=0.95 for PFS; HRa 0.8 [0.1-6.0], p=0.8 for OS). [Display omitted] ConclusionIsolated infradiaphragmatic disease is a risk factor for PFS and OS in HL patients that can be overcome with the current GHSG standard therapies for early favorable (2xABVD followed by 20Gy IFRT) and early unfavorable (2xBEACOPPescalated plus 2xABVD followed by 30Gy IFRT) disease. Disclosures:von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.

Clinical prognostic factors associated with outcome in renal cell cancer (RCC) patients with prior tyrosine kinase inhibitors or immunotherapy treated with everolimus.

e15544 Background: Everolimus was approved for treating RCC patients who failed sunitinib or sorafenib by the Food and Drug Administration in 2009. We sought to develop a predictive clinical model predicting benefit for patients treated with everolimus as 2nd- or 3rd-line therapy for metastatic RCC. Methods: The study included 66 patients with RCC who failed immunotherapy or tyrosine kinase inhibitors to identify risk factors for progression-free survival (PFS) and overall survival (OS). Forty-one patients were updated with outcomes from the original phase II study (Amato 2009 Cancer) and an additional 25 patients were added from the expansion study. Kaplan-Meier method was used to calculate PFS and OS. Univariate and multivariate analyses were constructed using COX Proportional Hazard model and step-wise procedure. The model was validated by measuring the overall concordance index using the rms R package. Results: For the entire population, median PFS was 5.9 months (range, 0.4-34.5), and median OS was 16.1 months (range, 1.3-39.5). The univariate analysis revealed 5 factors associated with PFS and 9 factors associated with OS. From the multivariate analysis, 3 variables were kept in the final PFS model (LDH&gt;203, no lung metastases, lymphocytes &lt;25). Patients were assigned to 1 of 2 risk groups: ≤1 factor (favorable risk, median PFS 9.7 months) or ≥2 factors (poor risk, median PFS 2.8 months). Four variables were kept in the final OS model (lymphocytes &lt;25, LDH &gt;203, presence of bone metastasis, platelets ≥300). Patients were assigned to 1 of 3 groups: ≤1 factor (favorable risk, median OS 29.6 months), 2 factors (intermediate risk, median OS 14.3 months), or ≥3 factors (poor risk, median OS 7.2 months). Conclusions: A prognostic model was developed composed of 3 readily available clinical parameters for PFS and 4 clinical parameters for OS to help stratify patients into favorable, intermediate, and poor prognosis groups for the treatment of everolimus in clear cell RCC patients. These risk groups can be used by physicians to identify patients most likely to respond to everolimus. Results of the analysis will be presented.

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment.

637 Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a well-established role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p=0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p=0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p=0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.

The role of 18F-FDG PET/CT metabolic tumour volume in predicting survival in patients with metastatic nasopharyngeal carcinoma

To investigate the role of PET-derived imaging markers in predicting metastatic nasopharyngeal carcinoma (NPC) outcomes. A total of 56 patients with metastatic NPC were enrolled. Before treatment, all of the participants underwent (18)F-FDG PET/CT. The following (18)F-FDG PET parameters were assessed: standardised uptake value, metabolic tumour volume (MTV), and total lesion glycolysis. Multivariate Cox proportional hazards models were used to identify the independent predictors of survival. The multivariate analysis showed that performance status>1 (P=0.007), Epstein-Barr virus (EBV) DNA titre>5000 copies/mL (P=0.001), and MTV>110 mL (P=0.013) were independent risk factors for progression-free survival (PFS). Male sex (P=0.004), performance status>1 (P<0.0001), EBV DNA level>5000 copies/mL (P<0.0001), and MTV>110 mL (P=0.003) independently predicted overall survival (OS). The 2-year PFS and OS rates of the patients with MTV≤110 mL were 23.2% and 43%, respectively, compared with 0% and 9.1%, respectively, for those with MTV>110 mL. Combining the MTV with the EBV DNA titre allowed further survival stratification by dividing the patients into three groups with distinct PFS (2-year rates=30.8%, 7.1%, and 0%, P<0.0001) and OS (2-year rates=68.4%, 40%, and 0%, P<0.0001) rates. The MTV appears to be an independent risk factor in metastatic NPC patients. This factor is complementary to the EBV DNA titre for predicting survival in metastatic NPC.

Abstract P6-13-04: Thymidylate Synthase (TS) and Thymidine Phosphorylase (TP) Expression as Predictive Markers of Capecitabine Mono-Chemotherapy for Patients with Anthracyclin-Taxane Pretreated Metastatic Breast Cancer (MBC)

Abstract Background: Capecitabine, one of the widely used cytotoxic agents for breast cancer, achieved high tumor control rate with low toxicity even in heavily-pretreated patients with metastatic breast cancer (MBC). Capecitabine (Xeloda®) is an oral fluoropyrimidine pro-drug that is transformed to fluorouracil (FU) in several steps, the last of which is conversion of 5'-deoxy-5-fluorouridine to FU by TP. And TS is a target enzyme of 5-FU. The primary purpose of this study was to evaluate the role of TS and TP as biomarkers to predict clinical outcomes of capecitabine monotherapy for MBC. Method: Of Three hundreds fifty-three patients with MBC treated with capecitabine at Samsung Medical Center from 2000 to 2008, ninety patients who were previously treated with anthracycline and taxanes containing regimens and had available tissues for immunohistochemical stainings with estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor-2 (HER2), TS, and TP were included in this analysis. All patients had received capecitabine 2000-2500mg/m2/day for 14days q 3 weeks. Results: The median age of these 90 patients was 49 (26-76) years. The response rate (RR) was 25.6% and the disease control rate (DCR) was 65.6%. The median progression-free survival (PFS) and overall survival (OS) from the 1st day of capecitabine monotherapy were 4.8 (95% C.I.; 3.1-6.5) and 26.7 (95% C.I.; 17.1-36.3) months, respectively. High TS expression (TS score ≥100) was more common in patients with triple negative (TN) subtype than in those with other subtypes (16% for HR+, 22% for HER2+, 44% for TN, p=0.023). Median PFS was significantly lower in high TS expression (6.6 vs. 3.0 months; p=0.017) and low TP expression (TP&amp;lt;50) patients (6.0 vs. 3.3 months; p=0.013). High TS score and low TP score were identified as unfavorable independent risk factors for PFS to capecitabine monotherapy in Cox regression multivariate analysis (Hazard Ratio (HR) 1.7, p=0.037 for high TS score; HR 1.8, p=0.014 for low TP score). And, high TS and low TP score were associated with poorer overall survival.(29.9 vs. 14.1 months; p=0.008 for TS /29.9 vs. 20.4 months; p=0.043 for TP) Conclusion: Our data suggests that high TS score and low TP score correlated with shorter PFS for capecitabine monotherapy of patients with anthracycline and taxane pretreated MBC. Potential role of TS, TP expression as predictive markers of capecitabine monotherapy in patient with MBC should be confirmed by prospective studies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-04.

Influence of lymph vascular space invasion on prognosis of patients with early-stage cervical squamous cell carcinoma

In the past decade, no remarkable improvement has been made in the 5-year survival of cervical cancer patients. This study was to explore the influence of lymph vascular space invasion (LVSI) on the prognosis of patients with early-stage cervical squamous cell carcinoma. A total of 111 eligible patients with FIGO stage IB and IIA cervical squamous cell carcinoma underwent radical hysterectomy and pelvic lymphadenectomy at Sun Yat-sen University Cancer Center between January 1995 and December 2002. The histopathological slides of the 111 patients were reviewed by a senior gynecological pathologist. LVSI, invasion depth, tumor differentiation and lymph node metastasis were evaluated. LVSI was present in 62 patients. The univariate analysis showed that the risk factors of overall survival (OS) included positive LVSI (P = 0.019) and lymph node metastasis (P = 0.002), while the risk factors of progression-free survival (PFS) included LVSI (P = 0.029), lymph node metastasis (P = 0.002), SccAg value (P = 0.018), invasion depth (P = 0.022) and positive surgical margin (P = 0.002). The multivariate analysis showed that lymph node metastasis was the independent prognostic factor of OS (P = 0.015), while lymph node metastasis and positive surgical margin were the independent factors of PFS (P = 0.006, P = 0.006). LVSI was correlated with lymph node metastasis (P = 0.011). Whether LVSI is an independent prognostic factor of early-stage cervical squamous cell carcinoma cannot be determined currently while LVSI is a risk factor of metastasis and relapse.

Identification of Prognostic Factors in Early Unfavorable Stage Hodgkin's Lymphoma (HL): An Individual Patient Data Meta-Analysis.

Background: In patients with early unfavorable stage HL, generally defined as stage I and II patients with mediastinal bulk, elevated ESR, 3 3 involved nodal regions, older age or extranodal involvement, progression-free-survival (PFS) is low compared to patients with early favorable or advanced stages disease. This indicates suboptimal treatment strategies and clinical heterogeneity within the group of patients with early unfavorable stage HL. An international collaborative study was initiated to identify factors that may predict for poor prognosis in this patient group.Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials (n>100 patients per study arm) in early stage HL patients with one or more risk factors receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. Individual patient data were collected and risk factors for PFS (including disease progression, relapse or death) identified using multivariate analysis (linear stepwise proportional hazards) stratified by study.Results: Six studies were identified; data from 4,490 adult patients enrolled between 08/1982 and 01/2003 were available for analysis. The median follow up was 64 months; 663 patients experienced an event leading to an overall 5-year PFS rate of 85% (95% CI 83%–88%). Six factors were significantly (P<0.01) associated with poor PFS: male gender (Hazard ratio (HR) 1.69), age (HR per additional life year 1.03), B symptoms (HR 1.25), anemia (HR per 1 g/dL Hb decrease 1.09), WBC (HR per 1000 WBC increase 1.02) and large mediastinal tumor (HR 1.54). Split into quintiles by predicted risk, observed 5-year PFS rates differed significantly (p<0.001): 80% of patients with early unfavorable stage HL achieved 5-year PFS rates ranging from 84% (95% CI 81%–87%) to 92% (95% CI 90%–94%) while 20% of patients had poor 5-year PFS, i.e. 76% (95% CI 73%–79%). Compared to low risk patients, those with high risk were more often male (81% vs 40%), older (median age 50 vs 29 years) and presented more often with B symptoms (62% vs 28%) and large mediastinal tumor (42% vs 27%). These data show that among stage I and II patients with at least one risk factor heterogeneity exists.Conclusion: Using basic characteristics and routine tests, it is possible to identify a subgroup of early unfavorable stage patients with poor PFS while receiving 4–6 cycles of ABVD or similar chemotherapy plus radiotherapy. For these patients, treatment optimization is open to discussion in particular when compared to that of patients with advanced stage disease.

Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience

Background: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis.Patients and methods: We reviewed the clinical records of 365 Japanese patients with NSCLC who received gefitinib (250 mg/day).Results: Of 324 (89%) patients assessable for response, 147 (45%) obtained disease stabilisation and 71 (22%) patients achieved an objective response. Overall survival in patients obtaining disease stabilisation was significantly longer than in patients with progressive disease (median survival time 12.1 versus 4.4 months; P <0.0001). In patients obtaining disease stabilisation, those who continued gefitinib treatment until disease progression tended to have longer overall and progression-free survival compared with those discontinuing gefitinib treatment (1-year survival rate 52.1% versus 36.6%, P = 0.08; 1-year progression-free survival rate 31.8% versus 5.2%, P = 0.001). Multivariate analysis showed discontinuing gefitinib was an independent risk factor for progression-free survival (hazard ratio 1.66; 95% confidence interval 1.07–2.56; P = 0.022) but not for overall survival.Conclusions: Our findings indicate the importance of achieving disease stabilisation with gefitinib treatment and continued gefitinib treatment in Japanese patients with disease stabilisation, although further studies are required to confirm these findings.

Genetic Polymorphisms in the Tumor Necrosis Factor Locus Influence Non-Hodgkin's Lymphoma Outcome

Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

Genetic Polymorphisms in the Tumor Necrosis Factor Locus Influence Non-Hodgkin's Lymphoma Outcome

AbstractSystemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.