Progression-free Time Research Articles

Clinical efficacy of tumor antigen-pulsed DC treatment for high-grade glioma patients: evidence from a meta-analysis.

BackgroundThe effectiveness of immunotherapy for high-grade glioma (HGG) patients remains controversial. To evaluate the therapeutic efficacy of dendritic cells (DCs) alone in the treatment of HGG, we performed a systematic review and meta-analysis in terms of patient survival with relevant published clinical studies.Materials and methodsA total of 409 patients, including historical cohorts, nonrandomized and randomized controls with HGG, were selected for the meta-analysis.ResultsThe treatment of HGG with DCs was associated with a significantly improved one-year survival (OS) (p<0.001) and 1.5-, 2-, 3-, 4-, and 5-year OS (p<0.001) compared with the non-DC group. A meta-analysis of the patient outcome data revealed that DC immunotherapy has a significant influence on progression-free survival (PFS) in HGG patients, who showed significantly improved 1-,1.5-, 2-, 3- and 4-year PFS (p<0.001). The analysis of Karnofsky performance status (KPS) demonstrated no favorable results for DC cell therapy arm (p = 0.23).The percentages of CD3+CD8+ and CD3+CD4+ T cells and CD16+ lymphocyte subset were not significantly increased in the DC group compared with the baseline levels observed before treatment (p>0.05), whereas CD56+ lymphocyte subset were significantly increased after DC treatment (p = 0.0001). Furthermore, the levels of IFN-γ in the peripheral blood of HGG patients, which reflect the immune function of the patients, were significantly increased after DC immunotherapy (p<0.001).ConclusionsThus, our meta-analysis showed that DC immunotherapy markedly prolongs survival rates and progression-free time, enhances immune function, and improves the efficacy of the treatment of HGG patients.

Phase I/II Study of Induction Chemotherapy of Carboplatin and Irinotecan Followed By Sequential Thoracic Radiotherapy (Trt) for Elderly Patients with Limited-Stage Small-Cell Lung Cancer (Ld-Sclc): Torg 0604

ABSTRACT Aim: The effect of irinotecan in treatments for LD-SCLC in the elderly is unclear, and the optimal timing of TRT when combined with chemotherapy has not been fully evaluated. We report a phase I/II trial of induction chemotherapy with carboplatin and irinotecan followed by sequential TRT in this population? Methods: Patients with untreated, measurable LD-SCLC >70 years with performance status (PS) 0 to 2 and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8 every 21 days for four cycles. TRT of 54Gy in 27 fractions was then administered sequentially. Carboplatin dose was escalated from AUC of 4 to 5 (Levels 1 and 2, respectively)?with a fixed dose of irinotecan at 50 mg/m2. The primary objective of the phase II portion was evaluation of efficacy. Results: A total of 41 patients were enrolled [median age 75 years, range 70-86 years; 31 male, 10 female; PS 0/1/2: 22/18/1]. At Level 1 (n=6), one patient experienced dose-limiting toxicity (DLT) as Grade 3 hypertension. At Level 2 (n=6), two patients experienced DLT as Grade 4 thrombocytopenia. Therefore, level 1 was chosen as the recommended dose. The phase II trial was then expanded by 35 patients in the level 1 based on the Simon minimax design. In all cohorts, the median chemotherapy cycle was 4 (1/2/3/4 courses administered as 4/2/2/33); median radiation dose was 54Gy (range 36-60). Toxicities were generally mild, as expected.?Gr 3/4 leukopenia and thrombocytopenia were both observed in six (15%) patients. No Gr 3/4 diarrhea or esophagitis was noted. Although Gr 3 febrile neutropenia and Gr 3 pneumonitis were seen in two patients each, no treatment-related deaths occurred. There were five complete responses and 32 partial responses, for a response rate of 90%. With median follow-up of 80.4 months (n=41), median progression-free and overall survival times were 12.4 and 27.1 months, respectively. Conclusions: Induction chemotherapy with carboplatin plus irinotecan followed by sequential TRT was well tolerated and highly active in elderly patients with LD-SCLC. Further confirmatory studies are warranted. Disclosure: All authors have declared no conflicts of interest.

Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

A joint test for progression and survival with interval‐censored data from a cancer clinical trial

Clinical trials often assess efficacy by comparing treatments on the basis of two or more event-time outcomes. In the case of cancer clinical trials, progression-free survival (PFS), which is the minimum of the time from randomization to progression or to death, summarizes the comparison of treatments on the hazards for disease progression and mortality. However, the analysis of PFS does not utilize all the information we have on patients in the trial. First, if both progression and death times are recorded, then information on death time is ignored in the PFS analysis. Second, disease progression is monitored at regular clinic visits, and progression time is recorded as the first visit at which evidence of progression is detected. However, many patients miss or have irregular visits (resulting in interval-censored data) and sometimes die of the cancer before progression was recorded. In this case, the previous progression-free time could provide additional information on the treatment efficacy. The aim of this paper is to propose a method for comparing treatments that could more fully utilize the data on progression and death. We develop a test for treatment effect based on of the joint distribution of progression and survival. The issue of interval censoring is handled using the very simple and intuitive approach of the Conditional Expected Score Test (CEST). We focus on the application of these methods in cancer research.

Correlation between overall survival and other efficacy endpoints in advanced biliary tract cancer: Literature-based analysis from 13 randomized trials of first-line chemotherapy.

352 Background: Chemotherapy for advanced biliary tract cancer (ABC) has progressed. Now gemcitabine plus cisplatin combination is considered the standard 1st-line treatment based on the results of many randomized studies. However, the impact of various efficacy parameters on overall survival (OS) remains unclear. Methods: We searched PubMed database with the key words of (“biliary tract neoplasms” or “bile duct neoplasms” or “gallbladder neoplasms” or “cholangiocarcinoma” [All fields]) AND (“chemotherapy”[All fields]) AND Clinical trial [ptyp] between Apr 1984 to Jun 2013 and abstracts presented at the meetings of ASCO/Gastrointestinal Cancers Symposium (2004–2013) and ESMO/WCGC (2002–2013). Then we identified randomized trials of 1st-line chemotherapy for ABC, and analyzed the relations between the results of OS and those of progression-free survival (PFS) or time to progression (TTP), response rate (RR), disease control rate (DCR), post-progression survival (PPS = median OS − median PFS/TTP), and the proportion of patients who received 2nd-line chemotherapy (%2nd). Results: Among 329 papers/abstracts retrieved, 13 randomized trials, 26 treatment arms of first-line chemotherapy for ABC were identified. Number of trials with information on median OS, median PFS/TTP, hazard ratio (HR) for OS and PFS/TTP, RR, DCR, and %2nd were 13, 13, 6, 13, 12, and 7, respectively. The analysis of all these trials demonstrated the median values (range) of OS, PFS/TTP, HR of OS, HR of PFS/TTP, RR, DCR, PPS, and %2nd were 9.4 (4.6–13) months, 5.3 (2.7–8.5) months, 0.71 (0.39–0.93), 0.65 (0.44–0.85), 20 (7.1–36) %, 67 (21–87) %, 4.0 (1.0–7.6) months, and 41 (15–79) %, respectively. Spearman rank correlation coefficient of differences (Δ) OS with ΔPFS/TTP, ΔRR, ΔDCR, and ΔPPS were 0.66, − 0.07, 0.66, and 0.34, respectively. The correlation coefficient between HRs for PFS/TTP and OS was 0.60. The correlation coefficient between ΔPPS and Δ%2nd was − 0.15. Conclusions: OS was moderately associated with PFS/TTP and DCR.

Relationship between BIM gene polymorphism and therapeutic efficacy in the retreatment of advanced non-small cell lung cancer with tyrosine kinase inhibitor

背景与目的BIM基因是BCL-2家族成员之一，是参与细胞死亡的重要介质。在非小细胞肺癌（non-small cell lung cancer, NSCLC）中，BCL-2家族成员蛋白介导的EGFR基因突变癌细胞能够激活PI3K/AKT/mTORC和MER/ERT信号通道，决定着细胞的存活或者凋亡。BIM基因的BH3域缺失，则容易引起凋亡受阻。本研究通过检测BIM基因多态性，探讨其与复治晚期NSCLC表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）治疗疗效的关系。方法入选2009年1月1日-2012年10月1日就诊于浙江省肿瘤医院的123例复治晚期NSCLC患者，所有患者既往均接受过化疗，失败后接受吉非替尼或厄洛替尼靶向治疗。采用多聚酶链反应方法检测患者外周血白细胞中BIM基因多态性。采用SPSS 13.0统计软件分析。结果在疾病控制率上，BIM基因无多态性的患者较BIM基因有多态性的患者呈略好趋势（DCR 75.5% vs 57.1%, χ2=2.931, P=0.087）。单因素分析中位PFS，女性长于男性（6.9个月vs 4.5个月，χ2=7.077，P=0.008)；不吸烟者长于有吸烟史者（8.0个月vs 2.5个月，χ2=15.277，P < 0.001)；病理类型为腺癌的长于其它类型（7.0个月vs 2.0个月，χ2=14.978，P < 0.001)；BIM基因无多态性的患者中位PFS长于BIM基因有多态性的患者（6.0个月vs 3.5个月，χ2=7.035，P=0.008)。多因素分析结果显示吸烟、病理类型、BIM基因多态性为影响PFS的预后因素。BIM基因型与不良反应差异无统计学意义（P>0.05）。结论BIM基因多态性的有无对复治晚期NSCLC EGFR-TKI治疗患者的中位无进展时间有统计学差异，检测患者BIM基因多态性对复治晚期NSCLC EGFR-TKI治疗患者的评估预后有重要意义。

Early Ofatumumab Treatment For High-Risk, Treatment-Naive Patients With Chronic Lymphocytic Leukemia

Background Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 on normal B cells and on B chronic lymphocytic leukemia cells, resulting in B cell lysis. Ofatumumab has single-agent activity in patients (pts) with refractory CLL (Wierda, JCO 2010). Pts with CLL who have early stage disease (Rai 0-II) but have high-risk prognostic markers such as deletion 17p or deletion 11q have an increased risk of disease progression. Currently, these pts are offered watch-and-wait approach. The objective of this Phase II study is to evaluate the efficacy of ofatumumab in treating these pts with the goal to delay time to first chemoimmunotherapy treatment. Methods Pts with CLL/SLL were eligible provided they had high-risk for progression based on the presence of at least one of the following features: Rai stage II, serum beta-2 microglobulin (β2M) ≥3 mg/L, absolute lymphocyte count ≥25,000/µL, unmutated (≤2%) IGHV gene or mutated IGHV3-21, ZAP70 positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. Pts having a 2008 IWCLL/NCI-WG indication for CLL treatment were not eligible. Pts with Rai stage III-IV CLL were not eligible. Ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 additional weeks (8 doses) was administered. Response assessment, including bone marrow evaluation, was done at least 2 months after last dose of ofatumumab and pts were followed for progression-free survival and time to first chemoimmunotherapy. Results Twenty-five pts (9 women, 16 men) were enrolled so far. The median age was 59 yrs (range, 40-81). The baseline characteristics are listed in the Table. Fifty percent of pts had unmutated IGHV gene. Thirty-four percent of pts had high-risk cytogenetic by FISH analysis. The median follow-up on the study is 4.7 months (range, 0.5-26). Grade 3-4 adverse events included infusion reaction in 6 pts. Autoimmune hepatitis with grade 4 ALT, grade 4 AST, and grade 4 alkaline phosphatase elevations was seen in 1 pt. Other grade 3-4 toxicities included rash (1 pt), shingles (1 pt), and tumor lysis (1 pt). Tumor lysis was seen in the pt with the WBC count of 207 K/µL. Eighteen pts (7 too early) are evaluable for response. Responses are as follows: 6 CR, 3 nPR, 3 PR, and 6 with stable disease. Three pts have progressed at 18.8, 14.1 and 3.2 months after starting the study treatment; 2 pts had unmutated IGHV gene (FISH negative) and one pt had trisomy 12 (IGHV mutation status unknown). None of the pts with deletion 17p or deletion 11q have progressed. All pts are alive at this time. The median overall follow up time is 7.6 months (range, 1-28). Conclusions Ofatumumab is well tolerated in pts with early stage CLL and may delay time to first chemoimmunotherapy. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding.

Pattern of Lymph Node Metastases and Its Implication in Radiotherapeutic Clinical Target Volume in Patients With Upper Thoracic Esophageal Squamous Cell Carcinoma

To study the pattern of lymph node metastases after esophagectomy in patients with upper thoracic esophageal squamous cell carcinoma (ESCC) and provide the criteria of the clinical target volume (CTV) delineation; to analyze the 2-year overall survival (OS) and progress free time (PFS) rates of postoperative patients with upper thoracic ESCC and evaluate the effectiveness of postoperative radiation therapy.

Comparative efficacy of everolimus versus fulvestrant for hormone-receptor–positive (HR+) advanced breast cancer (ABC) following progression/recurrence after first-line treatment: A network meta-analysis.

e11602 Background: Everolimus (EVE), an oral mammalian target of rapamycin (mTOR) inhibitor, is approved in combination with exemestane (EXE) to treat postmenopausal women (PMW) with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC that progressed after nonsteroidal aromatase inhibitor therapy. Fulvestrant (FUL), an estrogen receptor antagonist, is another treatment option for PMW previously treated with endocrine therapy. However, the comparative efficacy of EVE + EXE vs FUL is unknown. Methods: Six randomized, controlled trials in HR+, HER2–ABC patients were identified by systematic literature review (Cochrane library, National Horizon Scanning Centre, and NICE Web sites) that formed a network permitting indirect comparisons of EVE + EXE or EVE + tamoxifen (TAM) vs FUL: BOLERO-2, CONFIRM, EFECT, Paridaens (2008), SoFEA, and TAMRAD. All 6 trials had EXE, TAM, or FUL 250 mg as the common comparator to form the network. Relative efficacy of EVE and FUL was obtained using a Bayesian network meta-analysis based on these 6 trials. The primary endpoint was local assessment of progression-free survival (PFS) or time to progression (TTP). The hazard ratio (HR) of EVE + EXE relative to FUL and its 95% credible intervals (CrI) were calculated. Evidence of a difference between treatments is suggested by the 95% CrI not including 1. A HR &lt;1 indicates that the hazard rate is higher in the comparator group and that the treatment is more effective. Results: EVE + EXE was found to be more efficacious for PFS/TTP than FUL 250 mg (HR = 0.47; 95% Crl, 0.38-0.58) and more efficacious than FUL 500 mg (HR = 0.59; 95% Crl, 0.45-0.77). EVE + TAM was found to be numerically better for PFS/TTP than FUL 250 mg (HR = 0.65; 95% Crl, 0.40-1.04) and numerically better than FUL 500 mg (HR = 0.81; 95% Crl, 0.49-1.33). Conclusions: The indirect evidence from this analysis suggests that EVE in combination with EXE is more efficacious than FUL 250 and 500 mg in PMW with HR+, HER2– ABC that progresses after endocrine therapy. These data should be interpreted with caution as there is no randomized trial that directly compares EVE + EXE vs FUL.

Absolute Lymphocyte/Monocyte Ratio at Diagnosis and Interim Positron-Emission Tomography Predict Survival in Classical Hodgkin Lymphoma

Interim Positron-Emission Tomography (int-PET) and the peripheral blood absolute lymphocyte/monocyte ratio at di- agnosis (ALC/AMC-DX) have been shown to be predictors for progression-free survival (PFS) and time to progression (TTP) in classical Hodgkin lymphoma (cHL). Therefore, we studied if the combination of ALC/AMC-DX and the (int-PET) can further stratified PFS and TTP in cHL patients. Patients were required to be diagnosed, treated, and followed with int-PET at Mayo Clinic, Rochester, Minnesota. From 2000 until 2008, 111 cHL patients qualified for the study. The median follow-up was 2.8 years (range: 0.3 - 10.4 years). Patients with a negative int-PET (N = 98) pre- sented with a higher ALC/AMC-DX (median of 2.32, range: 0.26 - 37.5) compared with patients with a positive int-PET (N = 13) (median of 0.9, range: 0.29 - 3.10), p 1.1. Group 1 experienced superior PFS and TTP in comparison with the other groups. In conclusion, the combination of ALC/AMC-DX and the int-PET provides a simple model to assess clinical outcomes in cHL.

Treatment and prognosis of stage IV alveolar soft part sarcoma

To analyze the clinical features, treatment and prognosis of Stage IV alveolar soft part sarcoma. To analyze the clinical and pathological features, therapeutic methods and follow-up results in 21 patients with stage IV alveolar soft part sarcoma. There were 11 males and 10 females, in the age of 26-57 years (average 37.0 years old). All the 21 patients had metastasis: nine cases had multiple pulmonary metastasis, three cases had multiple pulmonary and brain metastasis, two cases had multiple brain metastasis, two cases had multiple pulmonary and bone metastasis, two cases had single pulmonary metastasis, one case had single bone metastasis, one case had single brain metastasis and one case had single soft tissue metastasis. Eight patients were treated by surgical operation, including five cases of complete resection for the primary and (or) metastatic tumor and 3 cases of palliative operation for the primary tumor. All patients received chemotherapy, including seven cases of CAVD regimen and 14 cases of MAID regimen treatment. One patient with single bone metastasis and five patients with multiple brain metastasis received post-operative whole brain radiation therapy. All the eight patients with surgical operation had healing by first intention, and pathological examination showed that seven patients achieved R0 surgical margin and one case with R2 status. One patient with single brain metastasis had recurrence after operation. The toxic and adverse reactions of all patients treated with chemotherapy were tolerable. Among them, 17 cases had stable disease and 4 cases had disease progression after chemotherapy. The disease control rate (DCR) was 81.0%. The DCR of patients with CAVD regimen chemotherapy was 85.7% and that of patients treated with MAID regimen was 78.6% (P = 0.862). All patients were followed up for 8 - 86 months (average 32.4 months). The median survival time of all patients was 32.6 months. The 2-year survival rate was 55.1% and the 5-year survival rate was 21.8%. The median survival time in the patients with complete resection was 60.0 months, and that in patients with palliative operation was 27.0, showing a significant difference between them (P = 0.048). The median progression-free survival in patients with complete excision was 57.2 months and that in patients with palliative operation or without operation was 19.6 months, with a significant difference (P = 0.029). The median survival time in patients who received CAVD regimen chemotherapy was 30.0 months, and that in patients with MAID regimen was 51.0 months, with a non-significant difference (P = 0.511). The median progression-free time in patients with CAVD regimen chemotherapy was 13.0 months, and that in patients with MAID regimen was 38.0 months, also with a non-significant difference (P = 0.066). Alveolar soft part sarcomas are rarely seen and highly malignant tumors, and the prognosis of stage IV ASPS is poor. Complete resection of all tumors is the key of successful treatment of Stage IV ASPS, and the site and number of tumor metastasis are important factors affecting prognosis. The curative effects of radiotherapy and chemotherapy for ASPS need to be further investigated.

Progression and Persistence of Low-Grade Cervical Squamous Intraepithelial Lesions in Women Living With Human Immunodeficiency Virus

This study aimed to investigate the progression and persistence of low-grade squamous intraepithelial lesions (SILs) in human immunodeficiency virus (HIV)-infected women. Study participants for this retrospective cohort study were 1,720 women who had LSIL as their first abnormal Pap smear. A comparison of the survival of LSIL without progression to high-grade SIL as progression-free time and the survival of SIL without clearance of the lesion as persistence of SIL was done for women of HIV-positive, HIV-negative, or unknown status using the Kaplan-Meier method. Multivariable Cox proportional hazards regression model was applied to identify independent risk factors for disease progression or persistence. We found progression of LSIL not different between HIV groups but that persistence occurred more in HIV-positive women (63.8% vs 35.0%, p < .001). For the HIV group, antiretroviral therapy that was started before the first LSIL was associated with decreased risk for progression compared with no antiretroviral therapy (hazard ratio = 0.66, 95% CI = 0.54-0.81, p < .001). Antiretroviral therapy also improved clearance when corrected for excision treatment and age (hazard ratio = 1.71, 95% CI = 1.29-2.27, p < .001). Excision of LSIL reduced the risk of progression. In HIV-negative women, progression was reduced from 54.7% to 0.0% (p < .001), and from 46.9% to 6.4% in HIV-positive women (p < .001). Excision also reduced persistence in HIV-negative women from 39.5% to 7.1% (p = .001), but for HIV-positive women, the effect was smaller (from 66.3% to 45.5%, p < .001). Antiretroviral treatment reduced the risk for progression and persistence of LSIL in HIV-infected women.

Moving Beyond Response Criteria: New Measures of Success in the Treatment of Sarcomas

There is an urgent need to develop new therapies for soft tissue sarcomas. Traditional cytotoxic therapies, such as doxorubicin and ifosfamide, have been the standard approach to this disease. However, newer paradigms are emerging that are less toxic while targeting dysregulated pathways, tumor hypoxia, and genetic translocations. These newer therapies require different measures of activity as standard response criteria may inaccurately measure their effectiveness. Serious consideration of select endpoints and measures of tumor response are crucial to make significant strides in the treatment of sarcomas. Current studies on soft tissue sarcomas are slowly abandoning response rates while employing progression-free survival and time to progression as improved endpoints. With time and data, our understanding of the relative activity of these agents will grow and lead to improved benefits for our patients.

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer.

4067 Background: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy (Shitara, K et al. Invest New Drug 2011; Shitara K and Burzykowski T, et al, ASCO 2011). However, no corresponding analysis had been done in patients who underwent second-line chemotherapy for AGC. Methods: We evaluated the potential of PFS, TTP, response rate (RR), or disease control rate (DCR) to act as surrogates for OS in phase II and III trials of second-line chemotherapy for AGC by comprehensive literature-based analysis. Correlations between each endpoint and OS were evaluated by Spearman rank correlation coefficient (ρ). Subgroup analyses by trial region or type of failure to previous chemotherapy were also conducted. Results: Fifty-six trials, including four randomized studies, were selected for analysis and covered a total of 61 treatment arms and 3,038 patients; 34 studies were conducted in Asia, 20 studies in Non-Asian countries, and two studies in both regions. Median PFS were similar in Asian and Non-Asian trials (3.0 vs. 3.3 months). In contrast, median OS tended to be longer in Asian vs. Non-Asian trials (8.0 vs. 6.0 months; p&lt;0.01). Median PFS/TTP and OS showed a moderate correlation with ρ of 0.51 (95% CI, 0.31-0.73). Correlation tended to be higher in PFS (ρ = 0.62) than TTP (ρ = 0.29) and higher in non-Asian trials (ρ = 0.73) than Asian trials (ρ = 0.32). Correlation between PFS/TTP and OS among the trials in which eligibility required failure to previous fluorouracil and cisplatin also showed low correlation (ρ = 0.48). The RR and DCR also did not show high correlation with OS (ρ = 0.30 for RR; 95% CI 0.04-0.56; ρ = 0.53 for DCR; 95% CI 0.31-0.75). The hazard ratio (HR) of PFS and OS in each arms of the four randomized studies showed a low correlation with ρ of 0.10. Conclusions: Our results indicate that PFS/TTP, RR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who underwent second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.

CD105 and placental growth factor – Potent prognostic factors in childhood acute lymphoblastic leukaemia

The studies aimed at identifying a prognostic significance of angiogenesis-related factors: CD105 and placental growth factor (PlGF) in a course of acute lymphoblastic leukaemia (ALL). Research protocol was based on detection of RNA and protein expressions in bone marrow blasts using quantitative PCR and immunocytochemical assays respectively.Kaplan–Meier statistics revealed CD105 and PlGF expression as managed separately do not correlate with relapse-free time in ALL patients. On the other hand, an associated analysis of CD105 and PlGF demonstrated a significantly shorter progression-free time in children who were CD105+ and PlGF+ or CD105− and PlGF+ at the moment of ALL diagnosis.

Economic Evaluation of Sequential Treatments for Follicular Non-Hodgkin Lymphoma

BackgroundThe cost-effectiveness analyses of follicular lymphoma (FL) treatments have focused on the second-line rituximab maintenance in patients with relapsed FL. The assessment of full FL treatment chain has been lacking. ObjectiveThe aim of this study was to assess the cost-effectiveness of FL treatment sequences. MethodsTransitions between progression-free first-line treatment (PF1), progression-free second-line treatment (PF2), progression, and death health states were simulated with a probabilistic Markov model with half-cycle correction. At first, patients were assumed to be receiving rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) induction. The first-line RCHOP induction responders continued without (RCHOP) or with (RCHOPR) the first-line rituximab-maintenance treatment. In the case of PF1 failure, patients received RCOPR/bendamustine or RCOPR/COP according to the European Society for Medical Oncology guidance. In the case of PF2 failure, patients were expected to receive the best supportive care (BSC). The survivals and adverse events were estimated with direct and indirect comparisons. Health outcomes and Finnish payer (drug, drug administration, monitoring, test, progression, serious adverse event) costs valued in 2010 euros were discounted with 3% per annum. ResultsThe mean discounted lifetime overall survival with FL was 9.6 to 11.5 years, quality-adjusted survival was 7.2 to 8.8 quality-adjusted life-years (QALYs), progression-free time was 7.7 to 10.2 years, and costs were €153,425 to €168,549, depending on the treatment sequence. The incremental cost-effectiveness ratios for RCHOPR→RCOPR/bendamustine→BSC, RCHOPR→RCOPR/COP→BSC, and RCHOP→RCOPR/bendamustine→BSC were €9575/€8014/€5900, €9881/€8310/€6013, and €8812/€7194/€5808, respectively, per QALY/life-year/progression-free year gained in comparison with RCHOP→RCOPR/COP→BSC. According to the cost-effectiveness acceptability frontier, the treatment of 61.8% to 72.7% patients with RCHOPR→RCOPR/bendamustine→BSC was cost effective at €20,000 to €30,000/QALY gained (expected value of perfect information [EVPI], €1287 to €1976/patient). The relative results were found to be robust in sensitivity analyses, and, in the direct comparison that included only head-to-head data, the first-line rituximab maintenance had 93.1% cost-effectiveness probability at €20,000/QALY gained (EVPI, €282/patient). ConclusionSequences that included first-line rituximab maintenance is and second-line bendamustine are potentially cost effective in the treatment of FL. LimitationsBecause of data available, health outcomes of the first-line rituximab induction were excluded, the second-line patients on COP were assumed to incur the cost of COP, and the efficacy and adverse events of CHOP and the efficacy and adverse events of bendamustine were estimated indirectly according to a comparison of rituximab+bendamustine and RCHOP, and treatment benefits were truncated.

Prognostic Nomogram for Disease-Free Survival in Patients with Renal Adenocarcinoma

Objective: The aim of this study was to develop a postoperative prognostic nomogram for disease-free survival in patients with renal adenocarcinoma. Materials and Methods: A total of 224 patients with organ-confined or locally advanced renal adenocarcinoma were treated with radical or partial nephrectomy. The variables included in the model were age, histological type, pathological stage, Fuhrman grade and DNA ploidy. Tumor recurrence was defined as any clinical evidence of recurrence. The probability of progression-free survival was calculated using the Kaplan-Meier estimate, and multivariate analysis was performed using a Cox regression. The nomogram was created using the data obtained from the Cox regression. Results: Tumor recurrence was detected in 89 patients (39.74%). The median progression-free time in these patients was 9.55 months (range 0–133). Of these patients, 70.9% relapsed during the first 2 years, and only 15 patients (6.9%) were alive but ill at the end of the study. The probability of progression-free survival at 5 and 10 years was 66.64 and 61.97%, respectively. We performed a statistical validation of the model with accurate predictions that were discriminated with a confidence interval of 0.75 (comparing the predicted and actual probability). According to the nomogram obtained, patients with low-grade, diploid, organ-confined tumors would be candidates for follow-up not exceeding 5 years due to the low probability of recurrence (<40 points). Conclusion: The nomogram we developed is clinically relevant and can provide prognostic information for both patients and researchers. In addition, it can be used by researchers during the monitoring protocols that categorize patients based on their relative risk of disease progression.

A Phase I/II Study of Second-Line Chemotherapy with Fractionated Docetaxel and Nedaplatin for 5-FU/Cisplatin-Resistant Esophageal Squamous Cell Carcinoma

There are few second-line regimens available for esophageal cancer. The use of fractionated docetaxel and nedaplatin as second-line chemotherapy was examined in this study. Eligibility criteria were follows: histologically-proven squamous cell carcinoma, surgically unresectable disease, failure to respond to chemotherapy with 5-FU and cisplatin and no more than 2 prior chemotherapy regimens. A total of 12 patients were enrolled in this study. To reduce toxicities, fractionated docetaxel (50 mg/m² in day 1 and 8) and nedaplatin (50 mg/m² in day 8) were administered as second-line chemotherapy. Stable disease (SD) was observed in 4 cases (33%) and the disease control rate was 33%. Regarding toxicities, leukopenia was the most frequently observed (8 cases, 67%); however, there were no cases of grade 4 nonhematological toxicity. The 1-year overall survival was 26.7% and the median survival time was 7.8 months (95% CI=3.328-12.272 months). The 1-year progression-free survival was 0% and the median progression-free time was 2.0 months (95% CI=1.319-2.681). Combination chemotherapy using fractionated docetaxel and nedaplatin is safe and effective and appears to be a feasible regimen to use as second-line chemotherapy for FP-resistant advanced esophageal squamous cell carcinoma.

Abstract A9: Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

Abstract The androgen receptor (AR) signaling pathway is central to the emergence of castration-resistant prostate cancer (CRPC). We set out to identify androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. We found miR-32 to be an androgen regulated miRNA which is differentially expressed in CRPC compared to benign prostate hyperplasia (BPH) according to microarray analyses. qRT-PCR analyses confirmed that miR-32 expression increases in CRPC compared to BPH, and that in untreated prostate cancer (PC) miR-32 expression is higher in tumors of stage pT3 compared to pT2. Transfection of pre-miR-32 to prostate cancer cell line LNCaP provided a significant growth advantage to the cells, and miR-32 was further demonstrated to reduce apoptosis. To identify target genes for miR-32, an mRNA microarray analysis was performed with LNCaP cells transfected with pre-miR-32. In this assay, B cell translocation gene 2 (BTG2) was identified as a novel putative target for miR-32. BTG2 was reduced both at mRNA and protein level in the cells transfected with pre-miR-32, and BTG2 was confirmed to be a miR-32 target by 3′-UTR-luciferase assay. Furthermore, BTG2 was able to partially rescue the growth advantage of miR-32 in LNCaP cells. Immunostainings of prostate cancer patient material showed a statistically significant (p &amp;lt; 0.0001) reduction of BTG2 protein in CRPCs compared to PC. The lack of BTG2 staining was also associated (p=0.0021) with a short progression-free time in patients who underwent prostatectomy and inversely correlated to miR-32 expression levels. In conclusion, we find that miR-32 is an androgen-regulated miRNA targeting BTG2 and overexpressed in CRPC. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC. Citation Format: Sanni E. Jalava, Leena Latonen, Mauro Scaravilli, Kati K. Waltering, Janne Seppälä, Harri Lähdesmäki, Teuvo L.J. Tammela, Tapio Visakorpi. Androgen-regulated miR-32 targets BTG2 and is overexpressed in castrationresistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A9.

Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer

The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Here, we identified several androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. Seven miRNAs, miR-21, miR-32, miR-99a, miR-99b, miR-148a, miR-221 and miR-590-5p, were found to be differentially expressed in CRPC compared with benign prostate hyperplasia (BPH) according to microarray analyses. Significant growth advantage for LNCaP cells transfected with pre-miR-32 and pre-miR-148a was found. miR-32 was demonstrated to reduce apoptosis, whereas miR-148a enhanced proliferation. Androgen regulation of miR-32 and miR-148a was confirmed by androgen stimulation of the LNCaP cells followed by expression analyses. The AR-binding sites in proximity of these miRNAs were demonstrated with chromatin immunoprecipitation (ChIP). To identify target genes for the miRNAs, mRNA microarray analyses were performed with LNCaP cells transfected with pre-miR-32 and pre-miR-148a. Expression of BTG2 and PIK3IP1 was reduced in the cells transfected with pre-miR-32 and pre-miR-148a, respectively. Also, the protein expression was reduced according to western blot analysis. BTG2 and PIK3IP1 were confirmed to be targets by 3'UTR-luciferase assays. Finally, immunostainings showed a statistically significant (P<0.0001) reduction of BTG2 protein in CRPCs compared with untreated prostate cancer (PC). The lack of BTG2 staining was also associated (P<0.01) with a short progression-free time in patients who underwent prostatectomy. In conclusion, androgen-regulated miR-32 is overexpressed in CRPC, leading to reduced expression of BTG2. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC.