Median Time To Disease Progression Research Articles

EGFR-TKIs Combined with Allogeneic CD8+ NKT Cell Immunotherapy to Treat Patients with Advanced EGFR-Mutated Lung Cancer.

Background: To evaluate the efficacy and safety of allogenic CD8 + natural killer T (CD8+ NKT) immunotherapy combined with gefitinib in the treatment of advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC). Methods: This study is prospective. The NSCLC patients with exon 19 (Ex19del) or exon 21 L858R point mutations, and response to gefitinib treatment were enrolled into the trial to be randomly assigned into the gefitinib arm and the gefitinib/NKT arm. Allogenic CD8+ NKT cells were cultured in vitro and adaptive transferred into the patients via vein in the gefitinib/NKT arm. The primary endpoint was progression-free survival (PFS). Secondary endpoint analysis included time to disease progression (TTP), overall survival (OS), levels of serum tumour markers for carcinoembryonic antigen (CEA) and alanine aminotransferase (ALT) in the blood, the response rate and safety. From July 2017 to June 2021, 19 patients were randomly assigned to the gefitinib arm (n = 8) and the gefitinib/NKT arm (n = 11). Results: The estimated median survival PFS in the gefitinib/NKT arm was significantly longer than that of the gefitinib arm (12 months vs 7 months). Similar results were also observed for the median TTP. Moreover, the gefitinib/NKT arm had better CEA control than the gefitinib arm. Clinical grade 3 adverse reactions occurred in 64% and 39% of patients in the gefitinib/NKT arm and the gefitinib arm, respectively. The most common grade 3 adverse events in the gefitinib/NKT arm included abnormal liver function in 8 cases (73%) and diarrhoea in 1 case (9%), both of which resolved after drug intervention. Conclusion: The PFS of EGFR-mutated advanced NSCLC treated with allogenic CD8+ NKT cells combined with gefitinib was longer than that of gefitinib alone. No obvious serious adverse reactions occurred, and the patients compliance and survival status were good.

Randomized Phase III Trial Comparing Epirubicin/ Doxorubicin Plus Docetaxel and Epirubicin/ Doxorubicin Plus Paclitaxel as First Line Treatment in Women with Advanced Breast Cancer

This study aimed to examine the efficacy of docetaxel plus epirubicin against docetaxel plus capecitabine as first-line therapy for women with advanced breast cancer (ABC). Patients with ABC who had not been treated in the past were split into two groups: those who received docetaxel and epirubicin (DE) on day 1 and those who received docetaxel and capecitabine (DC) on day 1 and twice daily on days 1-14 of each 21-day cycle. Prior neoadjuvant treatment with anthracyclines was permitted if it had been finished more than a year prior to enrolment. The study's major aim was to evaluate the difference in time to disease progression (TTP). Median TTP for DE was 10.6 months and for DC it was 11.0 months (P = 0.7), with each arm treating 170 women. Using the RECIST criterion, we found that the rates of complete responses were higher in DC (61%) than in DE (11%), and that the rates of partial responses were lower in DC (40%) than in DE (45%) (P = 0.8). Grade 3-4 neutropenia was more common with DE than DC (57% vs. 46%, P = 0.07), as were febrile neutropenia (11% vs. 8%, P = 0.4), hand-foot syndrome (0% vs. 4%, P = 0.02), grade 2-3 anemia (20% vs. 7%, P = 0.001), and asthenia (12% vs. 6%, P = 0.09).

Lanreotide Depot to Treat Gastroenteropancreatic Neuroendocrine Tumors in a US Community Oncology Setting: A Prospective, Observational Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can result in symptoms such as diarrhea, flushing, abdominal pain, and fatigue and are often associated with a significant disease burden and poor prognosis. This non-interventional, prospective, observational study evaluated the real-world safety and effectiveness of lanreotide depot, a somatostatin analog (SSA) used to treat GEP-NETs, in a community setting. In this prospective, non-interventional study (NCT02730104), adult patients with locally advanced (inoperable), metastatic GEP-NETs treated with lanreotide depot were evaluated by their physician every 6 months from enrollment for 24months. Clinically defined time to disease progression (TTDP) and overall survival (OS) were estimated for the total population and by primary tumor type (gastrointestinal [GI], pancreatic, unknown origin), and an exploratory analysis determined the rate of progression-free survival (PFS) at 12 and 24months. Patient satisfaction was evaluated via the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and safety information was recorded. Of 99 patients, the 24-month PFS rate was 73.7% (95% confidence interval [CI] 63.1-81.7) and 24-month OS rate was 84.2% (95% CI 74.0-90.7). Median TTDP was not reached because few patients experienced disease progression during the study period. The majority of responding patients expressed satisfaction with treatment on each domain of the TSQM-9. Treatment-related adverse events (AEs) occurred in 19.2% of patients, while no serious AEs (SAEs) were related to the study drug. Lanreotide depot is an effective and well-tolerated treatment for GEP-NETs in the real-world community setting. ClinicalTrials.gov identifier, NCT02730104.

Performance of initial LI-RADS 2018 treatment response in predicting survival of patients with hepatocellular carcinoma following TACE: a retrospective, single-center cohort study

PurposeTreatment response following transarterial chemoembolization (TACE) is frequently evaluated with Liver Imaging Reporting and Data System Treatment Response (LR-TR) algorithm, but its association with patients’ outcomes is not supported in the literature. The purpose of this study was to provide such data.MethodsA retrospective analysis of 99 TACE patients with stage A/B hepatocellular carcinoma according to Barcelona-Clinic Liver Cancer staging system was performed. Two radiologists assessed LR-TR, while a third radiologist re-assessed divergent results. Overall survival (OS) and time to disease progression (TTP) were the primary endpoints of the study, while the Cox proportional hazard model was used for outcome analyses.ResultsInterobserver agreement was substantial between the two readers with κ = 0.69 (95% CI 0.58–0.81). The median OS in viable, equivocal, and non-viable groups were 27, 27, and 73 months, respectively (p < 0.001). However, after adjustment for confounding factors, there was no significant association between initial viable response and OS (HR 0.98 [95% CI 0.37–2.63], p = 0.97), while equivocal response remained statistically significant (HR 3.52. [95% CI 1.27–9.71], p = 0.015). No significant association was noted when viable and equivocal groups were analyzed in aggregate (HR 1.03 [95% CI 0.4–2.4], p = 0.96). The median TTP did not differ between non-viable and viable groups (23 vs 18 months, respectively; p = 0.98). None of the analyzed predictors was associated with TTP.ConclusionInitial LR-TR response was not an independent predictor for OS nor TTP. The preliminary results suggest the necessity for more aggressive management of equivocal patients.

Active surveillance in metastatic pancreatic neuroendocrine tumors: A 20-year single-institutional experience.

BACKGROUNDPancreatic neuroendocrine tumors (PanNETs) are heterogeneous and indolent; systemic therapy is not essential for every patient with metastatic PanNET. The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis, if the patient has stable disease. However, specific factors that influence surveillance were not mentioned. In addition, data regarding the period of active surveillance in patients with metastatic PanNET are lacking.AIMTo specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs (NF-PanNETs).METHODSSeventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled. Time to disease progression (TTP) and time to initiation of systemic therapy were determined.RESULTSThirty-one (40.8%) patients had recurrent liver disease after R0 resection; 45 (59.2%) were diagnosed with liver metastasis. The median follow-up period was 42 mo and 90.7% patients were observed to have disease progression. The median TTP (mTTP) was 10 mo. Multivariate analysis showed that the largest axis of the liver metastasis > 5 mm (P = 0.04), non-resection of the primary tumor (P = 0.024), and T3-4 stage (P = 0.028) were associated with a shorter TTP. The mTTP in patients with no risk factors was 24 mo, which was significantly longer than that in patients with one (10 mo) or more (6 mo) risk factors (P < 0.001). A nomogram with three risk factors showed reasonable calibration, with a C-index of 0.603 (95% confidence interval: 0.47-0.74).CONCLUSIONActive surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors, and other patients progressed rapidly without treatment. Further studies with a larger sample size and a control group are needed.

Immunotherapy response evaluation with magnetic resonance elastography (MRE) in advanced HCC

BackgroundCurrently, there are no imaging predictors of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if stiffness changes measured by magnetic resonance elastography (MRE) can be a predictor of immunotherapy response in patients with advanced HCC.Materials and methodsThis was a prospective study of 15 patients with biopsy proven-advanced HCC treated with Pembrolizumab. All patients had liver MRE and liver biopsy at baseline and at 6 weeks of therapy. Change in HCC stiffness on MRE was compared with overall survival (OS), time to disease progression (TTP), and number of intratumoral CD3+ T lymphocytes. Analysis was performed using descriptive statistics and Spearman correlation (R); p-value < 0.05 was considered statistically significant.ResultsNine patients were evaluable. Median age was 71 years (range, 54–78). Etiology of liver disease was HCV (n = 4), HBV (n = 1) and NASH (n = 4). Median OS and TTP were 44 weeks and 13 weeks, respectively. Average baseline HCC stiffness and change in HCC stiffness were 5.0 kPa and 0.12 kPa, respectively. In contrast, average non-tumor liver stiffness was 3.2 kPa, and did not significantly change at 6 weeks (p = 0.42). Average size of measured tumor and change in size were 4 cm and − 0.32 cm, respectively. Change in HCC stiffness at 6 weeks correlated significantly with OS (R = 0.81), and TTP (R = 0.88,p < 0.01). Abundance of intratumoral T lymphocytes on tumor biopsy correlated significantly with HCC stiffness (R = 0.79,p = 0.007).ConclusionOur pilot MRE data suggests early change in tumor stiffness may be an indicator of immunotherapy response in patients with advanced HCC.

A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma.

Background: Mipsagargin (G-202) is a thapsigargin-based prodrug with cytotoxic activity masked by a peptide that is cleaved by prostate-specific membrane antigen (PSMA), a protease expressed in prostate cancer cells and the endothelium of tumor vasculature. It was hypothesized that PSMA-mediated activation of mipsagargin would result in disruption of the tumor vasculature, leading to a decrease in blood flow, and in direct cytotoxic effects on tumor cells, resulting in anti-tumor activity. Method: In this open-label, Phase II study, mipsagargin was administered intravenously on Days 1, 2, and 3 of a 28-day cycle to patients with hepatocellular carcinoma (HCC) who progressed on or after treatment with sorafenib or intolerant of sorafenib. Assessments included time to disease progression (TTP), response rate, progression-free survival (PFS), overall survival (OS), and safety. Blood flow metrics in hepatic lesions were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Of 25 treated patients, 19 were evaluable for efficacy. None had an objective response, 12 (63.2%) had a best response of stable disease, and 12 (63.2%) showed radiologic progression; seven patients (36.8%) were censored. The median TTP was 134.0 days, median PFS was 129.0 days, and median OS was 205.0 days. Of five patients with DCE-MRI data for 11 HCC lesions, all demonstrated a reduced Ktrans (mean, 52%). The most common treatment-emergent AEs were Grade 1–2 and consisted of increased blood creatinine (68.0%), fatigue (56.0%), and nausea (44.0%). Conclusions: Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in Ktrans upon treatment suggests mipsagargin reduces blood flow in hepatic lesions.

MS10.4 Prognostic Impact of Syntax II Score In Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Analysis of An 8-Year All-Comers Registry

The purpose of the study was to evaluate the efficacy of metastasectomy for urinary tract carcinoma (UTC) and to determine prognostic factors that affect survival.Data from a total of 30 patients with metastatic UTC who underwent a metastasectomy between February 2000 and July 2014 were analyzed retrospectively. Time to disease progression (TTP) and overall survival (OS) from metastasectomy, and potential prognostic factors were evaluated.The lung was the most frequent site of metastasectomy (n = 24) followed by the liver (n = 3) and lymph nodes (n = 3). With a median follow-up duration of 54.2 months, the median TTP was 15.2 months and the median OS was 30.0 months (95% confidence interval, 15.1-42.9) with a 3-year survival rate of 41%. In multivariate analysis, initial stage IV disease (P = .047), pure urothelial pathology (P = .034), and nonpulmonary metastasectomy (P = .040) were independent prognostic factors for a shorter TTP. Nonpulmonary metastasectomy was an independent factor affecting OS (P = .001).A metastasectomy has the potential to contribute to better oncologic outcome in select patients with metastatic UTC, especially those with a single rather than multiple and pulmonary rather than nonpulmonary metastases due to recurrent rather than initially metastatic urinary tract cancer.

Results of using tegafur in combination with irinotecan and oxaliplatin in patients with advanced colorectal cancer

A study that enrolled 30 patients with advanced colorectal cancer, who had not previously received any specific drug treatment, was conducted to develop and study a three-component regimen with oral fluoropyrimidine tegafur (Ftorafur) in outpatient practice. The study evaluated the time to disease progression (TDP), the overall survival (OS) of patients, who received irinotecan + oxaliplatin + Ftorafur in the first-line therapy, as well as the effectiveness and safety of this regimen. 6 patients received a 3-week chemotherapy cycle (Fig. 1), 24 patients – a 2-week chemotherapy cycle (Fig. 2). The preliminary results of the study have been obtained. The median OS was not reached, the median TDP was 8.5 months. In Group I, there was partial regression of metastasis in 3/6 patients, and prolonged disease stabilization (≥ 6 months) in 3 patients. The therapeutic effect (partial remission + long-term stabilization ≥ 6 months) was observed in all patients. The duration of TDP was from 6 to 15 months. In group II, the effect was evaluated in 24 patients, who received at least 2 chemotherapy cycles. 14/24 patients had a partial response (PR), of which 4 (16.6%) patients were radically operated, 6 patients elicited disease stabilization. Thus, control over the disease was achieved in 83.33% of patients in Group II. Oxaliplatin combined with irinotecan and fluorafur was effective, had an acceptable toxicity profile, and therefore, can be used in debilitated patients with disseminated disease.

Apatinib is effective for treatment of advanced hepatocellular carcinoma.

As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow-up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy.

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society.

Abstract CT122: BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Abstract The anti-apoptotic proteins BCL-2 and MCL-1 have been shown to promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, and orally bioavailable small-molecule inhibitor of BCL-2. Bortezomib (BTZ) is a proteasome inhibitor that can inhibit MCL-1 activity by increasing the MCL-1 antagonist, NOXA. Results presented herein describe correlative biomarker analyses in the ongoing phase 1b study of VEN in combination with BTZ and dexamethasone in patients with relapsed/refractory (R/R) MM (NCT01794507). As of 19 Aug 2016, 66 patients were enrolled on study. Baseline bone marrow aspirate samples were available from 52 patients, of which 45 were evaluable for BCL-2 family gene expression by droplet digital PCR in CD138-selected tumor cells. Correlation between BCL2 (BCL-2), BCL2L1 (BCL-XL) and MCL1 (MCL-1) mRNA expression (log2-transformed copies/ul normalized to housekeeping gene) and preliminary efficacy [overall response rate (ORR), time to disease progression (TTP) and duration of response (DoR)] were examined by Log-rank and Wilcoxon tests for binary biomarkers, and by risk ratio from Cox proportional hazard model for continuous biomarkers. The ORR was 68% (44/65) for all evaluable patients and 89% (31/35) in patients who had 1-3 prior therapies (31/35). A broad range of BCL2, BCL2L1 and MCL1 expression was observed, however higher BCL2 levels were detected in patients who achieved a partial response (PR) or better (median: 3.01 vs 0.87, p&amp;lt;0.01). Additionally, higher BCL2 levels were observed in patients who had 1-3 prior lines of therapy compared to 4 or more lines of therapy (median: 3.03 vs 0.94, p&amp;lt;0.01). In contrast, no association was observed between BCL2L1 or MCL1 gene expression and response or number of prior therapies. Bootstrapping and aggregating thresholds from trees was used to estimate a threshold value for BCL2 expression that would provide optimum selection of patients likely to have a response. Overall, seventeen of 18 patients with high BCL2 expression (≥3.0) achieved at least a PR (ORR 94%), with 12 patients (66%) achieving VGPR or better. Sixteen of 27 patients with low BCL2 expression achieved at least a PR (ORR 59%), with 6 patients (22%) achieving a VGPR or better. Median TTP (11.6 vs 5.7 months) and DoR (10.2 vs 7 months) were longer for patients with high versus low BCL2 expression. Responses in high BCL2 expressors were independent of cytogenetic status as determined by interphase FISH analysis, including t(11;14), t(4;14), del(13q) and del(17p). Targeting BCL-2 and MCL-1 with the combination of VEN, BTZ and dexamethasone provides a unique approach for MM treatment. Efficacy results in tumors expressing high BCL2 levels, including 94% ORR, provide supportive evidence for the evaluation of this combination regimen in the ongoing phase 3 study (NCT02755597) in R/R MM. Citation Format: Jeremy Ross, Brenda Chyla, Rasna Goswami, Lisa Roberts-Rapp, Yan Sun, Yanwen Jiang, Elizabeth Punnoose, Maria Verdugo, Anahita Bhathena, Paulo Maciag. BCL2 expression is a potential predictive biomarker of response to venetoclax in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT122. doi:10.1158/1538-7445.AM2017-CT122

A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study

PurposeThe PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).MethodsThis randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).Results210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).ConclusionBoth PLD and capecitabine are effective first-line agents for MBC.

Sunitinib scheduling in metastatic renal cell cancer: A single-center experience.

554 Background: Sunitinib is a receptor tyrosine kinase inhibitor that has proven activity as first line treatment for metastatic renal cell carcinoma (mRCC). The recommended dose is 50mg once daily in a 4 week on 2 week off schedule. However this regimen has a significant side effect profile and alternative schedules have been used to minimize dose reductions and maintain dose intensity. We sought to identify the incidence of dose modifications and assess toxicity in patients treated with two sunitinib schedules in a National Cancer Center. Methods: Patients with mRCC who had sunitinib as first line treatment were identified retrospectively and patient data reviewed. Two patient groups were identified: those who received sunitinib 50mg day 1-28 in 6 week cycles (cohort 1) and those who received sunitinib 50mg day 1-14 in 3 week cycles (cohort 2). Primary end point was incidence of dose modification. Secondary end points included incidence of common sunitinib-related side effects. Known prognostic variables, including prior nephrectomy, body mass index (BMI) and use of angiotensin system inhibitors (ASI) were correlated with time to disease progression (TTP). Results: Between 2009 and 2014, 28 patients were identified. Of those, 23 (83%) patients were treated in cohort 1, and 5 (17%) patients in cohort 2. Dose modifications were required in 13 (56.5%) patients in cohort 1, but only 2 (40%) patients in cohort 2. Common sunitinib-related side effects in cohort 1 included hypertension in 19 (79%), weight loss in 10 (41.6%), fatigue in 9 (37.5%) and nausea in 8 (33.3%) patients respectively. Overall, the use of ASIs correlated significantly with longer median TTP (10.5 months) compared to non-users (4 months) (p = 0.04). BMI ≥ 25 (TTP 9 vs. 3 months, p = 0.008) demonstrated a similar correlation. However, no difference in median TTP was noted between patients who had prior nephrectomy compared to those who had not (5 vs. 4 months) (p = 0.18). Conclusions: In this small retrospective study, standard sunitinib scheduling was associated with a high incidence of dose modifications and side-effects. Consistent with previous studies, we identified known prognostic variables. The use of sunitinib 50mg day 1-14 in 3 week cycles may be more tolerable for patients.

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer

BackgroundBicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). MethodsProstate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months.Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline’s RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded.Primary end-point was time to disease progression (TDP) up to 42months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FindingsThere was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425days (95% CI 302, 858) in the bicalutamide/placebo group and 623days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. InterpretationIn men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.

Pulmonary Metastasectomy Could Prolong Overall Survival in Select Cases of Metastatic Urinary Tract Cancer

BackgroundThe purpose of the study was to evaluate the efficacy of metastasectomy for urinary tract carcinoma (UTC) and to determine prognostic factors that affect survival. Patients and MethodsData from a total of 30 patients with metastatic UTC who underwent a metastasectomy between February 2000 and July 2014 were analyzed retrospectively. Time to disease progression (TTP) and overall survival (OS) from metastasectomy, and potential prognostic factors were evaluated. ResultsThe lung was the most frequent site of metastasectomy (n = 24) followed by the liver (n = 3) and lymph nodes (n = 3). With a median follow-up duration of 54.2 months, the median TTP was 15.2 months and the median OS was 30.0 months (95% confidence interval, 15.1-42.9) with a 3-year survival rate of 41%. In multivariate analysis, initial stage IV disease (P = .047), pure urothelial pathology (P = .034), and nonpulmonary metastasectomy (P = .040) were independent prognostic factors for a shorter TTP. Nonpulmonary metastasectomy was an independent factor affecting OS (P = .001). ConclusionA metastasectomy has the potential to contribute to better oncologic outcome in select patients with metastatic UTC, especially those with a single rather than multiple and pulmonary rather than nonpulmonary metastases due to recurrent rather than initially metastatic urinary tract cancer.

Efficacy and adverse events of transcatheter arterial chemoembolization in combination with sorafenib in the treatment of unresectable hepatocellular carcinoma.

The aim of the present study was to assess the association between the efficacy and adverse events (AEs) of transcatheter arterial chemoembolization (TACE) combined with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). Between July 2008 and May 2011, 50 patients with unresectable HCC were enrolled and assigned to receive TACE combined with sorafenib in the present study. The primary outcomes were considered as time to disease progression (TTP) and sorafenib-related AEs. In the present study, 34 of 50 patients had disease progression with a median TTP (mTTP) of 210 days. The most common AEs included hand-foot skin reaction (HFSR), fatigue, diarrhea and hypertension. The mTTP of patients with HFSR extended 140 days compared to that of the patients without HFSR. Kaplan-Meier analysis was used for mTTP between the two groups of patients. This difference was statistically significant when analyzed by the univariate COX proportional hazards regression model. In conclusion, TACE in combination with sorafenib had an acceptable safety profile in the treatment of unresectable HCC. Additionally, it also revealed that HFSR served as a good prognostic predictor in using combination therapy. Therefore, discontinuation of sorafenib treatment should be prevented to avoid disease progression.

Relationship between DNA repair gene XPD751 single-nucleotide polymorphisms and prognosis of colorectal cancer.

We examined the relationships between single-nucleotide polymorphisms (SNPs) in the DNA repair gene XPD751 and the efficacy and time to disease progression (TTP) in colorectal cancer patients after platinum-based chemotherapy. Ninety-eight patients diagnosed with advanced colorectal cancer were subjected to oxaliplatin and 5-fluorouracil combination therapy. DNA was extracted from venous blood before chemotherapy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect XPD751 SNPs. The relationship between genotypes and prognosis was compared. The frequencies of the XPD751 Lys/Lys, Lys/Gln, and Gln/Gln genotypes were 76 (77.55%), 17 (17.35%), and 5 (5.10%), respectively. The efficiency of XPD751 Lys/Lys, Lys/Gln and Gln/Gln genotypes were 50.00, 29.41, and 20%, respectively. The efficiency rate between XPD751 Lys/Lys and Lys/Gln showed a significant difference (c² = 4.04, P < 0.05). After adjusting for gender, age, and metastasis location, chemotherapy failure in patients carrying XPD751 Lys/Gln was 3.404-fold higher than in patients carrying the Lys/Lys genotype. Median TTP was 304 days (10.1 months) and median TTP in patients with XPD751 Lys/Lys and ≥1 Gln genotype was 340 and 87 days. After comparing TTP in patients carrying Lys/Lys and patients carrying ≥1 Gln, the difference was significant. SNPs in the DNA repair gene XPD751 may be associated with oxaliplatin and 5-fluorouracil chemotherapy sensitivity in colorectal cancer patients. These polymorphisms may be associated with TTP in patients with advanced colorectal cancer after first-line chemotherapy of oxaliplatin. XPD751 SNPs may be predictive factors of prognosis in colorectal cancer patients receiving oxaliplatin and 5-fluorouracil chemotherapy.

Bortezomib and Low-Dose Dexamethasone with or without Continuous Low-Dose Oral Cyclophosphamide for Primary Refractory or Relapsed Multiple Myeloma: Final Results of a National Multicenter Randomized Controlled Phase III Study

BackgroundMultiple myeloma (MM) typically follows a relapsing course and many patients require multiple lines of therapy. The combination of bortezomib and dexamethasone (VD), alone or with cyclophosphamide (VCD) has shown good efficacy and tolerability in patients with relapsed or refractory (rel/ref) MM in non-randomized trials (Mikhael Br J Haematol 2009, Kropff Br J Haematol 2007). This phase III, randomized, controlled study (NCT00813150) aimed to evaluate VCD vs VD in patients with rel/ref MM.MethodsAdult patients with rel/ref MM (1st–3rd relapse) with Karnofsky performance status ≥60% were eligible for inclusion; patients with grade ≥2 peripheral neuropathy (PN) were excluded. Patients were randomized 1:1 to receive VD (up to 8 x 3-week cycles of intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus oral dexamethasone 20 mg on the day of bortezomib administration and the following day) or VCD (as VD with the addition of oral cyclophosphamide 50 mg daily). The study was designed with 80% power to detect a difference of 2.8 months in the primary endpoint of time to disease progression (TTP) at the 5% significance level (two-sided); a sample size of 270 patients was required. Secondary endpoints included overall survival (OS), response rate (RR), and safety. Disease progression was assessed per IMWG guidelines and adverse events (AEs) were assessed using NCI-CTCAE v3.0. TTP and OS were calculated using Kaplan-Meier methodology and compared using two-sided log-rank test.ResultsIn total, 96 patients were randomized; 93 began study medication and were included in the safety population, and 90 received at least one dose of study drugs and one efficacy assessment and were included in the intention to treat (ITT) population. The planned sample size was not reached due to lack of recruitment and the study was stopped prematurely as a result of a joint decision of sponsor and coordinating investigator. The VD and VCD arms were well balanced in terms of baseline characteristics. Median age was 71 years (range 30–85) with most patients (97%) suffering from relapse of myeloma disease (3% refractory disease). One, 2, and 3 prior lines of therapy were reported by 57%, 30%, and 9% of patients, respectively; 14% had received prior bortezomib. In total, 19%, 24%, and 29% of patients were ISS disease stage I, II, and III, respectively. Patients in both VD and VCD arms received a median of 5 cycles of therapy. Reasons for premature termination of treatment included AEs (35% and 32% of patients in the VD and VCD arms, respectively) and progressive disease (2% in the VD arm only). After a median follow-up of 24 months, median TTP was 12.6 months in the VD arm vs 9.9 months in the VCD arm (p=0.192); the corresponding hazard ratio (HR) was in favor of the VD arm (HR 0.71, 95% CI 0.43–1.19), although this was not statistically significant (p=0.196). Median OS could not be determined in the VD arm vs 42 months in the VCD arm. The resulting Kaplan-Meier plots were superimposable with a HR of 0.85 (95% CI, 0.41–1.73; p=0.645). In total, 32 (74%) and 33 (70%) patients in the VD and VCD arms achieved ≥PR; 23 (54%) and 22 (47%) patients achieved ≥VGPR. The most common treatment-emergent non-hematologic AEs included PN (28% vs 47% in the VD vs VCD arms), fatigue (28% vs 40%), diarrhea (24% vs 36%), and constipation (22% vs 28%). Grade ≥3 PN occurred in 7 (15%) patients in the VCD arm vs 2 (4%) in the VD arm. Higher rates of grade ≥3 leukopenia (13% vs 0%) and grade ≥3 thrombocytopenia (34% vs 24%) were observed in the VCD arm; however, rates of clinically relevant infections were comparable (grade ≥3 infections 9 [19%] in the VCD arm vs 8 [17%] in the VD arm) and no clinically relevant bleeding events occurred.ConclusionsThese data indicate that both treatment regimens were similar in efficacy and safety. However, due to limited enrollment, the study is underpowered to draw firm conclusions. Further studies will be required to address the potentially enhanced neurotoxicity of VCD compared with VD. The dosing of cyclophosphamide also warrants further investigation, as other studies suggest that a dose intensified regimen may result in higher CR rates. DisclosuresKropff:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Mundipharma: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Vogel:Janssen: Employment. Knauf:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fiechtner:Onkovis: Consultancy. Berdel:Janssen: Honoraria.

Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: A pooled analysis of 7 prospective trials of gemcitabine‐based therapy with or without bevacizumab

Phase 3 studies of bevacizumab in patients with advanced pancreatic cancer (APCA) demonstrated no improvement in outcome. To the authors' knowledge, no validated predictive biomarkers for bevacizumab exist, although emerging data suggest that subsets of patients with APCA may benefit from treatment with bevacizumab. The authors evaluated baseline serum albumin (b-alb) as a predictive biomarker in a pooled analysis from 7 prospective clinical trials of gemcitabine-based therapy with or without bevacizumab. Data were collected from individual databases from 7 prospective clinical trials. Patients were grouped by exposure to bevacizumab and by b-alb level (≥ 3.4 g/L or < 3.4 g/dL). Overall survival (OS), time to disease progression (TTP), overall response rate, and disease control rate (overall response rate plus stable disease lasting ≥ 16 weeks) were compared between groups. Univariate and multivariable analyses of prognostic factors were performed. A total of 264 patients were included. The median age was 59 years (range, 31 years-85 years) and all patients had stage IV disease per TNM staging. Normal b-alb was associated with significantly improved median OS (10.2 months vs 4.1 months; P = .0001), median TTP (6.2 months vs 3.7 months; P = 0.0488), and disease control rate (71% vs 46%; P = .007) for patients receiving bevacizumab, but not for those treated without bevacizumab. Multivariable analysis revealed a significant influence of normal b-alb on OS (P = .0008) and TTP (P = .033). Patients with APCA with normal b-alb derive benefit from treatment with bevacizumab. Future prospective investigations of bevacizumab in patients with APCA should consider selecting patients with normal b-alb to maximize potential benefit.