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BACKGROUND Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ('TumorGrafts'). METHODS Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment. RESULTS Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy. CONCLUSIONS The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted. Cancer 2014;120:2006-2015. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. [ABSTRACT FROM AUTHOR]

The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a 'one-size-fits-all' approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness. [ABSTRACT FROM AUTHOR]

Summary: Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30mg/m2 for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3–11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM. [Copyright &y& Elsevier]

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.Methods: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.Conclusions: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC. [ABSTRACT FROM AUTHOR]

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy. [ABSTRACT FROM AUTHOR]

Objectives To determine the outcome of an expanded cohort of patients with relapsed germ cell tumours (GCTs) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting. Patients and Methods The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (29 patients), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (43), of which 32 patients proceeded to HDCT. Results The 2-year progression-free survival (PFS) and 3-year overall survival (OS) rates for the whole cohort were 30.2% (95% confidence interval [CI] 17.3-40.5%) and 33.4% (95% CI 20.1-43.8%), respectively. Complete remission was achieved in 3%, marker-negative partial response (PR) in 41%, marker-positive PR in 18%, stable disease in 17% and progressive disease in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95% CI 21.7-60.8%) and 3-year OS 49.1% (95% CI 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95% CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95% CI 11.7-38.2). According to the current international prognostic factor study group criteria for first relapse for the high- and very high-risk group the 2-year PFS rates were 50% and 30%, respectively. There were two treatment-related deaths from IPO, and four from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopaenia (18%), infection (15%), diarrhoea (11%) and lethargy (8%). Conclusions IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCTs. It appears particularly useful in high-risk patients and for those in whom cisplatin is ineffective or contra-indicated. [ABSTRACT FROM AUTHOR]

BACKGROUND The management of brain metastases in patients with germ cell tumors remains controversial. The authors assessed the outcome in this patient group after the introduction of GAMEC chemotherapy (14-day cisplatin, high-dose methotrexate, etoposide, and actinomycin-D with filgrastim support) and cessation of the routine use of cranial irradiation. METHODS Data were recorded prospectively from 39 patients with germ cell tumors and concurrent brain metastases who received treatment before and after the advent of GAMEC after they relapsed on conventional cisplatin-based chemotherapy. Neurosurgery was offered to selected patients. Radiotherapy generally was used only as a salvage therapy after chemotherapy failure. The primary outcome measure was overall survival and was depicted using a Kaplan-Meier plot. RESULTS The 3-year overall survival rates were 38% for the whole cohort, 69% for those who presented with brain metastases at diagnosis (group 1), and 21% and 0% for those who developed metastases after initial chemotherapy (group 2) and while receiving chemotherapy (group 3), respectively. For the whole cohort, the median overall survival was 10.6 months (range, 5.5 months to not evaluable); and, for groups 1, 2, and 3 individually, the overall survival was not yet reached (range, from 7.4 months to not evaluable), 6.2 months (range, 2.1-15.3 months), and 2.7 months (range, from 0.6 months to not evaluable), respectively. The 3-year survival rate for those who received GAMEC chemotherapy was 56% compared with 27% for those who received chemotherapy pre-GAMEC. CONCLUSIONS The prognosis for patients with germ cell tumors and brain metastases seems less bleak than previously thought. It is possible to achieve long-term survival with chemotherapy alone. Cancer 2014;120:1639-1646. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Although [18F]fluorothymidine positron emission tomography (FLT-PET) permits estimation of tumor thymidine kinase-1 expression, and thus, cell proliferation, high physiological uptake of tracer in liver tissue can limit its utility. We evaluated FLT-PET combined with a temporalintensity information-based voxel-clustering approach termed kinetic spatial filtering (FLT-PETKSF) for detecting drug response in liver metastases. FLT-PET and computed tomography data were collected from patients with confirmed breast or colorectal liver metastases before, and two weeks after the first cycle of chemotherapy. Changes in tumor FLT-PET and FLT-PETKSF variables were determined. Visual distinction between tumor and normal liver was seen in FLT-PETKSF images. Of the 33 metastases from 20 patients studied, 26 were visible after kinetic filtering. The net irreversible retention of the tracer (Ki; from unfiltered data) in the tumor, correlated strongly with tracer uptake when the imaging variable was an unfiltered average or maximal standardized uptake value, 60 min postinjection (SUV60,av: r = 0.9, SUV60,max: r = 0.7; p < 0.0001 for both) and occurrence of high intensity voxels derived from FLT-PETKSF (r = 0.7, p < 0.0001). Overall, a significant reduction in the imaging variables was seen in responders compared to non-responders; however, the two week time point selected for imaging was too early to allow prediction of long term clinical benefit from chemotherapy. FLT-PET and FLT-PETKSF detected changes in proliferation in liver metastases. [ABSTRACT FROM AUTHOR]

Thermosensitive liposome-mediated drug delivery has shown promising results in terms of improved therapeutic efficacy and reduced side effects compared to conventional chemotherapeutics. In order to facilitate our understanding of the transport mechanisms and their complex interplays in the drug delivery process, computational models have been developed to simulate the multiple steps involved in liposomal drug delivery to solid tumours. In this study we employ a multicompartmental model for drug-loaded thermosensitive liposomes, with an aim to identify the key transport parameters in determining therapeutic dosing and outcomes. The computational model allows us to not only examine the temporal and spatial variations of drug concentrations in the different compartments by utilising the tumour cord concept, but also assess the therapeutic efficacy and toxicity. In addition, the influences of key factors on systemic plasma concentration and intracellular concentration of the active drug are investigated; these include different chemotherapy drugs, release rate constants and heating duration. Our results show complex relationships between these factors and the predicted therapeutic outcome, making it difficult to identify the "best" parameter set. To overcome this challenge, a model-based optimisation method is proposed in an attempt to find a set of release rate constants and heating duration that can maximise intracellular drug concentration while minimising systemic drug concentration. Optimisation results reveal that under the operating conditions and ranges examined, the best outcome would be achieved with a low drug release rate at physiological temperature, combined with a moderate to high release rate at mild hyperthermia and 1 h heating after injection. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of programmed death-ligand 1 (PD-L1) expression, oncogenic mutations, and clinical characteristics on survival after treatment with anti-PD-1/PD-L1 antibodies versus chemotherapy in non-small cell lung cancer (NSCLC). Patients and Methods: This meta-analysis included randomized trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) for the trial population and prespecified subgroups were extracted. We calculated pooled estimates of treatment efficacy using the fixed-effects or random-effects model when appropriate. All statistical tests were two sided. Results: Seven trials involving 3871 patients were included. The pooled results showed that anti-PD-1/PD-L1 immunotherapy significantly prolonged OS (HR: 0.73; 95% CI, 0.63 to 0.84) and PFS (HR: 0.84; 95% CI, 0.71 to 0.99) compared to chemotherapy. OS benefit from immunotherapy were observed in all PD-L1 expression subgroups (negative: HR, 0.79; 95% CI, 0.67 to 0.93; weak-positive: HR, 0.80; 95% CI, 0.67 to 0.95; strong-positive: HR, 0.61; 95% CI, 0.47 to 0.78). Strong-positive PD-L1 expression showed a trend towards more benefit compared to weak-positive PD-L1 expression (interaction P = 0.08). KRAS mutant (HR: 0.60; 95% CI, 0.39 to 0.93), EGFR wild-type (HR: 0.73; 95% CI, 0.61 to 0.87) and smoker (HR: 0.70; 95% CI, 0.60 to 0.83) subgroups achieved significant OS benefit from immunotherapy compared to corresponding subgroups. Survival benefit to immunotherapy was not significantly associated with histology, CNS metastases, age, gender and performance status. Conclusion: This study confirmed that treatment with anti-PD-1/PD-L1 improves overall survival compared with chemotherapy. Benefit was seen, regardless of PD-L1 expression levels; however, PD-L1 strong-positive patients trended to have greatest benefit. Patients with a KRAS mutant or EGFR wild-type tumor have improved survival benefit from immunotherapy compared with KRAS wild-type or EGFR mutant NSCLC, respectively. [ABSTRACT FROM AUTHOR]