Predicting programmed death-ligand 1 (PD-L1) expression with fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in resectable non-small cell lung cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is a predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). PD-L1 and glucose transporter 1 expression are closely associated, and studies demonstrate correlation of PD-L1 with glucose metabolism. AIM: The aim of this study was to investigate the association of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) metabolic parameters with PD-L1 expression in primary lung tumour and lymph node metastases in resected NSCLC. METHODS: We conducted a retrospective analysis of 210 patients with node-positive resectable stage IIB-IIIB NSCLC. PD-L1 tumour proportion score (TPS) was determined using the DAKO 22C3 immunohistochemical assay. Semi-automated techniques were used to analyse pre-operative [18F]FDG-PET/CT images to determine primary and nodal metabolic parameter scores (including max, mean, peak and peak adjusted for lean body mass standardised uptake values (SUV), metabolic tumour volume (MTV), total lesional glycolysis (TLG) and SUV heterogeneity index (HISUV)). RESULTS: Patients were predominantly male (57%), median age 70 years with non-squamous NSCLC (68%). A majority had negative primary tumour PD-L1 (TPS < 1%; 53%). Mean SUVmax, SUVmean, SUVpeak and SULpeak values were significantly higher (p < 0.05) in those with TPS ≥ 1% in primary tumour (n = 210) or lymph nodes (n = 91). However, ROC analysis demonstrated only moderate separability at the 1% PD-L1 TPS threshold (AUCs 0.58-0.73). There was no association of MTV, TLG and HISUV with PD-L1 TPS. CONCLUSION: This study demonstrated the association of SUV-based [18F]FDG-PET/CT metabolic parameters with PD-L1 expression in primary tumour or lymph node metastasis in resectable NSCLC, but with poor sensitivity and specificity for predicting PD-L1 positivity ≥ 1%. CLINICAL RELEVANCE STATEMENT: Whilst SUV-based fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography metabolic parameters may not predict programmed death-ligand 1 positivity ≥ 1% in the primary tumour and lymph nodes of resectable non-small cell lung cancer independently, there is a clear association which warrants further investigation in prospective studies. TRIAL REGISTRATION: Non-applicable KEY POINTS: • Programmed death-ligand 1 immunohistochemistry has a predictive role in non-small cell lung cancer immunotherapy; however, it is both heterogenous and dynamic. • SUV-based fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) metabolic parameters were significantly higher in primary tumour or lymph node metastases with positive programmed death-ligand 1 expression. • These SUV-based parameters could potentially play an additive role along with other multi-modal biomarkers in selecting patients within a predictive nomogram.

Non-Small Cell Lung Cancer (NSCLC) in Young Adults, Age < 50, Is Associated with Late Stage at Presentation and a Very Poor Prognosis in Patients That Do Not Have a Targeted Therapy Option: A Real-World Study

(1) Background: Non-small cell lung cancer (NSCLC) in young patients is uncommon. Real-world evidence on the outcomes of these patients is limited. (2) Methods: We conducted a retrospective cohort study of young NSCLC patients, age < 50 years at diagnosis, who were treated between 2011−2020 in South-East-London cancer centres. Clinicopathological characteristics, treatment and outcomes were analysed. (3) Results: Of 248 NSCLC patients, median age was 46 years, 50% (n = 125) female, 58% (n = 145) white, 18% (n = 45) black and 4% (n = 10) Asian ethnicity. Amongst patients with a documented smoking history, 30% (n = 64) were never-smokers. Most patients had adenocarcinoma (77%, n = 191) and presented with metastatic disease (67%, n = 166). Only 31% (n = 76) had treatment with curative intent. In patients who presented or developed metastatic non-squamous NSCLC (n = 179), EGFR mutation status was known in 88% (n = 157) and mutation present in 19% (n = 34), ALK was known in 66% (n = 118) with a translocation in 10% (n = 18), ROS1 status was known in 57% (n = 102) with a translocation in 4% (n = 8), and KRAS status was known in 66% (n = 119) with a mutation in 12% (n = 22). Overall, 76% (n = 152) patients with metastatic NSCLC received first-line systemic anti-cancer therapy. Median overall survival in metastatic NSCLC was 9.0 months (95% CI 6.5−11.6 months), with superior median overall survival in those with a targeted therapy option (28.7 months) compared to those without (6.6 months; p < 0.001). (4) Conclusion: Young patients contribute a significant proportion of those presenting with lung cancer. They present with advanced stage at diagnosis and have a poor prognosis. Identification of a targeted therapy option is associated with improved survival. However, most patients do not have a known genomic driver, which is in part due to limited testing, particularly in the early years of this study period. These findings highlight the particular importance of rapid-turnaround comprehensive genomic profiling in this age group and the need to identify strategies to facilitate earlier diagnosis in young NSCLC patients.

Facilitating healthcare practitioners to deliver self-management support in adult cancer survivors: A realist review.

BACKGROUND: Supporting cancer survivors in self-management can empower them to take an active role in managing the long-term physical and psychosocial consequences of cancer treatment. Healthcare practitioners are key to supporting patients to self-manage, however, they do not routinely engage in these discussions. This review aimed to establish what works for whom and in what circumstances in relation to facilitating healthcare practitioners to provide self-management support in people living with long-term consequences of cancer treatment. METHODS: The review follows five steps: define the review's scope, develop initial programme theories, evidence search, selection and appraisal, and data extraction and synthesis. Database searches of Medline, EMBASE, CINAHL, Scopus, PsycINFO, ERIC and AMED databases, to September 2019 were supplemented with practitioner surveys. Insights into the mechanisms that operate in particular contexts to produce successful outcomes were illustrated using realist programme theories, developed using the Theoretical Domains Framework. Data selection was based on relevance and rigour. Data were extracted and synthesised iteratively to illuminate causal links between contexts, mechanisms and outcomes. RESULTS: Five programme theories were identified from 20 included articles and seven practitioner surveys: practitioners will engage patients in discussions about self-management if they have appropriate (1) knowledge and (2) consultations skills, (3) a clear understanding of their self-management support role and responsibilities, and if (4) organisational strategies and (5) health system configuration enable integration into routine care. The mechanisms facilitating practitioners to support self-management were practitioner confidence, mutual trust and shared responsibility between practitioners and cancer survivors, organisational prioritisation and ease of delivery of self-management support. CONCLUSION: The findings articulate the necessary components for embedding self-management support into routine cancer care. Operationalisation of these components into effective self-management support interventions will require reconfiguration of pathways and adaptation for local context, using strategies such as quality improvement and co-design to guide intervention development, implementation and evaluation.

Salvage pulmonary resection in stages IIIb-IV lung cancer after treatment with immune checkpoint inhibitors case series and literature review.

BACKGROUND AND OBJECTIVES: The role of salvage thoracic surgery in managing advanced-stage lung cancer following treatment with immune checkpoint inhibitors is currently unclear. We present a series of nine patients with advanced non-small-cell lung cancer who underwent pulmonary resection following treatment with pembrolizumab. METHODS: We performed a single-institution retrospective analysis of pulmonary resection undertaken following treatment with pembrolizumab for advanced-stage lung cancer. Nine patients met the inclusion criteria. RESULTS: In six cases, surgery was indicated for persistent localized disease after treatment, and in three cases for nonresponsive synchronous/metachronous lung nodules while on treatment for stage IV lung cancer. Dense hilar fibrosis was present in all patients. Minimal access surgery was achieved in five cases (video-assisted n = 2, robotic-assisted n = 3). There was no in-hospital mortality. One patient died within 60 days from community-acquired COVID-19 pneumonitis. Seven patients remain free of disease between 5 and 22 months follow-up. CONCLUSIONS: Pulmonary resection is safe and technically feasible following treatment with immune checkpoint inhibitors. Surgical challenges relate to postimmunotherapy fibrosis, but with increased experience and a robotic approach, minimal access surgery is achievable. Further prospective studies are required to assess the surgical impact on disease control and overall survival in this patient cohort.

Realist review protocol for understanding the real-world barriers and enablers to practitioners implementing self-management support to people living with and beyond cancer.

INTRODUCTION: Self-management support can enable and empower people living with and beyond cancer to take an active role in managing long-term consequences of cancer treatment. Healthcare professionals are key to promoting patients to self-manage, however, they do not routinely engage in these discussions. This review aims to understand what works for whom and in what circumstances in relation to practitioners engaging with supporting people living with and beyond cancer to self-manage long-term consequences of systemic anticancer treatment. METHODS AND ANALYSIS: We will follow five steps for undertaking the realist review: (1) define the review scope, (2) develop initial programme theories, (3) evidence search, (4) selection and appraisal and (5) data extraction and synthesis. We will combine an informal literature search with a theory-based approach, using the theoretical domains framework, and stakeholder feedback to develop initial programme theories. We will search Medline, EMBASE, CINAHL, Scopus, PsycINFO, ERIC and AMED databases to September 2019, and supplement this with citation tracking, grey literature and practitioner surveys. Data selection will be based on relevance and rigour. Data will be extracted and synthesised iteratively, and causal links between contexts, mechanism and outcomes illuminated in the process. The results will be reported according to the Realist And Meta-narrative Evidence Syntheses: Evolving Standards quality and publication standards. ETHICS AND DISSEMINATION: We have received ethical approval through the Research Ethics Committee, Faculty of Medicine and Health Sciences, University of East Anglia (ref 2 01 819-124). We will disseminate to the research community through conference presentations and a peer-reviewed journal article. We will work with healthcare organisations, cancer charities and patients to agree a strategy for disseminating to these groups. PROSPERO REGISTRATION NUMBER: CRD42019120910.

Tuberculosis associated with Triplet therapy for lung cancer.

We report the first case of TB associated with triplet therapy (chemotherapy and immunotherapy concurrently) for lung cancer, developing just 44 days after treatment initiation. We feel that several important learning points arise from the discussion that are likely to be very relevant to the broad readership of Thorax, and have important clinical and scientific implications. In the three discussion paragraphs, we highlight that: 1) Triplet therapy is now standard first-line treatment for inoperable lung cancer. 2) TB reactivation is increasingly recognised as an adverse effect of immune checkpoint inhibition, but sending diagnostic samples is critical to avoid a missed diagnosis. 3) These insights from novel cancer immunotherapies are challenging the traditional views of the host-pathogen interaction in TB, with wide implications for future control strategies. We propose that the cases reported in the literature are likely to be the tip of the iceberg as most people with lung cancer managed with antiprogrammed death-1 agents who develop new lung lesions will be treated with standard antibiotics and then palliated when they do not respond.

Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients.

PURPOSE: Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London. METHODS: We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity. RESULTS: Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar-plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity. CONCLUSIONS: Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.

An Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.

BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress.

Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).

Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.

Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.

Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition.

BACKGROUND AND PURPOSE: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. MATERIALS AND METHODS: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. RESULTS: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated (131)I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed (131)I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. CONCLUSION: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.

Oncolytic reovirus type 3 (Dearing) as a novel therapy in head and neck cancer.

INTRODUCTION: Locally advanced head and neck cancer carries a poor prognosis, even with standard combination (surgery, radiotherapy, chemotherapy) treatment regimens. There is a pressing need for novel therapies with activity against this tumour type. Oncolytic reovirus type 3 (Dearing) is preferentially cytotoxic in tumour cells with an activated Ras signalling pathway and represents a promising novel therapy with relevance in head and neck cancer. AREAS COVERED: In this review, we discuss the pre-clinical and clinical data that have underpinned the translational development of oncolytic reovirus thus far. In particular, we describe the iterative nature of the research programme through initial studies testing single-agent reovirus therapy and on to subsequent work in which reovirus has been combined with either radiotherapy or cytotoxic chemotherapy. We will trace the process by which oncolytic reovirus has reached Phase III evaluation in combination with carboplatin/paclitaxel in patients with platin-refractory, relapsed/metastatic head and neck cancer. EXPERT OPINION: Reovirus is a self-amplifying, cancer-selective agent that offers huge potential advantages over standard chemotherapy, targeted small molecules or monoclonal antibodies. However, it is most likely that reovirus will show efficacy and be approved in combination with standard modalities (cytotoxic chemotherapy or radiotherapy) or other targeted agents, especially those that modulate signal transduction pathways. The next 5 years are critical for the development of oncolytic reovirus as an anti-cancer therapy and hinge on the ongoing Phase III trial in head and neck cancer and other Phase II programmes.

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway.

BACKGROUND: Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. METHODS: To test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. RESULTS: Correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. CONCLUSIONS: In summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue.

Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies.

PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.

Bevacizumab-induced hypertension: pathogenesis and management.

Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.

The need for third-line treatment in non-small cell lung cancer: an overview of new options.

As a result of improved effectiveness of first-, second-line and maintenance therapeutic regimens in non-small cell lung cancer, there is need for new options as third-line treatment. Erlotinib and gefitinib are currently the only drugs of proven efficacy in the third-line setting. Chemotherapy drugs, such as pemetrexed, are being investigated, as are many new agents, such as cetuximab, sunitinib, sorafenib, everolimus, enzastaurin, afilbercept. These novel targeted therapies seem to improve response rates and progression-free survival and their toxicity is tolerable. In an effort to prolong survival while maintaining quality of life, large prospective studies are needed to examine the effectiveness and safety of third-line regimens in these patients.

Metastin is not involved in metastatic potential of non-small cell lung cancer.

Metastin, the product of the KISS-1 gene, seems to represent a strong suppressant of metastasis for some types of cancer. The aim of this study is to explore whether circulating levels of metastin could be used as a marker for the metastatic potential of non-small cell lung cancer (NSCLC) as well as a diagnostic marker in NSCLC patients. The possible correlation between metastin and leptin circulating levels was also evaluated. Fasting serum levels of metastin and leptin were determined in 96 NSCLC patients at diagnosis (76 with metastatic disease and 21 with locally advanced disease) and 49 healthy volunteers using commercial available ELISA. Serum metastin levels presented no differences between NSCLC patients and healthy volunteers (1.18 ± 0.98 vs. 1.17 ± 0.39 ng/ml, P = 0.979) as well as between patients with metastatic and locally advanced disease (1.17 ± 1.05 vs. 1.21 ± 0.64 ng/ml, P = 0.872). There was no statistically significant correlation between circulating metastin and leptin levels in NSCLC patients and patients with locally advanced and metastatic disease. This study shows a lack of direct involvement of metastin in the diagnosis and metastatic potential of NSCLC.

Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.

PURPOSE: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. EXPERIMENTAL DESIGN: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity. RESULTS: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. CONCLUSIONS: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.

Targeted therapeutic approaches for hormone-refractory prostate cancer.

Prostate cancer is one of the leading causes of cancer related death in men, and remains incurable in the metastatic setting. Despite the initial response to androgen deprivation, the disease gradually progresses to a hormone-refractory state due to cumulative genetic alterations in tumour cells or the microenvironment. Docetaxel represents the first chemotherapeutic agent with a small survival benefit for metastatic hormone-refractory prostate cancer (HRPC). In an attempt to improve survival benefit, several novel drugs targeting specific pathways involved in cell signaling, proliferation, angiogenesis, apoptosis and immune modulation are currently under investigation either as single agents or in combination with cytotoxic drugs. Clinical trials evaluate the inhibition of prostate cancer cells growth by targeting the nuclear receptor of vitamin D alongside cytotoxic therapy. Angiogenesis inhibitors as well as epidermal growth factor receptor blockage are also under clinical investigation in several combinations. Immunomodulatory agents and autologous dendritic cells or allogenic whole cell vaccines have progressed up to phase III trials. New drugs targeting bone microenvironment or apoptotic and proliferation pathways may enhance antitumour activity of chemotherapy in HRCP. Given the complexity of mechanisms underlying prostate cancer progression, future therapeutic strategies should rely on multidisciplinary approaches, thus exploiting newer molecular targets in concert with immunotherapy and cytotoxic chemotherapy. Here, we review the latest clinical evidence regarding the use of novel agents in HRPC.