Current landscape of immunotherapy for the treatment of metastatic non-small-cell lung cancer.

For patients with advanced non-small-cell lung cancer (nsclc) lacking a targetable molecular driver, the mainstay of treatment has been cytotoxic chemotherapy. The survival benefit of chemotherapy in this setting is modest and comes with the potential for significant toxicity. The introduction of immunotherapeutic agents targeting the programmed cell death 1 protein (PD-1) and the programmed cell death ligand 1 (PD-L1) has drastically changed the treatment paradigms for these patients. Three agents-atezolizumab, nivolumab, and pembrolizumab-have been shown to be superior to chemotherapy in the second-line setting. For patients with tumours strongly expressing PD-L1, pembrolizumab has been associated with improved outcomes in the first-line setting. Demonstration of the significant benefits of immunotherapy in nsclc has focused attention on new questions. Combination checkpoint regimens, with acceptable toxicity and potentially enhanced efficacy, have been developed, as have combinations of immunotherapy with chemotherapy. In this review, we focus on the published trials that have changed the treatment landscape in advanced nsclc and on the ongoing clinical trials that offer hope to further improve outcomes for patients with advanced nsclc.

Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations.

Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS: One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS: The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

Characterization of intestinal inflammation and identification of related gene expression changes in mdr1a(-/-) mice.

Multidrug resistance targeted mutation (mdr1a (-/-) ) mice spontaneously develop intestinal inflammation. The aim of this study was to further characterize the intestinal inflammation in mdr1a (-/-) mice. Intestinal samples were collected to measure inflammation and gene expression changes over time. The first signs of inflammation occurred around 16 weeks of age and most mdr1a (-/-) mice developed inflammation between 16 and 27 weeks of age. The total histological injury score was the highest in the colon. The inflammatory lesions were transmural and discontinuous, revealing similarities to human inflammatory bowel diseases (IBD). Genes involved in inflammatory response pathways were up-regulated whereas genes involved in biotransformation and transport were down-regulated in colonic epithelial cell scrapings of inflamed mdra1 (-/-) mice at 25 weeks of age compared to non-inflamed FVB mice. These results show overlap to human IBD and strengthen the use of this in vivo model to study human IBD. The anti-inflammatory regenerating islet-derived genes were expressed at a lower level during inflammation initiation in non-inflamed colonic epithelial cell scrapings of mdr1a (-/-) mice at 12 weeks of age. This result suggests that an insufficiently suppressed immune response could be crucial to the initiation and development of intestinal inflammation in mdr1a (-/-) mice.

Upper gastrointestinal bleeding as a metastatic manifestation of breast cancer: a case report and review of the literature.

CASE PRESENTATION: A 64-year-old woman with known metastatic lobular breast cancer presented with fever, epigastric pain, hematemesis, and melena. A bleeding, ulcerated gastric metastasis was found and was treated with endoscopic therapy, omeprazole, and hormonal therapy. The patient was alive and well 13 months later. The bleeding was probably precipitated by necrosis of the lesion during chemotherapy. DISCUSSION: Gastrointestinal tract metastases from primary breast carcinoma are present in 14% to 35% of cases in autopsy series, with gastric involvement in 6% to 18% of cases. Recognized much less commonly during life than in autopsy studies, they can occur anywhere in the gut and can mimic virtually any gastrointestinal disorder. Endoscopy and barium studies facilitate diagnosis. Gastric lesions that have been noted include "linitis plastica", nodules, polyps, and ulcers. They are usually due to lobular breast carcinoma and resemble primary gastric carcinoma on microscopy. Reported cases of bleeding gastric metastases have been treated successfully with various local and systemic modalities. The median survival time of reviewed cases was four months from presentation (with a range of zero to 24 months). CONCLUSIONS: Gastrointestinal metastasis is an underdiagnosed complication of breast cancer. Gastrointestinal bleeding from metastatic breast cancer is an uncommon presentation that is readily diagnosed and that can be treated successfully by endoscopic hemostatic therapy.

The impact of postchemotherapy nausea and vomiting on quality of life after moderately emetogenic chemotherapy.

The purpose of the study was to assess the impact of postchemotherapy nausea and vomiting (PCNV) after moderately emetogenic chemotherapy on health-related quality of life (HRQOL) in patients with cancer being treated in a routine clinical practice setting. The European Organization for Research and Treatment in Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) was administered on day 2 and day 6 following moderately emetogenic chemotherapy to 119 patients with a variety of cancers. Patients kept daily diaries to record the occurrence and severity of nausea and vomiting. The QLQ-C30 questions were modified, for this study only, to assess the impact of nausea and vomiting on HRQOL in patients who experienced nausea and/or vomiting during the six days following chemotherapy. Those patients who experienced either nausea or vomiting experienced a decrease in HRQOL from prechemotherapy levels on six functioning and five symptom scales at day 2, and on four functioning and four symptom scales on day 6. Comparison of mean scores between the unmodified QLQ-30 and the nausea and vomiting versions demonstrated that the HRQOL rating attributed to nausea and vomiting accounted for much, but not all, of the deterioration in HRQOL scores in patients who experienced these symptoms. It can be concluded that patients who experience PCNV experience a significant negative impact on their HRQOL and that this impact can be attributed in large part to their experience of nausea and vomiting. However, since not all of the deterioration is attributable to these symptoms, other reasons for some of the decrease in HRQOL must also be identified in future studies.