Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Markus V. Heppt, Theresa Steeb, J. Gabriel Schlager, Stefanie Rosumeck, Corinna Dressler, Thomas Ruzicka, Alexander Nast, Carola Berking
BackgroundThe use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.MethodsWe performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.ResultsOut of 1,327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n=186) with a response rate of 0-5%. Two reports investigated ipilimumab at 10 mg/kg (n=45) with radiological responses observed in 0-6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2-9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6-36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months.ConclusionsUM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.



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Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: does age really matter?

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Roberto Ferrara, Laura Mezquita, Edouard Auclin, Nathalie Chaput, Benjamin Besse
Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75 years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients.



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Healthcare cost of HER2-positive and negative breast tumors in the United States (2012−2035)

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Francesca Tartari, Matteo Santoni, Mirco Pistelli, Rossana Berardi
BackgroundIn this study, we estimated the current and future costs related to the use of targeted agents in patients with HER2-positive and negative advanced breast cancer (BC), aimed at identifying the subgroup associated with the higher cost in the coming years.MethodsWe calculated the patient cost considering an ideal patient who received therapeutic sequences including all approved agents for HER2-positive or negative BC. The duration of treatment was estimated by the median Progression-Free Survival (PFS) reported in the phase III trials which have led to the approval of these drugs by the US Food and Drug Administration. The estimated number of BC patients in the US from 2012 to 2035 refers to data published by the World Health Organization.ResultsThe per patient cost was $292,155 for HER2-positive and $224,955 for negative tumors, respectively. The total cost for HER2-positive patients was estimated for 2012 at $2,719,542,347, with an annual increase ranged from 4.3 (for 2035) to 7.7% (for 2020), leading to a total expense of $3,648,232,975 in 2035. Otherwise, the total cost for HER2-negative patients in 2012 was estimated as $8,376,028,459, with an increase of more than $2.5 billion from 2012 to 2035. The estimated cost for HER2-negative patients was $5.6 billion higher that for HER2-positive tumors, raising to $7.6 billion to 2035.ConclusionsOur data strongly suggest that cost-analyses should be carefully evaluated in the coming years, in particular in patients with HER2-negative tumors.



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Pancreatic Ductal Adenocarcinoma: State-of-the-Art 2017 and New Therapeutic Strategies

Publication date: Available online 23 August 2017
Source:Cancer Treatment Reviews
Author(s): Marta Chiaravalli, Michele Reni, Eileen M. O'Reilly
Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5-year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers.



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Roadmap for Investigating Epigenome Deregulation and Environmental Origins of Cancer

Abstract

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed as well as advances in epigenomics that may help an understanding of the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed as well as how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment. This article is protected by copyright. All rights reserved.

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The risk of preterm birth and growth restriction in pregnancy after cancer

It is unclear whether cancer and its treatments increase the risk of adverse pregnancy outcomes. Our aim was to examine whether cancer survivors have higher risks of poor outcomes in pregnancies conceived after diagnosis than women without cancer, and whether these risks differ by cancer type and race. Diagnoses from cancer registries were linked to pregnancy outcomes from birth certificates in three U.S. states. Analyses were limited to the first, live singleton birth conceived after diagnosis. Births to women without a previous cancer diagnosis in the registry were matched to cancer survivors on age at delivery, parity, race/ethnicity and education. Log-binomial regression was used to estimate risk ratios. Cervical cancer survivors had higher risks of preterm birth (Risk ratio = 2.8, 95% Confidence interval: 2.1, 3.7), as did survivors of invasive breast cancer (RR = 1.3, 95% CI: 1.1, 1.7) and leukemia (RR = 2.1, 95% CI: 1.3, 3.5). We observed a higher risk of small for gestational age (SGA) infants (<10% of weight for age based on a national distribution) in survivors of brain cancer (RR = 1.7, 95% CI: 1.1, 2.8) and extranodal non-Hodgkin lymphoma (RR = 2.3, 95% CI: 1.5, 3.6). We did not see an increased risk of infants born preterm, low birth weight, or SGA in pregnancies conceived after ductal carcinoma in situ, thyroid cancer, melanoma, or Hodgkin lymphoma. While our results are reassuring for survivors of many cancers, some will need closer monitoring during pregnancy.

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Perioperative management of rare coagulation factor deficiency states in cardiac surgery

Abstract

Rare bleeding disorders (RBDs) include the hereditary deficiency of fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI or FXIII. RBDs do not confer a protective effect against atheromatous plaque formation, and thus the need for cardiovascular (CV) surgery in RBD patients is expected to increase with improved healthcare access (diagnosis and management) and longevity of the population. Clinical data regarding the management of RBDs in this setting are sparse, but the perioperative care team is obliged to gain a better understanding on available biological and pharmacological hemostatic agents. Perioperative management of RBDs in CV surgery is further complicated by heparin anticoagulation, haemodilution, and consumption of procoagulant and anticoagulant proteins associated with cardiopulmonary bypass (CPB). The aims of this review are to summarize pathophysiology of RBDs and laboratory monitoring pertinent to CV surgery, available factor replacement agents, and to provide the framework for perioperative coagulation management of RBD patients.

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