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Cancer Journal

Mario Sznol
Despite the broad clinical antitumor activity of PD-1/PD-L1 antagonists, many patients who are treated with these agents either do not respond or achieve suboptimal responses. Improving overall outcome will require combinations with other agents to address potential innate or acquired mechanisms of resistance. Many combination trials have been initiated in patients with or without prior exposure to the PD-1/PD-L1 antagonists. In addition to the challenge of identifying optimal dose, schedule, and sequence for the combinations, current biomarker efforts lack the precision to identify optimal combination partners for the PD-1/PD-L1 antagonists in individual patients...
January 2018: Cancer Journal
Theodore S Nowicki, Siwen Hu-Lieskovan, Antoni Ribas
Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient...
January 2018: Cancer Journal
Tricia R Cottrell, Janis M Taube
PD-L1 checkpoint blockade is revolutionizing cancer therapy, and biomarkers capable of predicting which patients are most likely to respond are highly desired. The detection of PD-L1 protein expression by immunohistochemistry can enrich for response to anti-PD-(L)1 blockade in a variety of tumor types, but is not absolute. Limitations of current commercial PD-L1 immunohistochemical (IHC) assays and improvements anticipated in next-generation PD-L1 testing are reviewed. Assessment of tumor-infiltrating lymphocytes in conjunction with PD-L1 testing could improve specificity by distinguishing adaptive (interferon γ driven and cytotoxic T-lymphocyte associated) from constitutive (non-immune mediated) expression...
January 2018: Cancer Journal
Daniel Y Wang, Douglas B Johnson, Elizabeth J Davis
Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review briefly discusses the mechanisms of immune-related adverse events, overviews the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and reviews their management...
January 2018: Cancer Journal
Matthew J Pianko, Aaron D Goldberg, Alexander M Lesokhin
Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space...
January 2018: Cancer Journal
Matthew C Dallos, Charles G Drake
Genitourinary malignancies represent a diverse biologic and immunologic landscape. Recently, checkpoint blockade has transformed the treatment paradigms for bladder and kidney cancer. However, continued progress will be essential in bladder and kidney cancer, given response to inhibition of the PD-1/PD-L1 (PD-1/PD-L1) axis remains variable and only a minority of patients respond. In contrast with the clinical trial results in bladder and kidney cancer, studies of anti-PD-1/PD-L1 therapy in prostate cancer have generally been disappointing...
January 2018: Cancer Journal
Fernando C Santini, Matthew D Hellmann
Cancer immunotherapies have revolutionized the treatment of non-small cell lung cancer. Yet, only a small subset of patients will benefit from PD-1 or PD-L1 blockade. PD-L1 tumor cell expression is the only approved biomarker at present. Tumor mutational burden and other emerging biomarkers should improve patient selection. Combination therapy approaches with chemotherapy or cytotoxic T-lymphocyte-associated protein 4 blockade may increase the proportion of patients who benefit from immunotherapy. Although use of immunotherapy in lung cancers with targetable oncogenes has not been particularly successful, the benefit of PD-(L)1 inhibitors in early-stage disease is emerging...
January 2018: Cancer Journal
Rodrigo Ramella Munhoz, Michael Andrew Postow
The development of new treatment options has dramatically improved the landscape for patients with advanced melanoma. Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell-mediated responses termed "immune checkpoints." Indeed, blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients...
January 2018: Cancer Journal
Michael A Curran
Antibodies that block the PD-1 coinhibitory receptor on T cells or its primary ligand, PD-L1, have demonstrated unprecedented efficacy across a diverse array of both solid and hematologic malignancies in the clinic. These advances were built on a foundation of murine preclinical tumor model studies, which both demonstrated the therapeutic potential of PD-1/PD-L1 antibody blockade and also provided critical insights into the cellular and molecular processes underlying their capacity to elicit immune-mediated tumor regressions...
January 2018: Cancer Journal
Jedd D Wolchok, Margaret K Callahan
No abstract text is available yet for this article.
January 2018: Cancer Journal
Michael W Rabow, Maria Q B Petzel, Sarah H Adkins
Evidence documents the benefits of palliative care to ameliorate the symptoms of pancreatic cancer as well as those from its treatment. Professional organizations now recommend palliative care for all patients with pancreatic cancer early in the course of illness and concurrently with active treatment. Scrupulous symptom management as well as sensitive communication and advance care planning allow oncologists to provide "primary palliative care" and to care well for patients with pancreatic cancer throughout the course of their illness...
November 2017: Cancer Journal
Andrew H Ko
Most patients with pancreatic cancer either present with or eventually develop metastatic disease during the course of their illness. For such individuals, systemic therapy, namely, cytotoxic therapy, represents the mainstay of treatment and is administered with noncurative intent. Of the various chemotherapy options now available for treating metastatic pancreatic cancer, 2 combination regimens, FOLFIRINOX (infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the doublet of gemcitabine and albumin-bound paclitaxel, have emerged as frontline standards of care, based on phase III studies demonstrating a significant survival benefit compared with single-agent gemcitabine...
November 2017: Cancer Journal
Christopher H Crane, Eileen M O'Reilly
Standard palliative doses of radiation for locally advanced unresectable pancreatic cancer have had minimal to no impact on survival. Randomized trials evaluating these palliative doses have not shown a significant survival benefit with the use of radiation as consolidation after chemotherapy. Results from nonrandomized studies of 3- to 5-fraction low-dose stereotactic radiation (SBRT) have likewise had a minimal impact, but with less toxicity and a shorter treatment time. Doses of SBRT have been reduced to half the level that is necessary (biological equivalent dose, BED of 53 Gy) to achieve tumor ablation in the treatment of other solid tumors (100 Gy BED) to protect the gastrointestinal (GI) tract...
November 2017: Cancer Journal
Rebekah R White, Andrew M Lowy
Despite the identification of more active systemic therapy combinations for pancreatic cancer, cures remain elusive and feasible only in patients with localized, operable disease. When examining outcome data from phase III adjuvant trials conducted during the past decade, the survival for patients with localized disease has improved, likely owing to a combination of factors including more active adjuvant therapy and improved surgical and perioperative care. Perhaps the greatest recent change in the care of patients with localized pancreatic cancer has been the extension of surgery to tumors previously thought to be inoperable because of involvement of major blood vessels...
November 2017: Cancer Journal
Linda C Chu, Michael G Goggins, Elliot K Fishman
Computed tomography is the first-line imaging modality for suspected pancreatic cancer. Magnetic resonance cholangiopancreatography is a second-line modality for suspected pancreatic cancer and is usually reserved for equivocal cases. Both computed tomography and MR are highly sensitive in the detection of pancreatic cancer, with up to 96% and 93.5% sensitivity, respectively. Computed tomography is superior to MR in the assessment of tumor resectability, with accuracy rates of up to 86.8% and 78.9%, respectively...
November 2017: Cancer Journal
Martin C Whittle, Sunil R Hingorani
Recent advances in cytotoxic therapies for pancreatic ductal adenocarcinoma (PDA) are overshadowed by stalled clinical progress of more targeted strategies, the vast majority of which have failed in clinical trials. Inability to translate preclinical promise into clinical efficacy derives, in part, from imperfect disease modeling and mismatches between preclinical and clinical study design and execution. Into these gaps fall our patients who enter the clinical trial landscape expectantly and bear the brunt of its inadequacies...
November 2017: Cancer Journal
Stephanie K Dougan
Pancreatic ductal adenocarcinoma (PDAC) is composed of a minority of malignant cells within a microenvironment of extracellular matrix, fibroblasts, endothelial cells, and immune cells. Therapeutic failures of chemotherapy, targeted therapy, and immunotherapy have all been attributed to the PDAC microenvironment. In this review, we dissect the components of the microenvironment and explain how each cell type contributes to form a highly immunosuppressive, hypoxic, and desmoplastic cancer. New efforts in single-cell profiling will enable a better understanding of the composition of the microenvironment in primary and metastatic PDAC, as well as an understanding of how the microenvironment may respond to novel therapeutic approaches...
November 2017: Cancer Journal
Andrew J Aguirre, Eric A Collisson
Pancreatic ductal adenocarcinoma (PDA) remains one of the most devastating diagnoses in modern medicine. While the clinical management of the disease has improved, the complex biologic underpinnings of PDA enable both its aggressive nature and slow clinical translational progress. In this review, we provide an overview of the key features of PDA genetics and biology, highlighting translational challenges and providing a framework for improved diagnostic and therapeutic approaches.
November 2017: Cancer Journal
Paige M Bracci
PURPOSE: The aim was to provide a cohesive overview of epidemiological studies of periodontal disease, oral microbiome profiles, and pancreatic cancer risk. DESIGN: A PubMed search of articles published in English through July 2017 with additional review of bibliographies of identified articles. RESULTS: Risk estimates for periodontal disease associated with pancreatic cancer consistently ranged from 1.5 to 2, aligning with a meta-analysis summary relative risk of 1...
November 2017: Cancer Journal
Margaret A Tempero
No abstract text is available yet for this article.
November 2017: Cancer Journal
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