The oncologist
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Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined. ⋯ Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.
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Adenocarcinoma of the pancreas remains a highly lethal disease, with less than 5% survival at 5 years. Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC) account for approximately 30% of newly diagnosed cases of PC. The objective of BRPC therapy is to downstage the tumor to allow resection; the objective of LAPC therapy is to control disease and improve survival. There is no consensus on the definitions of BRPC and LAPC, which leads to major limitations in designing clinical trials and evaluating their results. A multimodality approach is always needed to ensure proper utilization and timing of chemotherapy, radiation, and surgery in the management of this disease. Combination chemotherapy regimens (5-fluorouracil, leucovorin, irinotecan, oxaliplatin, and gemcitabine [FOLFIRINOX] and gemcitabine/nab-paclitaxel) have improved overall survival in metastatic disease. The role of combination chemotherapy regimens in BRPC and LAPC is an area of active investigation. There is no consensus on the dose, modality, and role of radiation therapy in the treatment of BRPC and LAPC. This article reviews the literature and highlights the areas of controversy regarding management of BRPC and LAPC. ⋯ Pancreatic cancer is one of the worst cancers with regard to survival, even at early stages of the disease. This review evaluates all the evidence for the stages in which the cancer is not primarily resectable with surgery, known as borderline resectable or locally advanced unresectable. Recently, advancements in radiation techniques and use of better combination chemotherapies have improved survival and tolerance. There is no consensus on description of stages or treatment sequences (chemotherapy, chemoradiation, radiation), nor on the best chemotherapy regimen. The evidence behind the treatment paradigm for these stages of pancreatic cancer is summarized.
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The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC). ⋯ Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors.
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Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15-year period in an integrated health care setting to identify factors related to initiation. ⋯ National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status.
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A multidimensional geriatric assessment (GA) is recommended in older cancer patients to inventory health problems and tailor treatment decisions accordingly but requires considerable time and human resources. The G8 is among the most sensitive screening tools for selecting patients warranting a full GA but has limited specificity. We sought to develop and validate an optimized version of the G8. ⋯ Several screening tools have been developed to identify older patients with cancer likely to benefit from a complete geriatric assessment, but none combines appropriate sensitivity and specificity. Based on a large prospective cohort study, an optimized G8 tool was developed, combining a systematic statistical approach with expert judgment to ensure optimal discriminative power and clinical relevance. The improved screening tool achieves high sensitivity, high specificity, better homogeneity across cancer types, and greater parsimony with only six items needed, facilitating selection for a full geriatric assessment.