Therapeutic modalities in small cell lung cancer: a paradigm shift after decades of quiescence.

INTRODUCTION: Small cell lung cancer (SCLC) is known to be the most aggressive of all thoracic malignancies, notoriously known for its very poor prognosis. Platinum-based chemotherapy has been the standard of care for decades. Despite years of research, no treatment novelties with significant impact on survival have been achieved until recently. The last few years have witnessed light at the end of the tunnel with immunotherapy proving to improve survival. Nevertheless, responses were not homogeneous in all subgroups, and finding who would best benefit from treatment remains unanswered. Multiple limitations exist, and the quest for optimal biomarkers seemed unfruitful until the discovery of different SCLC phenotypes. AREAS COVERED: In this review, the authors briefly discuss SCLC phenotypes and biomarker assays. Then, the authors continue with the main trials of SCLC treatment using chemotherapy, immunotherapy, and targeted treatment in the frontline or subsequent line settings. EXPERT OPINION: Research has been extensively implemented to better understand the biology of SCLC and test for the optimal use of immunotherapy in patients with SCLC, as well as to enhance responses via possible combinations. Targeted mechanisms of action have also been attempted; yet no solid proof of efficacy has been established.

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas.

BACKGROUND: Intensified immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) improves outcomes in younger adults with diffuse large B-cell lymphomas (DLBCL) compared with R-CHOP. Due to vindesine unavailability, we assessed the safety and efficacy of replacing vindesine with vincristine in a modified R-ACVBP protocol (mR-ACVBP). METHODS: This is a retrospective study including all consecutive adult patients with newly diagnosed DLBCL who received first-line mR-ACVBP. Vindesine was replaced with vincristine 1.5 mg on days 1 and 5 of each cycle. Responders continued with published R-ACVBP consolidation. Patients with inadequate response on interim imaging were offered consolidative autologous stem cell transplantation. RESULTS: We identified 56 patients with DLBCL, with a median age of 41 years (range, 21-67). Thirty-seven (66%) patients had an age-adjusted International Prognostic Index of ≥ 2. Complete response was achieved in 41 (80%) patients and partial response in 6 (12%). The most common adverse events during induction were anemia (91%), febrile neutropenia (64%; grade 4 in 46%), thrombocytopenia (39%), and mucositis (21%). Peripheral neuropathy was encountered in 7 (12%) patients (grade 3; n = 1). Two deaths from septic shock were reported in patients with initial poor performance status. After a median follow-up of 17 months, the 2-year progression-free survival and overall survival rates were 86% and 87%, respectively. CONCLUSION: The replacement of vindesine with vincristine in mR-ACVBP seems feasible, with manageable adverse events and excellent 2-year progression-free survival. These data need validation in larger prospective trials.

Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma.

Central nervous system (CNS) relapse affects 5% of diffuse large B-cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS relapse based upon CNS-IPI score, double-hit lymphoma, or testicular involvement. Among 906 patients with median follow-up 35.3 months (range 0.29-105.7), CNS relapse occurred in 1.9% with CNS-IPI 0-1, 4.9% with CNS-IPI 2-3, and 12.2% with CNS-IPI 4-6 (p < .001). HD-MTX was administered to 115/326 (35.3%) high-risk patients, of whom 96 (83.5%) had CNS-IPI score 4-6, 45 (39.1%) had double-hit lymphoma, and four (3.5%) had testicular lymphoma. The median number of HD-MTX doses was two (range 1-3). Central nervous system relapse risk was similar with versus without HD-MTX (11.2% vs. 12.2%, p = .82) and comparable to previous reports of high-risk patients who did not receive CNS prophylaxis (10-12%). In multivariate and propensity score analyses, HD-MTX demonstrated no association with CNS relapse, progression-free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD-MTX in this high-risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL.

MET Inhibitors for the Treatment of Gastric Cancer: What's Their Potential?

Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.

Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non-small cell lung cancer.

INTRODUCTION: Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase (ALK) rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active ALK inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi. AREAS COVERED: Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug. EXPERT COMMENTARY: Lorlatinib is a potent ALK and ROS-1 inhibitor that also has activity against many acquired ALK resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in ALK rearranged advanced NSCLC. Adverse events of lorlatinib are unique and manageable. These include hypocholesteremia, hypertriglyceridemia, edema, cognitive effects, weight gain, and diarrhea. Loratinib will play an increasing role in the management of ALK-rearranged NSCLC with the optimal sequencing of ALKi undergoing further research.

Correction: Complete remission of seronegative rheumatoid arthritis following haplo-identical stem cell transplantation for peripheral T-cell lymphoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Successful treatment of severe aplastic anemia with syngeneic stem cell transplantation in the setting of active disseminated mucormycosis.

Severe aplastic anemia (SAA) is a hematological disease resulting in pancytopenia due to bone marrow failure. Treatment consists of immunosppressive therapy, or allo-SCT. Patients with aplastic anemia are predisposed to invasive fungal infections due to mucormycosis. Till now, syngeneic SCT in the context of active mucormycosis infection for patients with severe aplastic anemia is lacking in the literature. Here, we report a case of severe aplastic anemia with disseminated mucormycosis infection undergoing syngeneic transplant.

Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications.

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.

Management of leptomeningeal metastasis in breast cancer.

Leptomeningeal metastasis (LM), which occurs when malignant cells spread to the central nervous system, is becoming an increasingly common complication in patients with breast cancer. Diagnosis and treatment of LM is challenging. Moreover, prognosis of patients with LM is poor, with a median survival of 6 months after diagnosis. This review highlights the strengths and limitations of currently available diagnostic tools and therapies for LM. The current treatments for LM, including radiotherapy, systemic therapy, and intrathecal treatment, aim to maintain the quality of life of patients by correcting neurological deficits and arresting neurological degeneration. However, there is no standardized therapy for LM because of a lack of randomized trials on this condition.

Anxiety, Depression and Quality of Life in Breast Cancer Patients in the Levant

Background: Limited data are currently available regarding the psychological well-being and quality of life of breast cancer patients after active treatment in Lebanon and the Arab region in general. The objective of this study was to determine the prevalence of anxiety and depression among Arab breast cancer patients and assess the quality of life with reference to socio-demographic and clinical characteristics. Methods: This cross-sectional study was conducted among female breast cancer patients diagnosed between January 2009 and March 2014, who were recruited from the outpatient clinics of Naef K. Basile Cancer Institute at the American University of Beirut Medical Center (AUBMC) from November 2015 till December 2016. An interview was conducted utilizing two validated questionnaires: the Hospital Anxiety and Depression Scale (HADS) and the Functional Assessment of Cancer Therapy-Breast (FACT-B). Socio-demographic and clinical characteristics that might predict patient quality of life were collected and summarized. Results: A total of 150 patients were interviewed (median age 53.5±10.4 years). Most were assessed 3 to 5 years (68.7%) after initial diagnosis and had undergone surgery, chemotherapy, radiation, or hormonal therapy (97.3%, 79.3%, 80.7% and 86.0%, respectively). The median total HADS score was 10.0 ± 8.0, with approximately 41.3% of study participants having abnormal scores on the anxiety subscale and 24.7% on the depression subscale. Significant predictors of total HADS score were nationality and level of education (p=0.001, p=0.001 respectively; R2=0.181). Participants who were Iraqi, had stage IV disease, had a household monthly income below 1000 USD, or had received chemotherapy exhibited significantly lower total FACT-B scores, these being highly negatively correlated with total HADS scores (rs= -0.73, p=0.001). Conclusion: There is a vital need for the development of individualized interventions and psychosocial support programs tailored to the physical and psychological well-being of breast cancer patients in the Levant region.