Retrospective Review of the Use of High-Dose Cyclophosphamide, Bortezomib, Doxorubicin, and Dexamethasone for the Treatment of Multiple Myeloma and Plasma Cell Leukemia.

BACKGROUND: Multiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to either autologous stem cell transplantation or novel therapies. We report our experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and plasma cell leukemia (PCL) patients. PATIENTS AND METHODS: We searched our electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m2 intravenously (I.V.) twice daily with mesna 400 mg/m2 I.V. daily (days 1-4), bortezomib 1.3 mg/m2 subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m2 daily continuous infusion (days 1-4), dexamethasone 40 mg orally daily (on days 1-4, 9-12, 17-20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ2, Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes. RESULTS: One hundred forty patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate was 85% in patients with RRMM (n = 116) and 100% in NDMM (n = 13) and PCL (n = 11) patients. Respective median progression-free survival (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95% confidence interval [CI], 5.26 to not applicable [NA]), 7.56 months (95% CI, 4.7 to NA), and 4.64 months (95% CI, 3.75-6.73). Patients with RRMM who used mCBAD as a bridge to autologous transplant (36.2%) had mPFS (11.48 months; 95% CI, 7.52-15.9 months) compared with those who did not (mPFS: 3.19 months; 95% CI, 2.4-3.75 months). Cytopenias occurred in more than 90% of patients, and febrile neutropenia was noted in 26%. All cases of treatment-related mortality (8%) occurred in patients with RRMM, except for 1 patient with PCL. CONCLUSION: mCBAD results in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other treatment options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. mCBAD can be a treatment option for patients with PCL.

Efficacy and safety of everolimus in hormone receptor positive breast cancer in a developing country: Real-life single institutional experience.

INTRODUCTION: Breast cancer is the second leading cause of cancer-related mortality despite the staggering improvement in cancer therapeutics. So far, published data illustrate endocrine therapy as the cornerstone treatment for patients with hormone receptor-positive metastatic breast cancer. Unfortunately, most patients eventually develop resistance to this treatment. METHODS: The purpose of this study is to evaluate the efficacy of mammalian target of rapamycin inhibition in reversing hormone resistance in the Lebanese breast cancer patients. Efficacy of the intervention according to the independent factors and notable side effects encountered were the primary points of the evaluation. RESULTS: In total, fifty patients received the combination of everolimus and exemestane. The mean age of the study population was 61 ± 11 years. Sensitivity to hormonal therapy before the start of the combination treatment was estimated at 64%. Response rate was 14%, and all patients were partial responders. After regular interval evaluation, the median progression-free survival was 5.2 months since the initiation of therapy. The main toxicities associated with the combination were stomatitis (22%), myalgia (22%), skin toxicity (8%), and hyperglycemia (4%), all Grades 1 and 2. CONCLUSION: Everolimus has been shown to be effective in overcoming hormonal resistance in Lebanese breast cancer patients with results inferior to those reported in the BOLERO-2 population. The particular differences in molecular and pathological aspects of breast cancer in our region should stimulate the extensive research for a better understanding of the particular pattern of the disease.

Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma: an argument for overcoming trastuzumab resistance.

AIM: Patients with advanced gastric cancer have a relatively poor prognosis with few therapeutic alternatives beyond first-line therapy. The purpose of this manuscript is to highlight the potential for prolonged responses in patients with HER-2-positive disease. Patients, materials & methods: We analyzed the data of patients diagnosed with HER-2-positive-advanced gastric cancer who progressed on trastuzumab-based combination therapy and subsequently received second-line therapy consisting of ramucirumab in combination with paclitaxel. RESULTS: Most patients had a stable disease after ramucirumab-based therapy (50%, 5/10), median duration to disease control was 8 months. CONCLUSION: The prolonged duration of response that we observed indicates that an interaction between the EGF pathway and the angiogenesis pathway requires further clinical investigations.

Management of stage III non-small cell lung cancer.

Optimal management of patients with locally advanced non-small cell lung cancer remains challenging in the context of this heterogeneous disease. Despite aggressive therapeutic approaches, survival benefits are still unsatisfactory for what might be viewed as a localized malignancy. A combined modality approach offers patients superior outcomes, especially because technological advances and refined surgical procedures now provide better results with fewer complications. Nevertheless, several features of therapy remain controversial and lack formal prospective data. Traditional cytotoxic chemoradiation therapy may have reached a plateau and future perspectives opting to integrate molecularly targeted agents and immunotherapy might be the way to improve outcomes in this disease subset.

Checkpoint inhibitors in gastrointestinal cancers: Expectations and reality.

Immune checkpoint inhibitors represent revolutionary anti-cancer agents, being rapidly approved in different malignancies and settings. Gastrointestinal (GI) cancers represent a wide variety of tumors with specific characteristics and different responses to various therapeutic alternatives; while some are chemo-sensitive others are chemo-resistant and only respond to more aggressive cytotoxic regimens, targeted therapies or a combination of both. Preliminary results of immune checkpoint inhibitors in some GI cancers are promising, namely in hepatocellular carcinoma, anal cancers and microsatellite instability high colorectal cancers. An impressive instead of a impressive number of immune checkpoint inhibitors are being evaluated in different indications in GI cancers as single agents or in combination with other agents. We reported in this paper ongoing and published trials evaluating immune checkpoint inhibitors in hepatocellular carcinoma and biliary tract cancers, esophageal, gastric, pancreatic, colorectal and anal cancers and we discussed the future perspectives of these agents in GI cancers.

Antiangiogenesis for Advanced Non-Small-Cell Lung Cancer in the Era of Immunotherapy and Personalized Medicine.

Over the past decade, patients with advanced non-small-cell lung cancer (NSCLC) have witnessed substantial advances in regards to therapeutic alternatives. Among newly developed agents, angiogenesis inhibitors were extensively tested in different settings and have produced some favorable outcomes despite several shortcomings. Bevacizumab is the most examined agent in this context and has demonstrated significant survival benefits when combined with standard chemotherapy in eligible patients. Preliminary results on the addition of bevacizumab to erlotinib in patients with EGFR-mutated NSCLC seem promising. Other antiangiogenic agents were also tested, but ramucirumab and nintedanib are the only agents with a positive impact on survival. More recently, immune checkpoint inhibitors (ICIs) have had considerable success due to their prolonged durations of response, yet response rates are still deemed suboptimal, and various combination therapies are being tested in an effort to improve efficacy. Preclinical evidence suggests an immunosuppressive effect of pro-angiogenic factors, which sets up a plausible rationale for combining ICIs and antiangiogenic agents. Herein, we review the landmark data supporting the success of angiogenesis inhibitors, and we discuss the potential for combination with immunotherapy and targeted agents.

Single-center comparison of multiple chemotherapy regimens for concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer.

PURPOSE: To date, the best chemotherapy regimen to combine with concurrent radiotherapy in stage III non-small-cell lung cancer remains undetermined. We compared the survival outcomes and toxicities in patients who were treated with etoposide-cisplatin (EP), paclitaxel-carboplatin (PC), or vinblastine-cisplatin (VP) in one large cancer referral center. METHODS: We enrolled patients who received concurrent chemoradiotherapy at our university-affiliated hospital between January 1, 2009 and December 31, 2013. Demographic and clinical characteristics were identified. Progression-free survival (PFS) and overall survival (OS) between the different treatment groups were compared using Kaplan-Meier and Cox proportional hazards regression models. Treatment-related toxicities were also compared. RESULTS: A total of 107 patients were treated with EP (31.8%), PC (32.7%) or VP (35.5%). Treatment with VP was significantly superior to PC, both in terms of median PFS [29.2 vs. 10.5 months; hazard ratio (HR) 0.43; 95% CI 0.21-0.85; p = 0.01] and in terms of median OS [40.7 vs. 17.8 months; (HR) 0.42; (0.21-0.84); p = 0.01]. However, there was no survival difference between EP and either one of the other regimens, but there was significantly more toxicities reported with the use of EP (73.5%) compared to PC (44.7%) or VP (37.1%); (p = 0.001). The most frequent non-hematologic toxicities for the entire cohort were esophagitis (28%), fatigue (22.4%), pneumonitis (14%), and nephrotoxicity (9.3%). CONCLUSION: Although the present study is limited by its small cohort and its retrospective nature, the results suggest that VP might be superior to PC and is less toxic than EP.

Concurrent driver mutations/rearrangements in non-small-cell lung cancer.

PURPOSE OF REVIEW: The concept of mutually exclusive oncogenic driver alterations has prevailed over the past decade, but recent reports have stressed the possible occurrence of dual-positive non-small-cell lung cancer (NSCLC) and even triple-positive disease for these oncogenes. This entity presents novel prognostic and therapeutic challenges. The present review highlights the available data in an effort to clarify the clinical and pathological significance of coexisting mutations as well as the subsequent therapeutic consequences. RECENT FINDINGS: Patients with a known driver oncogene can be successfully treated with the appropriate tyrosine kinase inhibitor, which will provide them with significant responses and lesser toxicities compared with cytotoxic therapy. Unfortunately, most patients will eventually progress. Although some resistance mechanisms have been identified, others remain to be determined but the emergence of secondary oncogenes could be part of the answer. SUMMARY: Approximately 20-25% of NSCLC harbor treatable driver mutations/rearrangements; epidermal growth factor receptor mutation, anaplastic lymphoma kinase and ROS-1 gene rearrangements are the main alterations for which a Food and Drug Administration-approved tyrosine kinase inhibitor can be used.Because of recent technological advances, high sensitivity assays with a broad range of genomic targets have become more easily accessible in clinical practice, which has led to an increased detection of coexisting driver alterations in patients with advanced NSCLC. The prognostic/predictive and therapeutic implications of this novel entity are still unsettled for the time being. Randomized trials specifically designed to address this subset of patients will soon be necessary to help determine the optimal therapeutic agent to administer.

Severe agranulocytosis in a patient with metastatic non-small-cell lung cancer treated with nivolumab.

Immune checkpoint inhibitors are novel agents in the process of revolutionising cancer care. These agents have become a very appealing therapeutic alternative since they are much better tolerated than cytotoxic therapy, due to their relatively favorable toxicity profile. However, adverse events associated with these agents usually involve the immune system and can have serious implications jeopardising survival. Herein we report the first case of immune-mediated agranulocytosis due to Nivolumab therapy. The patient suffered from Staphylococcus infection during her agranulocytosis which only responded to high dose corticosteroid therapy.

Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer: a new therapeutic strategy.

After the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement. Combining TKI targeting EGFR/ALK with checkpoint inhibitors seems a promising therapeutic option and is being evaluated in different trials. We aimed in this paper to elucidate the rationale behind this combination, to report the premilinary results of ongoing trials evaluating this association and finally, to discuss briefly the possible future indication of this treatment modality.

Immune-mediated respiratory adverse events of checkpoint inhibitors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors have demonstrated remarkable efficacy with durable responses in the treatment of various malignancies. This new class of therapeutic agents is associated with a toxicity profile that differs from conventional cytotoxic therapy. The present review is focused on one of these toxicities affecting the respiratory system. RECENT FINDINGS: Many types of immune-related adverse events (irAEs) have been identified since the emergence of checkpoint inhibitors including colitis, nephritis, myasthenia gravis-like syndromes, acute interstitial nephritis, pneumonitis, and endocrinopathies. Although pneumonitis is relatively less frequent than other irAEs, this toxicity is by no means inconsequential as it has led to treatment-related deaths during the initial testing phases. SUMMARY: Immune-mediated pneumonitis is a potentially serious but relatively infrequent adverse event associated with the use of immune checkpoint inhibitors. IrAEs can be challenging for oncologists who are still unfamiliar with the early presenting symptoms and subsequent management of these toxicities, especially in the context of a rapidly expanding science. A high index of suspicion for pneumonitis must be maintained in patients receiving checkpoint inhibitors and who present new onset respiratory symptoms because this type of toxicity can be severe and potentially fatal.

Metastatic gastric cancer treatment: Second line and beyond.

Advanced gastric cancer (aGC), not amenable to curative surgery, is still a burdensome illness tormenting afflicted patients and their healthcare providers. Whereas combination chemotherapy has been shown to improve survival and tumor related symptoms in the frontline setting, second-line therapy (SLT) is subject to much debate in the scientific community, mainly because of the debilitating effects of GC, which would impede the administration of cytotoxic therapy. Recent data has provided sufficient evidence for the safe use of SLT in patients with an adequate performance status. Taxanes, Irinotecan and even some Fluoropyrimidine analogs were found to provide a survival advantage in this subset of patients. Most importantly, quality of life measures were also improved through the use of adequate therapy. Even more pertinent were the findings involving antiangiogenic agents, which would add measurable improvements without significantly jeopardizing the patients' well-being. Further lines of therapy are cause for much more debate nowadays, but specific targeted agents have shown considerable promise in this context. We herein review noteworthy published data involving the use of additional lines of the therapy after failure of standard frontline therapies in patients with aGC.

Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the past 2 decades, advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC. The advent of targeted therapy, coupled with more efficient chemotherapy regimens, was the pillar achievement that contributed to the success of CRC therapy. Cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor pathway, are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker, the Kristen rat Sarcoma viral oncogene (KRAS). More recently, another biomarker, the neuroblastoma rat sarcoma viral oncogene (NRAS), was found to be as valuable for the refinement of this targeted therapy. The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy.

Validation of the EORTC QLQ-INFO 25 questionnaire in Lebanese cancer patients: Is ignorance a Bliss?

INTRODUCTION: Despite worldwide trends toward optimizing full disclosure of information (DOI), the prevailing belief that cancer diagnosis should be concealed from patients, for their own good, has endured for a substantial period of time in Middle Eastern communities. OBJECTIVES: This study would assess the reliability of the Arabic translated version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-INFO 25). The study was also designed to quantify DOI to Lebanese cancer patients and determine patient satisfaction with this DOI. Moreover, we compared the differences in the level of information among groups based on clinical and biographical variables. METHODS: A sample of patients, being treated for a variety of malignancies, was prospectively evaluated. A physician interviewed patients using the Arabic version of the EORTC QLQ-INFO 25, on the day of hospitalization for chemotherapy, before treatment was administered. RESULTS: In total 201 patients were interviewed. The translated version of the EORTC QLQ-INFO 25 showed high reliability when assessed using Cronbach's alpha coefficients for internal consistency with values scoring higher than 0.7 for all scales and the full questionnaire. There was a considerable lack of information provided to the participants with 38.8 % being unaware of their diagnosis and more than half being uninformed about the extent of their disease. Paradoxically, 86.5 % of patients expressed their satisfaction about the amount of information they received and 89.5 % believe the information provided was helpful. Further analysis showed no significant association between gender, marital status, cancer site and stage and the amount of information received. However, age and level of education were associated with DOI such as younger and more educated patients received more information. Older patients were also found to be the most satisfied with the information they received, despite having less access to information. CONCLUSIONS: Although a high proportion of patients were not properly informed about their diagnosis, the overwhelming majority were satisfied with the amount of information they received and believed it was useful, reflecting the complexity of Middle Eastern cultural influences on cancer patients' perspectives.

Unusual Destruction of the Nasal Septum.

Extranodal Natural Killer/T-cell lymphoma (ENKTL) is the most common cause of nasal cell lymphoma. It manifests by progressive destruction of the facial midline features with nasal obstruction and local destruction of soft tissue. Therefore, establishing the diagnosis of this disease tends to be difficult. This is attributed to an extensive differential diagnosis of infectious, autoimmune, neoplastic and inflammatory etiologies. We herein report the case of a 63-year-old female who presented to our department for persistent nasal congestion resistant to symptomatic treatment that was found to have an ENKTL. In this paper, we discuss the pathogenesis, clinical and imaging findings, differential diagnosis, prognosis and treatment.

EARLY INCREASE of CA 19-9 in ADVANCED PANCREATIC CANCER RECEIVING FOLFIRINOX. Is it a sign of efficacy?.

INTRODUCTION: Advanced pancreatic cancer (APC), one of the most aggressive tunors, was considered to be resistant to chemotherapy for decades. FOLFIRINOX (5-FU, leucovorin, iNinotecah and oxaliplatin) regimen showed an improvement of quality of life and overall sUrvival.ir APb patients with good performance status (ECOG < 2). MATERIAL AND METHODS: Seven patients diagnosed with APO, during a six-month period, received FOLFIRINOX as first line treat- ment. Tumor measurement Was assesed every two months and CA 19-9, tHe specific tumor marker of pahcteatid can6er, was assessed every two wedks at every cycle. RESULTS: Three patients ouf of seven receiving FOLFiRINOX dtpe- riented an early And transitory increase of CA 19-9 after th6 first two cybles resulting ih a considerable response with a median survival of 15 mnths and suggesting a fhdel of fdmor release syndrome. CONCLUSION: This phenoMenon of early and transitory increase of CA 19-9 in APC could reflect the high efficacy of FOLFIRINOX and could predict better out- come in these patients.