Fadi Farhat

Cutaneous manifestations of anti-angiogenic therapy in oncology: Review with focus on VEGF inhibitors.

The role of the VEGF signaling pathway in angiogenesis has been extensively investigated, and many new targeted anti-angiogenic drugs have evolved from this knowledge. The recent approval and introduction of these anti-neoplastic drugs has revolutionized the treatment of many types of cancers, but has also revealed numerous toxicities to the skin and its adnexae. Since these cutaneous side effects may have a significant impact on the physical, emotional and psychosocial health of patients, it is important for dermatologists and oncologists alike to be aware of the cutaneous complications of these drugs in order to properly diagnose and treat them. This review will detail the presentation of the cutaneous complications of the anti-angiogenic drugs, most notably bevacizumab, sorafenib and sunitinib, and shed light on the management of such adverse reactions.

Treatment of cancer patients in their last month of life: aimless chemotherapy

PurposeThe use of chemotherapy in the last month of life (CLML) of cancer patients is considered an aggressive approach to be avoided. We examined the practice of CLML in Lebanese cancer patients, and we investigated patient and tumor characteristics that justify this practice. To our knowledge, this is the first study describing CLML of Middle Eastern patients with advanced cancer.MethodsWe conducted this study at Hotel-Dieu de France University Hospital (HDF), Lebanon. Cases eligible for this study were all individuals diagnosed with cancer who died at HDF between the 1st of January and the 31st of December 2014. Demographic and clinical characteristics of the patients were obtained from the hospital registration records. Data concerning the management plan, primary malignancy and stage, chemo-sensitivity, line, type, and timing of chemotherapy in the last month of life were also obtained.ResultsAmong the 130 cancer patients who were enrolled, CLML was administered to a total of 55 patients (42.3xa0%), of whom 26 patients (50xa0%) received more than one cytotoxic drug. Oral drug was only given to 9 patients (16.4xa0%). Interestingly, CLML increased the risk of death in the last month of life (pu2009=u20090.02), yet progression of disease constituted the major cause of death in this subgroup (54.6xa0%). The only variable to have statistical significant correlation with CLML was performance status (pu2009=u20090.03). The type of tumor and recent diagnosis of less than 2xa0months were also correlated to CLML (pu2009=u20090.03 and 0.024, respectively).ConclusionThe high percentage of patients receiving CLML underlines the difficulty of end-of-life discussions in patients from Middle Eastern societies. This is true in the context of a country with little availability of palliative care resources, where health policies should be more focused on incorporating palliative medicine in all medical strategies.

Triple-Negative Breast Cancer in Lebanon: A Case Series

OBJECTIVESnTo determine the incidence, characteristics, and survival outcomes of triple-negative breast cancer patients in a medical oncology practice in Lebanon.nnnMETHODSnThe pathology reports of all breast cancer cases diagnosed or treated in 1997-2008 were reviewed.nnnRESULTSnOne hundred seventy breast cancer cases (9.3%) of the 1,834 cases that were identified in this practice over a 10-year span had a triple-negative phenotype, with a median age at diagnosis of 52 years. The pathology distribution of those cases was as follows: invasive ductal carcinoma, 85%; medullary carcinoma, 5%; invasive lobular carcinoma, 5%; 95 cases (63%) were grade III. At diagnosis, 17% presented with stage I, 47% had stage II, 24% had stage III, and 12% had stage IV disease, whereas 11% had an inflammatory component. After a median follow-up of 17 months, 43 patients (25.3%) had relapsed and the most common sites of relapse were the brain (19%), lungs (19%), and bones (12%). The risk for recurrence peaked at 1.5 years and became almost nil after 3 years. Twenty patients received induction chemotherapy, among whom six (42.9%) had a complete response and six (42.9%) had a partial response to treatment. None of the patients progressed on neoadjuvant chemotherapy. The 5-year disease-free survival rate was 75% for stage I, 58% for stage II, and 40% for stage III patients, whereas the 5-year overall survival rate was 88% for stage I, 72% for stage II, and 63% for stage III patients. Adjuvant therapy was administered to 96% of patients, using a taxane-based regimen in 38% of cases. The median survival time for stage IV patients was 19 months, with a first line taxane-based regimen used in 50% of cases.nnnCONCLUSIONSnThe incidence of triple-negative breast cancer in Lebanon is similar to that described in the literature. In order to determine targets for future therapeutic options, it is essential to understand the biology of this particular breast cancer subtype.

PET/CT Scanner and Bone Marrow Biopsy in Detection of Bone Marrow Involvement in Diffuse Large B-Cell Lymphoma

Evaluation of bone marrow involvement (BMI) is paramount in diffuse large B-cell lymphoma (DLBCL) for prognostic and therapeutic reasons. PET/CT scanner (PET) is now a routine examination for the staging of DLBCL with prognostic and therapeutic implications. This study evaluates the role of PET for detecting marrow involvement compared to bone marrow biopsy (BMB). This monocentric study included 54 patients diagnosed with DLBCL between 2009 and 2013 and who had FDG PET/CT in a pre-treatment setting. A correlation analysis of the detection of BMI by PET and BMB was performed. A prognostic evaluation of BMI by BMB and/or PET/CT and correlation with an overall 2-year survival were analyzed. PET was more sensitive for the detection of BMI than BMB (92.3% vs. 38.5%). It can be considered a discriminatory Pre-BMB test with a negative predictive value of 97.6%. In addition, BMI by PET had a prognostic value with strong correlation with progression-free survival (PFS) (HR = 3.81; p = 0.013) and overall survival (OS) (HR = 4.12; p = 0.03) while the BMB had not. PET shows superior performance to the BMB for the detection of marrow involvement in DLBCL. It may be considered as the first line examination of bone marrow instead of the biopsy.

Review and results of a survey about biosimilars prescription and challenges in the Middle East and North Africa region

BackgroundOnly drafts of regulatory guidelines for the registration of biosimilars are available in Lebanon. We analyzed the results of a regional survey conducted in Lebanon to understand the impact of different parameters on the acceptance and future prescription of biosimilars. We also reviewed the current situation of biosimilars around the world. The study surveyed healthcare professionals from the Arab countries, Iran, Belgium and Italy. Data about the participants’ specialty, country of residence, their knowledge about biosimilars, biosimilars’ prescription, price influence and the manufacturer’s credibility were collected.Results117 questionnaires were completed and returned: 46 (39.3%) respondents were oncologists. 72 (61.5%) respondents were Lebanese, and the others from Egypt, Syria, Algeria, Iraq, Sudan, Jordan, Iran, Belgium and Italy. 77 (65.8%) respondents had knowledge about biosimilars, of whom 48 (62.3%) considered biosimilars as biologics that demonstrate bioequivalence with the original biodrug and have all preclinical and clinical trials equal to those already performed with the original biodrug. 74 (63.2%) out of 117 respondents agreed that biosimilars in the Arab and Middle Eastern market are already marketed. Among the 48 participants who prescribe biosimilars, the main prescription driver was the drug’s approval by the FDA and EMA (68.8%). 71 (60.7%) respondents considered that the main advantage of biosimilars is their lower price and 41 (35%) out of the 117 respondents declared that they should know in which country the drug has been tested/created before using it in their own country. 35% of the respondents thought that the cost of a treatment should not come before its effectiveness or safety/tolerance, given that the biosimilar will be less expensive than the reference drug.ConclusionsBiosimilars’ acceptance and use is increasing worldwide. Only few physicians are aware of biosimilars presence in the market and do prescribe them in Lebanon and the Arab region. This could be mainly explained by lack of confidence in efficacy, safety, manufacturing process and price of these products, and lack of clear legislation. Thus, WHO is finalizing a new guideline for similar biotherapeutic agents. This could be a starting point for the Lebanese government to support the authorization of biosimilars.

Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer

SummaryBackground Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25xa0mg/m2 Docetaxel weekly for 3 consecutive weeks every 4xa0weeks, 4xa0mg Zoledronic acid every 4xa0weeks, and 200xa0mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7xa0cycles per patient. The median overall survival (OS) was 9.8xa0months (range 0.7 to 24.1xa0months) with 36xa0% and 4.5xa0% survival rates at 1 and 2xa0years, respectively. Our patients had a biologic response in 40.1xa0% of cases and a palliative response in 72.7xa0%. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5xa0%. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1xa0%), 5 had sensory neuropathy (22.7xa0%) and 2 had stomatitis (9.1xa0%). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials.

Oral vinorelbine in combination with trastuzumab as a first-line therapy of metastatic or locally advanced HER2-positive breast cancer

PurposeVinorelbine–trastuzumab combination proved to be an effective first-line treatment for patients with locally advanced or metastatic breast cancer (MBC). Oral chemotherapy represents a step forward in MBC management. To improve patients’ comfort using the oral form of vinorelbine, we conducted a multicenter phase II study to investigate the efficacy and safety of the oral vinorelbine–trastuzumab combination in women with MBC with human epidermal growth factor receptor 2 (HER2) overexpression.MethodsMain eligibility criteria: HER2-positive disease, no adjuvant chemotherapy within the last 6xa0months and no prior chemotherapy for MBC. Patients were treated with oral vinorelbine 80xa0mg/m2 D1, D8, D15 (following first 3 administrations at 60xa0mg/m2 during the first cycle) for a total of 8 cycles (1 cyclexa0=xa03xa0weeks), in combination with trastuzumab 6xa0mg/kg on D1 (loading dose: 8xa0mg/kg) every 3xa0weeks or 4xa0mg/kg (loading dose: 6xa0mg/kg) weekly. Response was evaluated every 2xa0cycles using RECIST 1.0. Primary endpoint: objective response rate (ORR); secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsIn the full population (nxa0=xa026), median age was 50.7xa0years and median WHO PS 0. Median disease-free interval was 50.7xa0months [95xa0% CI (43.6–57.9)]. In the evaluable patients population, ORR was 56xa0% [95xa0% CI (34.9–75.6)], including 3 complete responses (12xa0%) and 11 partial (44xa0%); 8 (32xa0%) patients had stable disease resulting in a clinical benefit (or disease control) rate of 88xa0% [95xa0% CI (68.8–97.5)]. Median DOR was 7.1xa0months [95xa0% CI (3.9–10.2)], median PFS 6.7xa0months (95xa0% CI 3.5–10), and median OS 27.9xa0months (95xa0% CI 17.4–38.3). Treatment was generally well tolerated with main observed grade 3/4 hematological toxicities being neutropenia (46xa0%) and anemia (4xa0%). Grade 3–4 nausea–vomiting were observed in 11.5xa0% of patients.ConclusionsOur results confirm the efficacy of oral vinorelbine–trastuzumab combination as a first-line treatment in HER2-positive locally advanced or MBC patients with an acceptable safety profile. Oral vinorelbine–trastuzumab optimizes the convenience of this chemotherapy regimen, especially for patients receiving trastuzumab every 3xa0weeks.

Oral vinorelbine plus cisplatin followed by maintenance oral vinorelbine as first-line treatment for advanced non-small cell lung cancer

AbstractPurposeVinorelbine plus cisplatin is a commonly used doublet for the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy of oral vinorelbine as maintenance therapy in advanced NSCLC.nMethodsThis multicenter phase II open-label, non-comparative study was designed to evaluate the three-weekly combination of cisplatin 80xa0mg/m2 on day 1 in combination with oral vinorelbine on day 1 and 8 in advanced NSCLC.ResultsThirty-nine patients were enrolled; median age was 63xa0years (range 42–82). In the response-evaluable population (nxa0=xa038), objective response after induction therapy was observed in 18 (47xa0%) patients with two (5xa0%) patients achieving complete response. Stable disease was observed in nine (24xa0%) patients. The median duration of response was 6xa0months. Eighteen (46xa0%) patients received oral vinorelbine as maintenance therapy. The median PFS for the whole population and for the maintenance therapy group was 4.9 [95xa0% CI (2.8–6.9)] and 6.7 [95xa0% CI (3.7–9.7)] months, respectively, while the overall survival was 8.7 [95xa0% CI (5.4–11.9)] and 11 [95xa0% CI (8.3–13.7)] months, respectively. The main observed overall hematologic toxicities were grade 3 anemia (8xa0%) and grade 3/4 neutropenia (8xa0%).ConclusionMaintenance therapy with single-agent oral vinorelbine is feasible and well tolerated; it seems to extend the efficacy of the combination regimen with the advantage of being convenient to patients.

Characteristics of Gastric Cancer in Lebanon: a Descriptive Study from a Single Institutional Experience

BackgroundThe epidemiology of gastric cancer in the Middle East has never been described. Therefore, the characteristics of gastric cancer in the Lebanese population will be reported in this study.Patients and MethodsA retrospective study that included all patients diagnosed with gastric cancer at Hotel Dieu de France University Hospital in Beirut, Lebanon between 2010 and 2016 was conducted. All eligible patients were reviewed for demographic and epidemiologic analysis.ResultsThe study included 123 patients diagnosed with gastric cancer. The median age at diagnosis was 59xa0years (range 15–72xa0years), and the median ECOG performance status was 2 (range 1–4). Most patients were metastatic at diagnosis (52.8%), and diffuse pathology type was predominant (39%). HER2 was positive in 16.2% and correlated with the occurrence of hepatic metastasis (pxa0=xa00.048). The HER2 status did not differ significantly between the histological subtypes, the site of the tumor, the stage of the gastric cancer at diagnosis, and the recurrence of cancer (pxa0>xa00.05).ConclusionGastric cancer in the Lebanese population is characterized by aggressive features such as advanced stage at diagnosis, high prevalence of diffuse type histology, and HER2 positivity.

The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review

Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords biosimilars, market, and regulatory. In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the pharmerging economies.nnnIMPLICATIONS FOR PRACTICEnThis article highlights the importance of biosimilars, as a cost-cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost.