Second-line Treatments of Advanced Hepatocellular Carcinoma: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) constitutes the second leading cause of cancer-related deaths. First-line therapy is either sorafenib or lenvatinib. Several treatment options have been recently added to the second-line treatment of advanced HCC. The aim of this network meta-analysis of randomized controlled trials was to compare the second-line treatments of advanced HCC. METHODS: Network meta-analyses were computed for overall survival (OS), progression-free survival, rates of grade 3 to 5 adverse events, and for treatment discontinuation due to adverse events. OS was considered to be the primary outcome of this study, and everolimus was chosen to be the common comparator for efficacy analyses and placebo for safety analyses. Subgroup analyses were computed for OS in patients with hepatitis B, patients with hepatitis C, Asian patients, patients with macrovascular invasion, and patients with extrahepatic metastases. RESULTS: Thirteen randomized controlled trials including 5076 patients and evaluating 11 agents were found to be eligible. Regorafenib [hazard ratio (HR)=0.60, 95% confidence interval (CI)=0.44-0.81] and cabozantinib (HR=0.72, 95% CI=0.55-0.95) were found to significantly prolong OS compared with everolimus. The effect of regorafenib on OS tended to be conserved across patient subgroups. Regorafenib was also found to significantly prolong progression-free survival (HR=0.46, 95% CI=0.35-0.62) and significantly increase the rates of grade 3 to 5 adverse events (odds ratios=3.18, 95% CI=2.22-4.54) and treatment discontinuation due to adverse events (odds ratios=2.67, 95% CI=1.21-5.87). CONCLUSIONS: This network meta-analysis concludes that, based on current evidence, regorafenib could be the agent of choice in the second-line treatment of HCC, with cabozantinib as a possible alternative for sorafenib-intolerant patients.

Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials.

INTRODUCTION: There is a lack of studies on the optimal anti-tumor necrosis factor (anti-TNF) agent for postoperative prophylaxis of Crohn's disease (CD) recurrence. Therefore, we conducted a network meta-analysis (NMA) of prospective trials to compare the efficacy of anti-TNF agents in the prevention of postoperative endoscopic and clinical recurrence of CD following ileocolonic resection. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and recent American gastroenterology association (AGA) meeting abstracts through August 2017. We selected prospective studies comparing anti-TNF agents among each other or to other agents in the setting of postoperative prevention of CD recurrence. We performed a NMA using a frequentist approach with generalized pairwise modeling and inverse variance heterogeneity method. RESULTS: We identified 9 studies, including 571 patients and 5 treatment agents, among which 2 anti-TNF drugs (adalimumab and infliximab). Compared with infliximab, our NMA yielded the following results for endoscopic recurrence: adalimumab [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.18-4.75], thiopurines (OR, 4.11; 95% CI, 0.68-24.78), placebo (OR, 4.39; 95% CI, 0.70-27.68), and Mesalamine (OR, 37.84; 95% CI, 3.77-379.42). For clinical recurrence: adalimumab (OR, 1.03; 95% CI, 0.17-6.03), thiopurines (OR, 1.40; 95% CI, 0.20-10.02), placebo (OR, 1.77; 95% CI, 1.01-3.10), and mesalamine (OR, 16.54; 95% CI, 1.55-176.24). CONCLUSIONS: On the basis of a NMA combining direct and indirect evidence either adalimumab or infliximab may be used in the postoperative prophylaxis of CD recurrence. There is currently a lack of evidence on the use of other anti-TNF agents in this setting.

Comparison of second-line treatments of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

AIM: The literature lacks direct evidence comparing the different regimens evaluated in the second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: We conducted a network meta-analysis (NMA) of the randomized controlled Phase III trials reporting on the second-line drug treatment options in R/M SCCHN. RESULTS: The eligible trials included 11 regimens among which six targeted therapies, two immune checkpoint inhibitors and three chemotherapy regimens. Only nivolumab has shown statistically significant superiority over methotrexate in terms of overall survival (HR: 0.64; 95% CI: 0.43-0.96) and objective response rate (OR: 2.51; 95% CI: 1.07-5.86). CONCLUSION: Based on the efficacy and safety outcomes of this network meta-analysis, nivolumab seems the most favorable regimen inthe management of R/M SCCHN.

Lung cancer and immunotherapy: a real-life experience from second line and beyond.

Aim: This study assessed the efficacy of anti-PD-1/PD-L1 agents in real life when used in second line or beyond. Materials & methods: Patients with advanced non-small-cell lung cancer progressing after standard chemotherapy and receiving immunotherapy in the second line or beyond were included. Results: One hundred and ten patients were included with PD-L1 expression above 50%, between 1-49 and <1% in 38.6, 27.3 and 34.1% of patients, respectively. Checkpoint inhibitors were used as second, third and fourth line in 74.7, 21.8 and 3.5%, respectively. Partial response was observed in 25.6% of patients. Median progression-free survival was 4 months and median overall survival was 8.1 months. Conclusion: Immunotherapies are emerging as important tools in the oncologic field with good responses in real-life practice.

Factors associated with the time to first palliative care consultation in Lebanese cancer patients.

INTRODUCTION: Early palliative care is recommended for cancer patients. However, palliative care consults (PCC) are often delayed in Lebanon. The aim of this study was to identify the factors associated with timing of PCC and their impact on the place of death. METHODS: This is a retrospective, single institution, study conducted at Hotel Dieu de France University Hospital in Lebanon. The clinical and demographic characteristics of oncology patients who received PCC were obtained. Cox and logistic regression models were used to evaluate the factors determining the time to first PCC and location of death, respectively. RESULTS: Two hundred and ten patients were included in our analyses with a median age of 69 years (range 22-92 years). The median survival times were: overall survival 18.7 months, time to first PCC 17.9 months, and survival post-PCC 0.6 months. Among patients who were followed-up at home, the median time spent at home was 0.6 months. Late PCC were associated with a childless status (HR = 0.57, 95%CI = 0.37-0.86, p = 0.007), awareness of the diagnosis (HR = 0.64, 95%CI = 0.45-0.91, p = 0.013), and lack of palliative home care (HR = 0.42, 95%CI = 0.25-0.65, p < 0.001). Older patients (OR = 1.03, 95%CI = 1.01-1.05, p = 0.026) and those who had been followed up at home during the PCC (OR = 160.56, 95%CI = 21.39-1205.50, p < 0.001) were significantly more likely to have died at home as opposed to the hospital. DISCUSSION: Cancer patients often receive PCC only shortly before their death. PCC for Lebanese cancer patients were found to be significantly delayed in patients that are childless, knowledgeable of their diagnosis, and lack home palliative care.

Different inhibitors for the same target in metastatic luminal breast cancer: is there any difference?

AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication. CONCLUSION: In the absence of direct comparative evidence, the results of this network meta-analysis represent the best available evidence for decision making in the first-line treatment of metastatic luminal breast cancer.

Evaluation of chronic kidney disease in cancer patients: is there a preferred estimation formula?

BACKGROUND: The evaluation of chronic kidney disease (CKD) in cancer patients seems to rely mostly on the Cockcroft-Gault (CG) formula or the creatinine levels to adjust treatment dosages which is a practice refuted by internists. AIMS: We evaluate the overall agreement of the CG, modification of diet in renal disease (MDRD) and CKD-epidemiology collaboration equations (CKD-EPI) equation with the newly devised Janowitz and Williams' (JW) equation. METHODS: The renal function was estimated in 235 cancer patients according to the CG, MDRD, body surface area (BSA)-adjusted MDRD, CKD-EPI, BSA-adjusted CKD-EPI and JW formulae. RESULTS: JW equation was more in agreement with CG and CKD-EPI estimations than the other equations. Taking JW equation as reference, receiver operating characteristic curve analysis showed that CG eGFR had the higher area under the curve when compared with other equations. Hierarchical cluster analysis showed more proximity between CG and JW equations than the other equations. CONCLUSION: The newly proposed JW eGFR estimation was more in agreement with CG equation than the other equations.

Response of an ovarian granulosa cell tumor with everolimus and exemestane after initial response to letrozole.

Granulosa cell tumors of the ovaries (GCTO), the most common sex cord tumors of the female genitalia, are characterized by a remarkably favorable prognosis but tend to recur even after several years of follow-up. Standard approach to manage these relapsing tumors is almost inexistent and physicians' choice is most commonly based on his/her personal expertise. Recently, the use of hormone therapy in GCTO has induced prolonged response and survival. In this case report, we report the first successful use of everolimus in the combination of exemestane to reverse the resistance to hormonal therapy with letrozole in a 53-year-old woman with GCTO.

The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?

AIM: To determine whether abiraterone acetate or docetaxel should be regarded as the current standard of care for metastatic hormone-naive prostate cancer (mHNPC). METHODS & MATERIALS: A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The results of this NMA favored abiraterone acetate over docetaxel-based regimens (hazard ratio: 0.79; 95% CI: 0.64-0.99) in patients with mHNPC. The results also suggest a reconsideration of the role of prednisone in view of the absence of a survival benefit (hazard ratio: 0.98; 95% CI: 0.59-1.65) with its use. CONCLUSION: Despite the paucity of direct comparative evidence, the results of this NMA favor the use of abiraterone acetate in the first-line treatment of mHNPC.

Network meta-analysis of second-line treatment in metastatic renal cell carcinoma: efficacy and safety.

This paper aims to compare the approved second-line treatment options in metastatic renal cell carcinoma. A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed for the approved drugs in this setting. The results of this NMA showed that the combination of lenvatinib and everolimus yielded the lowest hazard ratio (HR) for progression-free survival (HR: 0.4; 95% CI: 0.21-0.75) and overall survival (HR: 0.55; 95% CI: 0.30-1.00). The great efficacy of this combination is limited by the prevalence of grade 3-4 adverse events (70.6%) leading to treatment discontinuation in 17.6%. This NMA is to the best of our knowledge, the first analysis of the approved regimens for the second-line treatment of metastatic renal cell carcinoma.

The role of palliative care in the last month of life in elderly cancer patients.

INTRODUCTION: One major health care issue encountered in elderly cancer patients is the alteration of the quality of life. The purpose of our study is to evaluate the administration of chemotherapy in the last month of life (CLML) and to evaluate the impact of the palliative care consult (PCC) in the elderly patients. METHODS: We conducted a retrospective observational study that included elderly patients diagnosed with an end-stage cancer and who were deceased between the 1st of January 2012 and the 31st of December 2015. Patient medical records were reviewed for patients' characteristics and management during the last month of life. RESULTS: This study enrolled 231 patients that fulfilled the eligibility criteria. CLML was administered in 91 patients (39.4 %) among which 43 patients (47.3 %) had their treatment within the last 2 weeks of life. Seventy-seven patients (33.3 %) had a palliative care consult (PCC) with a median duration of follow up of 13 days (range 2-56 days). Overall, PCC failed to decrease CLML administration, the duration of hospitalization, and ICU admissions. However, CLML administration decreased by 69 % among patients that had their PCC before receiving treatment (OR = 0.31; 95 % CI 0.15-0.63). PCC also led to a change in the pattern of treatment administered in the last month of life with less cytotoxic therapy (OR = 0.27 CI 95 % 0.09-0.9, p = 0.02) and higher rates of oral agents being prescribed (OR = 3.8; 95 % CI 1.3-11.3, p = 0.014). CONCLUSION: Our elderly patients seem to receive aggressive management similar to the general oncology population. Early PCC was shown throughout our results to decrease the aggressiveness of cancer treatment in elderly patients which seems to improve the quality of care of our patients.

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

Background 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 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg 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 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. 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 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). 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.

Prediction of preterm delivery by second trimester inflammatory biomarkers in the amniotic fluid.

OBJECTIVE: To search for a correlation between mid-pregnancy altered levels of inflammatory markers and preterm delivery. METHODS: A prospective cohort series included 39 patients undergoing amniocentesis one additional milliliter of amniotic fluid (AF) was stored for later dosage of interleukin-6 (Il-6), matrix metalloproteinase-9 (MMP-9), glucose and C-reactive protein (CRP). Maternal serum CRP and glucose levels were also obtained. Exclusion criteria were multiple pregnancies, chorioamnionitis, group B streptococcus colonization, bacterial vaginosis and cases with proven aneuploidy. We searched for correlation between AF and plasmatic markers and also for a difference between patients with term and preterm delivery. RESULTS: 33 participants were eligible and one third had preterm delivery. Levels of the plasmatic biomarkers did not correlate with the AF biomarkers except for plasmatic glucose and AF IL-6 levels (r=0.350; p=0.016). The levels of all AF biomarkers did not differ significantly between the pre-term and the term groups (p>0.05). The optimal screening cutoffs for identifying pregnancies at risk were different than the ones initially indicated. CONCLUSION: Mid-pregnancy amniotic fluid biomarker levels do not correlate with preterm delivery. Plasma CRP is not correlated with these markers. Cutoff levels suggested are sparse and heterogeneous. Larger studies are needed before advising routine measurement of these markers.

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

PURPOSE: The 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. METHODS: We 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. RESULTS: Among the 130 cancer patients who were enrolled, CLML was administered to a total of 55 patients (42.3 %), of whom 26 patients (50 %) received more than one cytotoxic drug. Oral drug was only given to 9 patients (16.4 %). Interestingly, CLML increased the risk of death in the last month of life (p = 0.02), yet progression of disease constituted the major cause of death in this subgroup (54.6 %). The only variable to have statistical significant correlation with CLML was performance status (p = 0.03). The type of tumor and recent diagnosis of less than 2 months were also correlated to CLML (p = 0.03 and 0.024, respectively). CONCLUSION: The 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.

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.