Prognostic factors for regorafenib treatment in patients with refractory metastatic colorectal cancer: A real-life retrospective multi-center study

Regorafenib, an oral multikinase inhibitor, has improved survival in metastatic colorectal cancer (mCRC) patients who have progressed on standard therapies. Our study aimed to evaluate prognostic factors influencing regorafenib treatment and assess the optimal dosing regimen in a real-life setting. We retrospectively analysed 263 patients with mCRC from multiple medical oncology clinics in Turkey. Treatment responses and prognostic factors for survival were evaluated using univariate and multivariate analysis. Of the patients, 120 were male, and 143 were female; 28.9% of tumors were located in the rectum. RAS mutations were present in 3.0% of tumors, while BRAF, K-RAS, and N-RAS mutations were found in 3.0%, 29.7%, and 25.9% of tumor tissues, respectively. Dose escalation was preferred in 105 (39.9%) patients. The median treatment duration was 3.0 months, with an objective response rate (ORR) of 4.9%. Grade ≥ 3 treatment-related toxicity occurred in 133 patients, leading to discontinuation, interruption, and modification rates of 50.6%, 43.7%, and 79.0%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.0 and 8.1 months, respectively. RAS/RAF mutation (hazard ratio [HR] 1.5, 95% confidence interval [CI] 1.1-2.3; P = 0.01), pretreatment carcinoembryonic antigen (CEA) levels (HR 1.6, 95% CI 1.1-2.3; P = 0.008), and toxicity-related treatment interruption or dose adjustment (HR 1.6, 95% CI 1.1-2.4; P = 0.01) were identified as independent prognostic factors for PFS. Dose escalation had no significant effect on PFS but was associated with improved OS (P < 0.001). Independent prognostic factors for OS were the initial TNM stage (HR 1.3, 95% CI 1.0-1.9; P = 0.04) and dose interruption/adjustment (HR 0.4, 95% CI 0.2-0.9; P = 0.03). Our findings demonstrate the efficacy and safety of regorafenib. Treatment line influences the response, with dose escalation being more favorable than adjustment or interruption, thus impacting survival

Hepatitis C Virus Reactivation In Cancer Patients In The Era Of Targeted Therapies

The purpose of this review is to summarize the evidence of hepatitis C reactivation in cancer patients in the era of targeted therapies. Targeted therapies are novel therapeutics frequently used in cancer patients. During treatment with targeted therapies, viral replication is one of the major problems that can occur. The PubMed database, ASCO, and ASCO Gastrointestinal Cancer Symposium abstracts were searched up until September 15, 2013 using the following search keywords: "targeted therapies, rituximab, alemtuzumab, brentuximab, hepatitis, hepatitis C reactivation, tyrosine kinase inhibitors, imatinib, mammalian target of rapamycin (mTOR) inhibitors, everolimus, anti-HER therapies, trastuzumab, pertuzumab, lapatinib, anti-epidermal growth factor receptor therapies, cetuximab, panitumumab, and ipilimumab". Papers considered relevant for the aim of this review were selected by the authors. The data about rituximab-induced hepatic flare in hepatitis C virus (HCV) positive patients is controversial. However, there is the possibility of life-threatening hepatic flare that can develop after HCV ribonucleic acid (HCV-RNA) viral load increases. Routine follow-up of liver function tests should be advised. Especially in high-risk patients, such as those with baseline chronic active hepatitis and cirrhosis, and where there are plans to administer rituximab concomitantly with corticosteroids, it is advised to have close follow-up of HCV viral load. The data is insufficient to make accurate statements about the association of alemtuzumab therapy and HCV reactivation. However, alemtuzumab may cause deep immunosuppression. Due to this, it is better to follow up with liver function tests and HCV RNA levels during alemtuzumab therapy. Brentuximab has effects on antibody dependent cellular toxicity and may decrease humoral immunity. Thus, we believe that during brentuximab treatment of HCV infected patients, clinicians may encounter hepatitis C reactivation. There have been no reported cases of hepatitis C reactivation with imatinib therapy. However, there are many reports of hepatitis B reactivation with imatinib treatment. Based on the evidence of hepatitis B reactivation with imatinib and the effects of imatinib on immune system functions, we suggest that imatinib therapy might be a risk factor for HCV reactivation. Anti-human epidermal growth factor receptor 2 therapies are not associated with hepatic flare in HCV infected patients. Post-transplant studies reported that mTOR was safely administered to patients with active hepatitis C without causing hepatic flare. Cetuximab and panitumumab have not been associated with HCV reactivation. Two cases of HCV infected melanoma were safely treated with ipilimumab without any HCV reactivation or hepatic flare. Targeted therapies are a new and emerging area of oncology treatment modalities. While treating HCV infected cancer patients, clinicians should be mindful of the immunosuppressive properties of targeted therapies. Further randomized trials are needed to establish algorithms for this issue. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.WoSScopu

Impact Of Acetylsalicylic Acid On The Clinicopathological Characteristics And Prognosis Of Patients With Invasive Breast Cancer

Background: The impact of acetylsalicylic acid (ASA) on the clinicopathological characteristics of breast cancer has not yet been elucidated in detail; we therefore aimed to investigate the effects of ASA on the clinicopathological characteristics of patients with breast cancer. Patients and Methods: Patients diagnosed with breast cancer were retrospectively analyzed. Breast cancer patients who were taking ASA at the time of breast cancer diagnosis were enrolled as ASA users (n = 84); matching patients with the same age who were not taking ASA were included as control group (n = 890). Results: The median age was 56 (range 34-82) years in both groups. ASA users had a significantly lower incidence of grade II-III tumors compared to non-users (P = 0.02). The other clinicopathological characteristics and treatment histories were similar in both groups. In patients using ASA, the disease-free survival (DES) rate was 97.3%, 89.4%, and 79.9% and in non-users it was 94.1%, 81.8%, and 70.9% in the 1rst, 3rd, and 5th year, respectively (P = 0.01). In aspirin users, the overall survival rate was 95.0%, 90.6%, and 87.6% and in non-users it was 98.1%, 91.2%, and 85.5% in the 1rst, 3rd, and 5th year, respectively (P = 0.50). Conclusion: Using ASA at the time of breast cancer diagnosis was associated with significantly improved DES in breast cancer patients.WoSScopu

The real-life efficacy and safety of osimertinib in pretreated advanced non-small cell lung cancer patients with T790M mutation: a Turkish Oncology Group Study

Introduction Osimertinib, an irreversible third-generation EGFR-TKI, is the standard of care for second-line treatment of T790M-mutant advanced NSCLC patients whose disease progressed after first-line EGFR-TKI therapy. In this multicenter study, we aimed to determine the real-life efficacy and safety of Osimertinib in pretreated advanced NSCLC patients with T790M mutation. Materials and methods This retrospective trial included advanced T790M-mutant pretreated NSCLC patients who received Osimertinib from 24 different centers in Turkey. Primary endpoint was time-to-treatment discontinuation (TTD). Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. Results Of 163 patients, 68.7% had EGFR exon 19 deletion and 22.7% had exon 21 L858R mutation. Osimertinib was given as second-line treatment in 96 patients (58.9%) and third-line in 48 patients (29.4%). After median of 13-month follow-up, median TTD was 21.6 months with an 82.2% ORR. Estimated median OS was 32.1 months. Grade 3-4 adverse events were seen in 11.7% of the patients. Conclusion Osimertinib is a highly effective option in second- or third-line treatment of NSCLC patients with T790M mutation, with a favorable safety profile

Comparison of responses to neoadjuvant and adjuvant chemotherapies in muscle-invasive bladder cancer

Abstract Background Bladder cancer surgery is critical for treatment, and systemic treatment before or after cystectomy may be necessary. We aimed to investigate the efficacy and response to neoadjuvant and adjuvant treatments. Methods Data on 93 patients with resectable muscle-invasive bladder cancer were analyzed retrospectively. Patients who received neoadjuvant and adjuvant chemotherapies were included. The neoadjuvant treatment group was divided into pathological responders and non-responders. Overall survival and disease-free survival were calculated. Results The median age was 61.5 years; there were 6 female and 87 male patients. Baseline characteristics were similar between the groups. While there was no difference in OS between the neoadjuvant and adjuvant treatment groups (20 months vs. not reached), DFS was significantly higher in the adjuvant group (20.6 vs. 25.3 months). While there was no significant difference in DFS between the responders and non-responders to neoadjuvant treatment (20.6 vs. 19.1 months), OS was significantly longer in the responders (Not reached vs. 12.3 months). Conclusions Our results concluded that neoadjuvant and adjuvant chemotherapies have similar survival rates, but no response was associated with poor outcomes. Determining the group for patient selection may be helpful for optimal management

Evaluation of Prognostic Factors and Adjuvant Chemotherapy in Patients With Small Bowel Adenocarcinoma Who Underwent Curative Resection

This is a multicenter study to assess the prognostic factors and adjuvant chemotherapy in patients with small bowel adenocarcinoma (SBA). A total of 78 patients with SBA diagnosed with completely resected SBA were involved in the study. Only status of surgical margin was determined to be an independent prognostic factor in patients with SBA who underwent curative resection. Neither disease-free survival nor overall survival was found to be significantly improved by the adjuvant chemotherapy Background: Small bowel adenocarcinoma (SBA) is a rare tumor of the gastrointestinal system with poor prognosis. Because these are rarely encountered tumors, the aim of this multicenter study was evaluation of prognostic factors and adjuvant chemotherapy in patients with curatively resected SBA. Materials and Methods: A total of 78 patients diagnosed with curatively resected SBA were involved in the retrospective study. Forty-eight patients received 1 of 3 different chemotherapy regimens, whereas 30 patients did not receive any adjuvant treatment. No adjuvant and adjuvant chemotherapy cohorts were matched (1: 1) by propensity scores based on the likelihood of receiving chemotherapy or the survival hazard from Cox modeling. Overall survival (OS) was compared with Kaplan-Meier estimates. Results: Median age of 78 patients with curatively resected SBA was 58, and 59% of these were men. According to TNM classification, 8 (10%) of the patients were at stage I, 26 (34%) were at stage II, and 44 (56%) were at stage III. Median follow-up duration was 29 months. Three-year median disease-free survival (DFS) and OS were 62.5% and 67.0%, respectively. In univariate analysis, presence of vascular invasion, perineural invasion, lymph node involvement, and presence of positive surgical margin were significant predictors of poor survival. Multivariate analysis showed that the only adverse prognostic factor independently related with OS was the presence of positive surgical margin (hazard ratio, 0.37; 95% confidence interval, 0.11-1.26; P = .01). Neither DFS nor OS was found to be significantly improved by the adjuvant chemotherapy in both matched and unmatched cohorts. Conclusions: Only status of surgical margin was determined to be an independent prognostic factor in patients with SBA who underwent curative resection

Prognostic significance of the programmed death ligand 1 expression in clear cell renal cell carcinoma and correlation with the tumor microenvironment and hypoxia-inducible factor expression

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most common renal malignancy. Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of ccRCC. Targeting immune checkpoints with the blockade of PD-1 and its ligand PD-L1 reorganizes T-cell activity in tumor microenvironment and provides important antitumor responses. PD-L1 upregulation has been found to be hypoxia-inducible factor (HIF) dependent. Our aim is to demonstrate the association between PD-L1 and HIF expression and to reveal the role of PD-L1 in prognosis and its association with tumor microenvironment. Methods Surgical specimens from 145 patients diagnosed with ccRCC, who had undergone radical or partial nephrectomy, were retrospectively analyzed. Immunohistochemistry on tissue microarrays (TMA) was performed to demonstrate expressions of PD-L1, HIF-1α, and HIF-2α in tumor cells and PD-1, CD4, and CD8 in lymphocytes to assess lymphocyte density in tumor microenvironment. Results PD-L1 tumor cell expression was detected in 20/125 (13.8%) cases, which correlated with higher levels of PD-1, CD4, CD8 and HIF-2α expression. Low or high expression of HIF-1α was similar in PD-L1-positive cases. When PD-L1-positive cases were compared with negative ones, there was no significant difference in terms of prognostic factors. However, the number of WHO/ISUP grade 3–4 tumors was significantly higher in PD-L1-positive cases than in negative ones. Conclusion PD-L1 tumor cell expression is strongly associated with increased HIF-2α expression and presence of dense lymphocytic infiltration in ccRCCs. Our findings confirm that PD-L1 positivity is associated with high ISUP nucleolar grade. The association between PD-L1, HIF, and lymphocyte density in tumor microenvironment must be clarified and especially taken into account in combination treatment

Evaluation Of Renal Function Using The Level Of Neutrophil Gelatinase-Associated Lipocalin Is Not Predictive Of Nephrotoxicity Associated With Cisplatin-Based Chemotherapy

Background: For early detection of renal damage during the usage of cisplatin based chemotherapy, changes in renal function should be monitored carefully. In recent years, neutrophil gelatinase-associated lipocalin, a small polypeptide molecule, has shown promise as a marker of acute renal failure. The aim of this present study was to assess possible risk prediction of cisplatin-induced nephrotoxicity using serum NGAL. Materials and Methods: A total of 34 consecutive patients with documented serum creatinine at least 24 hours before every cycle of cisplatin-based chemotherapy were included in the study. Demographic and medical data including age, performance status, tumor characteristics and comorbid diseases were collected from medical charts. Renal function was evaluated at least 48 hours before the treatment and at the end of the treatment based on the Modification of Diet in Renal Disease (MDRD) formula. Before and after cisplatin infusion serum NGAL levels were measured for the first and 3rd cycles of chemotherapy. Results: The median age of the study population was 54 (32-70) years. Fifteen patients (41.1%) were treated on an adjuvant basis, whereas 19 patients (58.9%) were treated for metastatic disease. There was no correlation of serum NGAL levels with serum creatinine (r=0.20, p=0.26) and MDRD (r=-0.12, p=0.50) and creatinine clearance-Cockcroft-Gault (r=-0.22, p=0.22) after cisplatin infusion at the end of the 3rd cycle of chemotherapy. Conclusions: In our study, serum NGAL levels were not correlated with the cisplatin induced nephrotoxicity. Further prospective studies are needed to conclude that serum NGAL level is not a good surrogate marker to predict early cisplatin induced nephrotoxicity.WoSScopu