A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer.

In metastatic breast cancer (MBC), the conventional doxorubicin (DOX) has various problems due to lack of selectivity with subsequent therapeutic failure and adverse effects. DOX- induced cardiotoxicity is a major problem that necessitates the presence of new forms to decrease the risk of associated morbidity. Nanoparticles (NPs) are considered an important approach to selectively increase drug accumulation inside tumor cells and thus decreasing the associated side effects. Tumor cells develop resistance to chemotherapeutic agents through multiple mechanisms, one of which is over expression of efflux transporters. Various NPs have been investigated to overcome efflux mediated resistance. To date, only liposomal doxorubicin (LD) and pegylated liposomal doxorubicin (PLD) have entered phase II and III clinical trials and FDA- approved for clinical use in MBC. This review addresses the effects of LD and PLD on the hematological and palmar-plantar erythrodysesthesia (PPE) in anthracycline naïve and pretreated MBC patients. For evidence, studies to be included in this review were identified through PubMed, Cochrane and Google scholar databases. The results derived from: four phase III clinical trials that compared LD with the conventional DOX in naïve MBC patients, and ten non-comparative clinical trials investigated LD and PLD as monotherapy or combination in pretreated MBC. This work confirmed the cardiac tolerability profile of LD and PLD versus DOX, while hematological and skin toxicities were more common. Other DOX-NPs in preclinical trials were discussed in a chronological order. Finally, the modern preclinical development framework for DOX includes exosomal DOX (exo-DOX). Exosomal NPs are non-toxic, non-immunogenic, and can be engineered to have high cargo loading capacity and targeting specificity. These NPs have not been investigated clinically. Our study shows that the full clinical potentiality of DOX-NPs remains to be addressed to move the field forward.

Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study.

BACKGROUND: Despite being chemosensitive, the majority of triple negative breast cancer (TNBC) patients recur. The primary study objectives were to compare disease free survival (DFS), and overall survival (OS) for TNBC after adjuvant chemotherapy, who underwent maintenance metronomic chemotherapy versus no maintenance therapy. METHODS: TNBC patients were eligible for enrolment if they had TNM stages II-III and fit with our inclusion criteria. Patients were assigned to either: group 1, 3 cycles FEC-100 then 3 cycles docetaxel, carboplatin, followed by maintenance metronomic chemotherapy for 1 year; and group 2, 3 cycles FEC-100 then 3 cycles docetaxel. RESULTS: Between November 2008 and December 2014, 158 patients (78 group 1, and 80 group 2) were enrolled. The mean age was 46 years. The median DFS for groups 1,2 were 28 and 24 months, respectively; P value 0.05. The median OS for groups 1,2 were 37 and 29 months, respectively; P values 0.04. Additionally, during the follow-up period, the overall distant metastasis recurrence rates for groups 1,2 were 26% and 37% respectively. Finally, treatment protocol was tolerated well in both groups with mild toxicity profiles. CONCLUSIONS: Extended adjuvant metronomic chemotherapy achieved significant improvement in the survival and was well tolerated.

Risk of selected gastrointestinal toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis.

We performed a systematic review and meta-analysis of the risk of gastrointestinal (GI) toxicities associated with MEK inhibitors. Eligible studies included randomized Phase II and III trials of cancer patients on the three MEK inhibitors (trametinib, selumetinib and cobimetinib), describing events of stomatitis, diarrhea and vomiting. Our search strategy yielded 250 potentially relevant citations from Pubmed/Medline, Google scholar and CENTRAL Cochrane registry. After exclusion of ineligible studies, a total of 16 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade stomatitis, diarrhea and vomiting were 2.03 (95% CI 1.41-2.96; p = 0.002), 1.92 (95% CI 1.48-2.50; p < 0.00001) and 1.35 (95% CI 1.06-1.71; p = 0.01). Subgroup analyses according to agent used (trametinib vs Selumetinib), the regimen used (monotherapy vs combination) and the cancer treated (melanoma vs nonmelanoma) did not reveal any significant difference between the subgroups. Our meta-analysis has demonstrated that MEK inhibitor-based treatment is associated with an increased risk of stomatitis, diarrhea and vomiting compared to control. Clinicians should be aware of this risk and perform regular assessment.

Sorafenib for Egyptian patients with advanced hepatocellular carcinoma; single center experience.

BACKGROUND: According to the results of a number of phase 3 randomized studies, sorafenib is the only approved systemic therapy for advanced HCC; however the issue of high economic cost remains challenging; thus we have conducted this retrospective analysis of our HCC patients treated with sorafenib. METHODS: HCC patients treated at Ain Shams University Hospitals, in the period between 2010 and 2012 were reviewed. Eligible patients were those who had received sorafenib for advanced HCC not eligible for or progressed after surgery or locoregional therapy. We investigated the impact of baseline clinicopathological factors (age, gender, child status, performance score, BCLC tumor stage, cause of chronic liver disease, median baseline alpha fetoprotein level and previous treatment received for HCC) on overall survival (OS) in an adjusted Cox regression model. RESULTS: 41 patients were included in the analysis fulfilling the inclusion criteria. At a median follow up period of 13 months, the median PFS for the whole group was 4 months; the median OS for the whole group is 6.25 months. Multivariate analysis identified three baseline characteristics that were prognostic indicators for overall survival: ECOG performance status (median OS for ECOG 1=7.01 months and for ECOG 2=3.03 months), Child-Pugh status (median OS for child A=12.04 months and for child B=5.23 months), and median baseline levels of alpha-fetoprotein. CONCLUSIONS: In limited resource countries like Egypt, we suggest that the use of sorafenib for the treatment of advanced HCC cases should be restricted to a highly selected subgroup of patients with good performance and child A.

Sorafenib versus capecitabine in the management of advanced hepatocellular carcinoma.

The only approved systemic therapy for patients with advanced hepatocellular carcinoma (HCC) till now is sorafenib. A preliminary study suggested that capecitabine, an oral fluoropyrimidine, may be effective in advanced HCC. We have tested this hypothesis in this phase 2 study. In this single-center, phase 2, open-label trial, we randomly assigned 52 patients with advanced HCC who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or capecitabine (1,000 mg/m(2) twice daily) (day 1-day 14). Primary outcome was progression-free survival. Secondary outcomes included the overall survival and safety. Median overall survival was 7.05 months in the sorafenib group and 5.07 months in the capecitabine group (hazard ratio in the capecitabine group 2.36; 95 % confidence interval 1.174-4.74; P < 0.016). The median progression-free survival was 6 months in the sorafenib group and 4 months in the capecitabine group (P < 0.005). Three patients in the sorafenib group (11.5 %) and one patient in the capecitabine group (3 %) had a partial response; one patient (3 %) had a complete response in the sorafenib group. Hand-foot skin reaction was more frequent in the sorafenib group, hyperbilirubinemia was more common in the capecitabine group, and diarrhea was equivalent between both groups. In patients with advanced HCC, capecitabine is inferior to sorafenib in terms of median progression-free survival and overall survival, and it should not be used alone for the treatment of advanced HCC, but rather, combination therapy with sorafenib should be considered.

An open-label phase I pilot study of continuous intrapleural infusion of escalated doses of methotrexate in malignant pleural mesothelioma.

OBJECTIVES: The aim of this study was to evaluate the toxicity from escalated methotrexate (MTX) doses infused intrapleural over 5 days and to determine pleural and systemic drug levels with this chemotherapeutic approach. PATIENTS AND METHODS: Five patients with malignant pleural mesothelioma were treated with 3 cycles of intrapleural MTX infused through a pigtail catheter inserted in the pleural space. MTX levels were estimated in the pleural fluid and serum once daily throughout the treatment cycles. Fourteen days between cycles were calculated from the last day of the previous one. The total dose for each cycle was infused over 5 days with simultaneous intravenous calcium folinate. The total cycle dose for the first, second, and third cycles were: 300, 501, and 750.5 mg/m, respectively. RESULTS: The mean serum MTX level was 1.72 µmole/L, whereas that of the pleural fluid was 503.224 µmole/L. The mean serum/pleural ratio was 0.00396, whereas the pleural/serum ratio was 396.21. No remarkable toxicity was observed in the 5 patients except for patient 1 who developed fluid leakage around the puncture site. Patient 2 developed grade I hepatotoxicity and both patients developed grade I pleuritic chest pain and dry irritative cough. CONCLUSIONS: This study demonstrates no grade II toxicity from 750.5 mg/m of MTX infused intrapleural over 5 days. This approach allows attaining MTX pleural levels that are 95 to 3000 times higher than systemic serum levels, with minimal toxicity. The results mandate performing this trial on a wider scale as a preliminary step for a formal phase II study.

Liver metastases in Egyptian patients with colorectal cancer: incidence and clinico-pathological predictors.

Carcinoma of the large bowel is the fourth commonest cancer worldwide. The most frequent site for metastasis is the liver. Overall 30% of patients develop liver metastasis during the course of their illness; of these, 23% to 47% are synchronous lesions. These data are based on western studies. No data are published on patients with colorectal cancer from Egypt. We aimed to assess the incidence of colorectal liver metastasis in Egyptian patients and to evaluate the differences in the clinicopathological features and tumor behavior in patients with and without liver metastasis. One hundred forty eight patients were prospectively enrolled in the study. Patients were classified into metastatic group (n=78) and non metastatic group (n=70). In the two groups macroscopic features compared including: tumor size (2 cm, 2-5 cm, and >5 cm), site of primary tumor, side of liver involved, clinical symptoms and liver profile. Carcino-embryonic antigen (CEA) and cancer antigen (CA19.9) levels were recorded. At microscopy, tumor differentiation, invasion and nodal status were evaluated. No difference was found in the distribution of the primary site and size of the tumor. Jaundice, hepatomegaly and ascites were significantly higher in patients with liver metastases. Patients with liver metastasis had higher levels of CEA, CA19.9, higher frequency of vascular invasion and nodal involvement.