Radiofrequency ablation combined with percutaneous ethanol injection for hepatocellular carcinoma: a systematic review and meta-analysis

Background: Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) are important treatments for patients with hepatocellular carcinoma (HCC) who are not eligible for resection and liver transplantation. Therefore, it is important to establish comparisons between RFA, PEI and the two therapies in combination.

Aims: To evaluate the clinical efficacy and safety of combined RFA-PEI versus monotherapy with either RFA or PEI for HCC to provide references for clinical practice and further research.

Methods: We searched all eligible studies published before September 2015 in the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases, such as CBM, CNKI, VIP and WanFang and also retrieved papers from other sources. All relevant controlled trials were collected. Meta-analyses were performed using RevMan version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Results: Thirteen trials with 1621 patients were identified. Compared with PEI, RFA was associated with significant improvement in overall survival (OS) rate at 1, 2, 3 and 4 years, cancer-free survival (CFS) rate at 1, 2 and 3 years and complete tumour necrosis. RFA was associated with a significant reduction in the local recurrence rate at 1, 2 and 3 years. However, RFA was also associated with a higher total risk of complications. Compared with RFA alone, combined RFA-PEI was associated with a significant improvement in the OS rate at 1.5, 2 and 3 years and a significant reduction in the local recurrence rate. However, combined RFA-PEI was also associated with a higher risk of fever.

Conclusion: The combination of RFA and PEI appears to be the optimal treatment strategy when considering combined RFA-PEI or either RFA or PEI alone. Combined RFA-PEI significantly improves OS and reduces the risk of local recurrence without increasing major complications. Further large-scale studies are needed to assess economic outcomes and quality of life.     

Preventing recurrence of diffuse malignant peritoneal mesothelioma

Introduction: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignancy with a poor prognosis when treated with systemic therapy. Cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) is considered the best therapy in DMPM, but a high risk of locoregional recurrence remains.

Areas covered: This review describes patient selection and operative goals with CRS and IPC, the reported outcomes with this approach, and the data supporting platinum-based IPC. We assess the pharmacokinetics supporting the use of dwell IPC. We outline clinical, imaging and laboratory surveillance for recurrence. In addition, we highlight the role of re-operation, both as a planned second procedure and in the context of disease recurrence. Literature review was performed via Medline search.

Expert commentary: CRS/IPC offers survival benefit in selected patients with DMPM, but given the high rate of recurrence, close surveillance is needed post-operatively. Strategies to prevent and treat recurrent disease include dwell IPC and second CRS/IPC.     

Improving postoperative radiotherapy following radical prostatectomy

Introduction: Prostate cancer has one of the highest incidences in the world, with good curative treatment options like radiotherapy and radical prostatectomy. Unfortunately, about 30% of the patients initially treated with curative intent will develop a recurrence and need adjuvant treatment.

Five randomized trials covered the role of postoperative radiotherapy after radical prostatectomy, but there is still a lot of debate about which patients should receive postoperative radiotherapy.

Areas covered: This review will give an overview on the available literature concerning post-operative radiotherapy following radical prostatectomy with an emphasis on the five randomized trials. Also, new imaging techniques like prostate-specific membrane antigen positron emission tomography (PSMA-PET) and multiparametric magnetic resonance imaging (mp-MRI) and the development of biomarkers like genomic classifiers will be discussed in the search for an improved selection of patients who will benefit from postoperative radiotherapy following radical prostatectomy. With new treatment techniques like Intensity Modulated Radiotherapy, toxicity profiles will be kept low.

Expert commentary: Patients with biochemical recurrence following radical prostatectomy with an early rise in prostate-specific antigen (PSA) will benefit most from postoperative radiotherapy. In this way, patients with only high risk pathological features can avoid unnecessary treatment and toxicity, and early intervention in progressing patients would not compromise the outcome.     

Expression analysis of liver-specific circulating microRNAs in HCV-induced hepatocellular Carcinoma in Egyptian patients

Objectives: Due to the absence of reliable and accurate biomarkers for the early detection of liver malignancy, circulating microRNAs have recently emerged as great candidates for prompt cancer identification. Therefore, the aim of this study was to investigate the potential of liver-specific circulating microRNAs as an accurate non-invasive diagnostic tool for early diagnosis of hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC).

Methodology: A total of 165 patients were enrolled in this study and categorized into four main groups: 42 chronic hepatitis C (CHC) without cirrhosis, 45 CHC with cirrhosis (LC), 38 HCC with HCV patients, and 40 healthy controls. The expression profiles of seven miRNAs (miR-16, miR-34a, miR-125a, miR-139, miR-145, miR-199a, and miR-221) were analyzed using real-time PCR.

Results: Serum levels of miRNA-125a, miRNA-139, miRNA-145, and miRNA199a were significantly lower (p < 0.01) in HCC than in both CHC and LC groups. On the other hand, no significant difference was shown in the expression of miR-16, miR-34a, and miR-221 between the CHC, LC, and HCC groups. MiR-16, miR-34a, and miR-221 were significantly elevated in the HCC group compared to the control group. MiR-34a showed the highest specificity and sensitivity.

Conclusions: The results indicated that the measurement of serum levels of miR-125a, miR-139, miR-145, and miR-199a can help to differentiate HCC from CHC and LC. Also, miR-16, miR-34a, and miR-221 serum levels would have a prognostic value. MiR-34a had the highest specificity and sensitivity, indicating that it might serve as a novel and potential non-invasive biomarker for HCV-induced HCC.     

Nivolumab in squamous cell carcinoma of the head and neck

Introduction: The prognosis of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC) after failure of first line chemotherapy is dismal. Until the publication of the results of CheckMate 141, not a single agent provided any survival benefit as a second line treatment for R/M HNSCC.

Areas covered: A comprehensive review of the literature was conducted on the role of nivolumab in HNSCC.

Expert commentary: Nivolumab is approved by the Food and Drug Administration for the treatment of patients based on the results of CheckMate 141 showing an overall survival benefit as compared to standard care (single agent docetaxel, methotrexate, or cetuximab). Of particular interest are immune-related adverse events which should be managed according to published guidelines.     

The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer

Introduction: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). (Avastin; Genetech, Inc, San Francisco, CA) Angiogenesis is blocked by the binding of bevacizumab to VEGF, inhibiting the binding of this ligand to the VEGF receptor. On 14 August 2014 the Food and Drug Administration (FDA) approved use of bevacizumab in persistent, recurrent, or metastatic cervical cancer.

Areas covered: Herein we review pharmacodynamics and kinetics, clinical data and treatment-related toxicities of bevacizumab in the treatment of metastatic, recurrent or persistent cervical cancer. Additionally, future areas of development are reviewed.

Expert commentary: Anti-angiogenesis therapy with bevacizumab is central to metastatic, persistent, and recurrent cervical cancer treatment. Additional anti-angiogenesis drugs are in development. Future studies will need to establish if the addition of multiple anti-angiogenesis agents or anti-angiogenesis in combination with immunotherapy is more effective than bevacizumab with chemotherapy.     

Management Strategies for Recurrent Endometrial Cancer

Introduction: Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence is increasing. Mortality from this cancer has not improved in recent decades and is primarily driven by high-grade carcinomas that are more likely to present at an advanced stage and ultimately are more likely to recur. The prognosis for recurrent endometrial cancer is poor, especially for the 50% of these women that present with extrapelvic disease recurrence. As a standard of care, recurrent disease has been treated with platinum-based chemotherapy; however, new therapies are emerging as we identify drivers of proliferation and metastasis at the cellular and molecular levels.

Areas Covered: We review currently available data for the management of recurrent endometrial cancer, with a focus on systemic treatment of recurrent disease. We discuss the available evidence for first-line, second-line, and subsequent systemic therapy and discuss emerging therapeutic targets including their biologic plausibility and early clinical data.

Expert Commentary: Endometrial cancer, though prevalent, remains underfunded and understudied. Recurrent and metastatic disease remains difficult to treat, and prospective randomized data are limited. Our ability to reduce mortality due to this cancer is dependent on identifying new and effective therapeutic strategies for recurrent disease.     

Screening and surveillance for hepatocellular carcinoma: perspective of a new era?

Introduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death with an increasing prevalence worldwide. Early diagnosis of HCC is important since observational studies have reported that, in patients undergoing surveillance, cancer is diagnosed at an earlier stage with increased chances of curative therapies. Anyway, despite the extensive use of screening for HCC, its effectiveness is still a controversial topic since supporting evidence is not unequivocal and some issues need to be explored.

Areas covered: The aim of this paper is to review main literature data supporting performance and effectiveness of screening for early detection of hepatocellular carcinoma.

Expert commentary: Clinical benefit of screening for HCC is controversial and there are no sufficient data supporting its effectiveness in reducing cancer specific mortality. Since it is unlikely that RCTs will be performed in the future, surveillance should be still reasonably recommended in all at-risk population, until potential data against its effectiveness will be provided. In the future additional and more effective non-invasive tests will be needed, as well as proper surveillance intervals and risk threshold for surveillance enrollment must be assessed and refined by prospective studies.     

Prognostic value of the combination of serum levels of vascular endothelial growth factor,C-reactive protein and contrast-enhanced ultrasound in patients with primary liver cancer who underwent transcatheter arterial chemoembolization

Background: This study aimed to evaluate the prognostic value of the combination of serum levels of vascular endothelial growth factor (VEGF), C-reactive protein (CRP), and contrast-enhanced ultrasound (CEUS) in patients with primary liver cancer (PLC) after transcatheter arterial chemoembolization (TACE).

Methods: Overall, 287 PLC patients who had undergone TACE were allocated into recurrence and non-recurrence groups. One day before and seven days after TACE, CEUS was performed, and serum VEGF and CRP levels were determined. All patients were assigned into either a short time-to-radiologic progression (TTRP) group (TTRP ≤ 12 months) or a long TTRP group (TTRP > 12 months).

Results: Serum VEGF and CRP levels were higher in the recurrence group than the non-recurrence group after TACE. The sensitivity and specificity of CEUS parameters, serum VEGF and CRP levels, and the three combined, were utilized for the purposes of predicting the postoperative recurrences of PLC, which were 80.9% and 87.8%, 81.7% and 71.5%, 67.0% and 69.8%, and 87.8% and 90.1%, respectively.

Conclusion: This study demonstrated that high serum levels of both VEGF and CRP in addition to a low time-to-peak (TTP) value in CEUS were indicators for poor prognosis in PLC patients.     

Optimizing treatment in recurrent epithelial ovarian cancer

Introduction: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients’ ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex.

Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC.

Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.     

Angiogenesis inhibitors in tackling recurrent glioblastoma

Introduction: Despite aggressive multimodality treatment of glioblastoma, outcome remains poor and patients mostly die of local recurrences. Besides reoperation and occasionally reirradiation, systemic treatment of recurrent glioblastoma consists of alkylating chemotherapy (lomustine, temozolomide), bevacizumab and combinations thereof. Unfortunately, antiangiogenic agents failed to improve survival either as a monotherapy or in combination treatments. This review provides current insights into tumor-derived escape mechanisms and other areas of treatment failure of antiangiogenic agents in glioblastoma.

Areas covered: We summarize the current literature on antiangiogenic agents in the treatment of glioblastoma, with a focus on recurrent disease. A literature search was performed using the terms ‘glioblastoma’, ‘bevacizumab’, ‘antiangiogenic’, ‘angiogenesis’, ‘resistance’, ‘radiotherapy’, ‘chemotherapy’ and derivations thereof.

Expert commentary: New insights in glioma neoangiogenesis, increasing understanding of vascular pathway escape mechanisms, and upcoming immunotherapy approaches might revitalize the therapeutic potential of antiangiogenic agents against glioblastoma, although with a different treatment intention. The combination of antiangiogenic approaches with or without radiotherapy might still hold promise to complement the therapeutic armamentarium of fighting glioblastoma.     

Therapeutic strategies for organ-confined and non-organ-confined bladder cancer after radical cystectomy

Introduction: In patients with muscle invasive or Bacillus Calmette-Guérin refractory urothelial carcinoma of the urinary bladder (UCUB) radical cystectomy represents the standard of care. However, a proportion of patients experience disease progression, local recurrence and/or metastatic disease.

Areas covered: This review provides an overview of available therapeutic strategies after radical cystectomy and examines ongoing clinical trials including cytotoxic chemotherapy and immunotherapy.

Expert commentary: Cytotoxic chemotherapy offers limited benefit in UCUB patients. However, the recent introduction of immunotherapy provides new hope for durable responses or possibly complete cures.     

Trabectedin for sarcomas in daily clinical practice: analysis of 45 patients treated in a French institution

Introduction: The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials.

Patients and Methods: We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies.

Results: Forty-five patients received trabectedin between January 2005 and May 2014. Sarcomas were histologically heterogeneous in our cohort (37.9% of other types of sarcomas than L-sarcomas). Our patients had poor baseline health status (ECOG ≥ 2 [17.8%]) and had received multiple previous lines of chemotherapy. Patients received a median of five cycles of treatment (1–22). The objective response rate was statistically superior in our study (37.8%) compared to the other works. However, median PFS was similar. Trabectedin-related serious adverse events (AEs) induced hospitalizations and treatment discontinuation in 22 and 15% of patients.

Conclusion: This analysis confirms the efficacy of trabectedin in clinical practice (with a third of patients experiencing prolonged disease control) and highlighted the importance of its administration as early line therapy to allow the best management of serious AEs.     

Lenvatinib as a therapy for unresectable hepatocellular carcinoma

Introduction: Since 2007 Sorafenib has represented the only approved drug for first-line treatment of advanced hepatocellular carcinoma (HCC). Lenvatinib, an orally active inhibitor of multiple receptor tyrosine kinases (VEGFR 1–3, FGFR 1–4, PDGFRa, RET and KIT), showed preclinical and clinical activity in the treatment of solid tumors, including HCC.

Areas covered: In this review, we summarize the current therapeutic paradigm for the systemic treatment of advanced HCC, focusing on Lenvatinib pre-clinical and clinical development. Keywords ‘Lenvatinib’, ‘ Target therapy’, ‘REFLECT trial’, ‘Hepatocellular carcinoma’, ‘HCC’, ‘Sorafenib’ were used for literature search on PubMed.

Expert commentary: In Phase-III multicentric REFLECT trial Lenvatinib demonstrated a non-inferior overall survival (OS) compared to Sorafenib in the first-line treatment of advanced HCC, with a manageable toxicity profile, becoming a valid alternative option in the therapeutic repertoire of this disease. Nevertheless, the potential role of Lenvatinib in real-life clinical practice has still to be defined, especially in the light of the positive results that have been achieved with other new therapeutic agents (e.g. immunotherapy).     

Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

Recovery of urinary continence after radical prostatectomy

Introduction: In the era of minimally-invasive surgery, urinary incontinence (UI) after radical prostatectomy (RP) still represents a troublesome issue for a considerable rate of patients. Factors associated with the risk of post-RP UI, need to be carefully assessed throughout the overall clinical management process thus including the pre-operative, intra-operative and post-operative setting.

Areas covered: This review analyses current published evidences regarding clinical and surgical aspects associated with urinary continence (UC) recovery after RP. A careful evaluation of patient’s clinical characteristics should be carried out before surgery in order to properly counsel the patients regarding the risk of UI. In the last two decades, the advent of robotic surgery has led to an overall improvement of functional outcomes after RP, thanks to the development of different surgical strategies based on either the ‘preservation’ or the ‘reconstruction’ of the anatomical elements responsible for urinary continence.

Finally, several therapeutic strategies including either a conservative approach, or pharmacological and surgical treatments, should be carefully considered for the post-operative management of UI.

Expert commentary: A comprehensive pre-operative patient’s clinical assessment, along with a proper and well-conducted surgical procedure and an effective post-operative care management are essential element to achieve a high probability of UC recovery.     

Limiting the morbidity of inguinofemoral lymphadenectomy in vulvar cancer patients; a review

Introduction: Inguinofemoral lymphadenectomy (IFL) is performed in the treatment for vulvar cancer. One or more complications after IFL is reported in up to 85% of the patients. This review presents an overview of surgical techniques and peri- and post-operative care that has been studied in order to reduce the morbidity associated with IFL in vulvar cancer patients.

Areas covered: Current knowledge on post-operative complications after different surgical techniques and peri- and post-operative protocols were discussed. A systematic literature review was conducted using MEDLINE, EMBASE and the Cochrane library on 20 February 2017. In order to be eligible for inclusion, studies must report the associated post-operative morbidity per surgical technique, or peri- or post-operative care given after IFL in vulvar cancer patients.

Expert commentary: After the implementation of several new surgical techniques, the morbidity after IFL decreased but remains high and clinically meaningful. More research is needed on surgical techniques and peri-or post-operative care to further reduce the complication rates after IFL in vulvar cancer patients.     

Cabozantinib for the treatment of kidney cancer

Introduction: Cabozantinib is a small molecule tyrosine kinase inhibitor that initially showed activity in medullary thyroid cancer and was recently approved by the Food and Drug Administration for the treatment of metastatic renal cell carcinoma after progression on first line therapy.

Areas covered: In the METEOR trial, cabozantinib demonstrated significantly improved efficacy in all three endpoints; response rates, progression free survival and overall survival in a randomized trial with everolimus as an active comparator. Cabozantinib also showed activity in the front line setting in RCC within the CABOSUN trial. The study randomized untreated metastatic RCC patients to either cabozantinib or sunitinib and the former showed improved progression free survival which was the primary endpoint. The future holds promise for indications in other malignancies, given the preliminary efficacy and unique mechanism of action of cabozantinib.

In this review we address the mechanism of action, pharmacodynamics and pharmacokinetics of cabozantinib, and also review the development pathway of this agent in the treatment of advanced renal cell carcinoma. The potential benefit in specific patient populations, such as poor risk patients and bone metastases subgroups is also discussed.

Expert commentary: The clinical applications of cabozantinib will be addressed within the context of the current competitive therapeutic landscape of RCC.     

Therapeutic approaches for T790M mutation positive non-small-cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50–60% of cases to the T790M resistance mutation.

Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance.

Expert commentary: Osimertinib is the current treatment option for T790M mutation positive NSCLC after progression to first or second-generation EGFR TKIs, with activity also on brain metastasis. However, the scenario is in continuous evolution and results from clinical trials are awaited in first-line setting and in combination strategies.     

The safety and efficacy of sonidegib for the treatment of locally advanced basal cell carcinoma

Introduction: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective.

Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.