First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population.

Patients and methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany.

Results: We evaluated 62 (median age: 63.5 [30–77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2–37] and a median overall survival (OS) of 10.5 [2–39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths.

Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.     

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.     

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.     

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.     

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.     

NGS analysis on tumor tissue and cfDNA for genotype-directed therapy in metastatic NSCLC patients. Between hope and hype?

Introduction: The advent of genomic based precision medicine led to the implementation of biomarker testing in metastatic non-small cell lung cancer (NSCLC) patients. Next generation sequencing (NGS) has been recently implemented to routine diagnostic requirements in lung oncology.

Areas covered: Two cases of patients with metastatic NSCLC for whom NGS analysis performed on both tumor and liquid biopsy has not improved the clinical course of their disease are reported. These cases illustrate the difficulty of the so-called ‘personalized or precision’ medicine in clinical routine practice for metastatic NSCLC.

Expert commentary: Discovery and detection of critical cancer-gene alterations better indicates targeted therapies that must be administered to improve the care of NSCLC patients in the personalized medicine era. There has been much interest in the literature and the scientific community for NGS tailored therapies approach for patients. However, there may be a gap between this theoretical stratified medicine and clinical practice. The advantages and drawbacks of NGS on tumor tissue and cell-free DNA for metastatic NSCLC are discussed.     

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.     

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.     

Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC

Background: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non–small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance.

Methods: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance.

Results: ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib.

Conclusions: Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC.     

Targeted therapy for metastatic colorectal cancer

Introduction: Outcomes in metastatic colorectal cancer are improving, with better understanding and use of targeted therapies.

Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This article reviews the current evidence for targeted therapies in advanced colorectal cancer, including up-to-date data regarding anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor (VEGF) agents, the relevance of primary tumor location and novel subgroups such as BRAF mutated, HER2 amplified, and mismatch-repair-deficient cancers.

Expert commentary: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for metastatic colorectal cancer (mCRC). The use of EGFR-targeted antibodies should be restricted to patients with extended RAS wild-type profiles, and there is evidence that they should be further restricted to patients with left-sided tumors. Clinically, mCRC can be divided into subgroups based on RAS, BRAF, HER2, and MMR status, each of which have distinct treatment pathways.     

Strategic overview on the best treatment option for intrahepaitc hepatocellular carcinoma recurrence

Introduction: The long-term survival after hepatectomy for HCC remains unsatisfactory because of the high incidence of recurrence. The cumulative 5-year recurrence rate ranged from 60–100% in previous studies and majority of them remains intrahepatic recurrence. The therapeutic modalities commonly used for primary tumors, including surgical resection, liver transplantation, TACE, local ablative therapy and radiotherapy have been used to treat recurrent tumors in the liver remnant and the outcomes with the heterogeneous therapeutic options are reviewed. It is important to note that the level of evidence for most therapeutic options is limited to cohort investigations with few RCTs and most were limited due to enrollment of various tumor stages and did not compare treatment modalities for specific tumor stages.

Areas covered: A literature search for recurrent HCC was performed using Medline and PubMed up to May 2016.

Expert commentary: The long term survival results after re-resection for recurrent HCC were favourable and aggressive management of postoperative intrahepatic recurrence remains the most important strategy in prolonging the survival of patients after resection of HCC.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

Biology and management of clear cell sarcoma: state of the art and future perspectives

Introduction: Clear cell sarcoma (CCS) is an aggressive tumor, typically developing in tendons or aponeuroses. The outcome of this orphan disease is poor, with 5-year and 10-year survival rates of localized CCS around 60–70% and 40–50%. Once the disease has metastasized, it is usually fatal due to its chemotherapy-resistant nature. Systemic treatment options are poorly standardized and the use of chemotherapy is based on weak scientific evidence.

Areas covered: In this review, we systematically discuss the current scientific evidence for the systemic treatment of CCS, including tyrosine kinase inhibitors, immunotherapy and MET inhibitors.

Expert commentary: Recent insights in the biology of CCS have identified new potential therapeutic targets, which should be tested in prospective clinical trials. Whenever possible, patients with metastatic CCS should be included in clinical trials with good biological rationale. Innovative trial methodology and new regulatory mechanisms are required to provide patients with uncommon cancers with active drugs.     

Liver-directed therapy in metastatic colorectal cancer

Introduction: Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions.

Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization.

Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence     

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.     

Current and future therapeutic approaches for osteosarcoma

Introduction: Current treatment of osteosarcoma includes surgical resection of all gross disease in conjunction with systemic chemotherapy to control micro-metastatic disease. This yields a 5-year event free survival (EFS) of approximately 70% for patients with localized osteosarcoma while patients with metastatic or recurrent disease fare poorly with overall survival rates of less than 20%.

Areas covered: This review outlines the current and future approach towards the treatment of osteosarcoma. A literature search was performed utilizing PubMed. Several recent clinical trials are reviewed in detail, as is innovative research evaluating novel agents and surgical techniques which hold promise.

Expert commentary: The outcome for patients with osteosarcoma has not changed in several decades. This plateau in survival rates highlights the need for a novel approach towards research. There remains a great deal of interest in utilizing the very high risk population of recurrent osteosarcoma patients to rapidly and sequentially evaluate novel agents to determine if any of these agents hold promise. Several phase II studies are ongoing or in development that offer hope based on intriguing preclinical data. Furthermore, initiatives in obtaining specimens to further explore the genetic and immunological profile behind osteosarcoma will be essential towards identifying novel pathways and targets to exploit.     

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.     

Combination targeted therapy of VEGFR inhibitor,sorafenib, with an mTOR inhibitor,sirolimus induced a remakable response of rapid progressive Uterine PEComa

Perivascular epithelioid cell tumor is a rare tumor. To date, there is no consensus of therapy to be recommended for unresectable disease. For a low incidence and a rarely curable disease, the finding of new therapy is essential.

Here we report the first case of a patient with perivascular epithelioid cell tumor whose disease had a rapid progression after surgery and had a rapid remarkable response of combination therapy of a VEGFR inhibitor, sorafenib, with an mTOR inhibitor, sirolimus.

This result may have potential to deliver a new treatment option and inhibiting the mTOR pathway combined with inhibiting the VEGF pathways may be a useful strategy for malignant PEComas.     

Application of dynamic thermal imaging in a photocarcinogenesis mouse model

Introduction: In clinical practice and experimental settings, cutaneous premalignant and malignant lesions are commonly diagnosed by histopathological biopsy. However, this technique is invasive and results in functional or cosmetic defects. Dynamic thermal imaging is a non-invasive technique that quantifies the infra-red (IR) radiation emitted by a subject after the introduction of external thermal stimuli (such as heat or cold).

Methods: Forty hairless albino (Crl:SKH1-hr) mice were randomised to the control group or the experimental group. The experimental group was regularly irradiated with artificial ultraviolet. Clinical photographs, immunohistochemical staining and dynamic thermal imaging results of both groups were obtained.

Results: As photocarcinogenesis proceeded, faster thermal recovery to basal temperature after heat stimuli was significant on dynamic thermal imaging. With histopathological correlations, it was possible to differentiate normal, premalignant and malignant cutaneous lesions according to thermal imaging results. CD 31 staining analysis showed that increased vasculature was the key change responsible for different thermal imaging results among photocarcinogenesis steps.

Conclusions: Dynamic thermal imaging is useful to differentiate normal, premalignant and malignant cutaneous lesions. Increased vasculature is the key change responsible for different thermal imaging results.