Stereotactic radiosurgery for intracranial metastases: linac-based and gamma-dedicated unit approach

Introduction: For intracranial metastases, the role of stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy is well recognized.

Areas covered: Historically, the first technology, for stereotactic device able to irradiate a brain tumor volume, was Gamma Knife® (GK). Due to the technological advancement of linear accelerator (Linac), there was a continuous increasing interest in SRS Linac-based applications. In those decades, it was assumed a superiority of GK compared to SRS Linac-based for brain tumor in terms of dose conformity and rapid fall-off dose close to the target.

Expert commentary: Recently, due to the Linac technologic advancement, the choice of SRS GK-based is not necessarily so exclusive. The current review discussed in details the technical and clinical aspects comparing the two approaches for brain metastases.     

Preventing central nervous system metastases in non-small cell lung cancer

Introduction: There are no effective central nervous system (CNS) metastases prevention methods in lung cancer patients. Prophylactic cranial irradiation has a limited effectiveness and relatively high toxicity. Systemic chemotherapy is not relevant in reducing the risk of CNS in lung cancer patients. The understanding of molecular background of brain metastases in non-small cell lung cancer (NSCLC) patients could contribute to the development of personalized treatments for such patients.

Areas covered: This article summarizes the latest clinical trials concerning the use of radiotherapy, chemotherapy, molecularly targeted therapies, and immunotherapy in lung cancer patients, with particular consideration of brain lung cancer metastasis prevention. The literature search was undertaken via PubMed and EMBASE searches and relevant articles are included in this review.

Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients. In the future, high hopes for the prevention of CNS metastases in NSCLC patients are associated with immunotherapy concerning immune check-points inhibitors.     

Understanding dendritic cell immunotherapy in ovarian cancer

Introduction: Approximately eighty percent of patients with ovarian cancer are diagnosed with advanced disease. Even with cutting edge surgical techniques and the best regimens of standard therapies most patients relapse and die of drug resistant disease within five years of diagnosis. Dendritic cell (DC) immunotherapy can induce anti-tumor T cell immunity in patients and holds great potential in the era of modern anti-cancer treatment.

Areas Covered: This review outlines critical factors regulating the outcome of DC immunotherapy in ovarian cancer, summarizes the important findings in ovarian cancer DC clinical trials, and discusses new directions which may improve the effectiveness of DC immunotherapy.

Expert Commentary: Administration of DC vaccines with other forms of immunotherapy may enhance the efficacy of these treatments, ultimately increasing cures for this disease.     

Improving patient outcomes to targeted therapies in melanoma

Introduction: The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years.

Areas Covered: In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas.

Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.     

Ipilimumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma

Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma.

The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.     

Intralesional therapy as a treatment for locoregionally metastatic melanoma

Introduction: The emergence of novel intralesional therapies have dramatically changed the treatment landscape for melanoma. The heterogeneous presentation of melanoma continues to pose challenges for clinicians, especially when dealing with advanced locoregional disease. Intralesional therapies have the benefit of causing local tumor destruction, while minimizing systemic toxicity. Moreover, the integration of immunotherapeutic agents into intralesional compounds has resulted in the additional benefit of a bystander effect, whereby untreated distant lesions also derive a benefit from treatment. Intralesional therapy has assumed an important role in the management of unresectable, locoregional disease for melanoma.

Areas covered: Multiple intralesional agents have been studied over the years, with only a few demonstrating promising results. This review will provide an overview of the different intralesional agents for melanoma. Mechanisms of action, clinical efficacy, and side effects will be the primary focus.

Expert commentary: Treatment options for advanced melanoma continue to evolve. Attractive new therapies delivered by an intralesional route has demonstrated promising results, with minimal side effects. The ideal treatment strategy for melanoma will remain a multimodal approach; intralesional therapy provides an additional tool in the treatment armamentarium for melanoma.     

Myoglobin does not predict local toxicity in isolated limb perfusion

Introduction: Isolated limb perfusion (ILP) is a treatment option for patients with in-transit metastases of malignant melanoma in the extremities, as well as locally advanced sarcoma. ILP allows for a delivery of high-dose chemotherapy to an isolated extremity with minimal systemic toxicity. However, local toxicity like oedema, blistering, nerve damage and compartment syndrome can occur. Myoglobin measurements have been used as a screening method to predict the most severe cases of local toxicity. The aim was to investigate if myoglobin is a predictive factor for local toxicity after ILP in patients with melanoma in-transit metastases.

Methods: One hundred and ninety-three patients were treated for the first time with ILP for in-transit metastases between 2001 and 2015. Myoglobin was measured once the first hours after the perfusion (POD0), and for the first five post-operative days (POD1-5). Local toxicity was graded according to Wieberdink, and grouped in mild (I and II), moderate (III), and severe (IV and V). Wieberdink-groups were compared with myoglobin measurements, and myoglobin measurements were compared between gender, perfusion time, perfusion temperature and cannulated vessels.

Results: There is no statistically significant difference in myoglobin serum levels during the first five days post perfusion between patients suffering from mild, moderate or severe local toxicity. There is no difference between toxicity groups when it comes to distribution of sex, tumour size, or tumour numbers.

Conclusion: Levels of myoglobin do not predict local toxicity for patients with melanoma in-transit metastases treated with ILP when measured during the first five post-operative days.     

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.     

Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy

Introduction: The success of the immune checkpoint inhibitors in melanoma has reinvigorated the field of immunotherapy. Immune checkpoint inhibitors are now the standard of care in multiple cancer types including lung cancer, head and neck cancer, urothelial cancer and renal cell cancer. The field of immunotherapy is currently expanding rapidly and will be a focus of research and development for decades to come.

Areas covered: This review covers the early development of immune checkpoint inhibitors and the changes that occurred in the drug development paradigm to facilitate the development of immunotherapy. The review will summarise the areas into which immune checkpoint inhibitors have been adopted and will review the data that supported this. Furthermore, we will discuss future developments in immunotherapy and the current landscape regarding maximising the potential of immunotherapy in clinical practice.

Expert commentary: In the author’s opinion, the potential of immunotherapy is vast. To date immune checkpoint inhibition has already delivered durable responses in a proportion of patients with cancer types which were previously universally lethal. The future of immunotherapy will rely upon the intelligent application of translational research to clinical practice, such that immunotherapy can be effective for a wider population and maintain its current growth.     

The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care

Introduction: The eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging system was implemented in the United States on 1 January 2018.

Areas covered: This article provides an overview of important changes in the eighth edition AJCC staging system from the seventh edition based on analyses of a large international melanoma database. The clinical implications of these changes for melanoma treatment are also discussed.

Expert commentary: A standardized and contemporary cancer staging system that facilitates accurate risk stratification is essential to guide patient treatment. The eighth edition of the AJCC staging system is currently the most widely accepted approach to melanoma staging and classification at initial diagnosis.     

Binimetinib for the treatment of NRAS-mutant melanoma

Introduction: Activating NRAS mutations occur in approximately 15–20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients.

Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy.

Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy.     

How to use neoadjuvant medical treatment to maximize surgery in melanoma

Introduction: The aim of this work is to discuss the role of neoadjuvant therapy in melanoma patients, namely the potential to improve control and surgical resectability of locoregional disease. Moreover, potential survival benefits for high-risk stage III and IV melanoma patients will be addressed.

Areas covered: In this review, the different available neoadjuvant treatments including chemotherapy, bio-chemotherapy, targeted therapy, immunotherapy and local therapy will be presented and discussed. The PubMed published articles were identified and searched using the following terms located in the publication title: neoadjuvant therapy and melanoma. Studies investigating targeted therapy, immunotherapy and local melanoma treatments were included. Clinicaltrial.gov was also used as a source for recruiting or ongoing but not recruiting neoadjuvant clinical trials, for which no published results are available.

Expert commentary: Targeted therapy and immunotherapy in a neoadjuvant setting are still under investigation and not yet approved, however several neoadjuvant trials are ongoing. Shortly, results from these trials will answer the question whether neoadjuvant treatment translates into survival benefit and improves local disease control in stage III and IV melanoma patients. Immunotherapy and targeted therapy will play as relevant a role as in the metastatic setting, whereas chemotherapy will be used seldom.     

Tackling non-muscle invasive bladder cancer in the clinic

Introduction: Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle-invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies.

Areas covered: This review summarizes the conventional management of NMIBC – which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed.

Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC.     

Anti-GD2 immunotherapy for neuroblastoma

Introduction: Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy.

Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development.

Expert commentary: Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory and relapsed neuroblastoma. As protein engineering technology has become more accessible, newer antibody constructs are being tested. GD2 is also being targeted by natural killer cells and T-cells. Active immunity can be elicited by anti-GD2 vaccines. The rational combination of currently available and soon-to-emerge immunotherapeutic approaches, and their integration into conventional multimodality therapies will require further investigation to optimize their use for HR-NB.     

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.     

The use of systemic therapies to prevent progression of inflammatory breast cancer: which targeted therapies to add on cytotoxic combinations?

Introduction: Inflammatory breast cancer is a rare but frequently fatal disease, essentially because of its high ability to develop distant metastases. Even though the prognosis of IBC was significantly improved by multimodal management, including the systematic use of cytotoxic-based induction, the prognosis remains largely dismal.

Areas covered: This review presents the main achievements in the systemic treatment of IBC during the past 30 years. It focuses more specifically on recent results obtained with targeted therapies, including anti-HER2 and anti-angiogenic agents. Novel approaches under investigation are presented.

Expert commentary: Current management of IBC is subtype-specific and the largest benefit has been achieved in HER2-positive disease. The identification of breakthrough therapeutic advances is eagerly awaited and will require the development of IBC-specific clinical trials. Future clinical investigations should not only aim to increase the pathological response rate but also to eradicate distant metastases, which ultimately lead to patient death.     

Intra-arterial therapies for liver cancer: assessing tumor response

Introduction: Intra-arterial therapies (IATs) play an integral role in the management of unresectable hepatocellular carcinoma and liver metastases. The ability to accurately assess tumor response to intra-arterial therapies is crucial for clinical management. Several one- and two-dimensional manual imaging-based response assessment techniques, based both on tumor size or enhancement, have shown to be highly subjective and merely surrogate for the actual tumor as a whole.

Areas covered: Given the currently existing literature, we will discuss all available tumor assessment techniques and criteria for liver cancer with a strong emphasis on 3D quantitative imaging biomarkers of tumor response in this review.

Expert commentary: The growing role of information technology in medicine has brought about the advent of software-assisted, segmentation-based assessment techniques that address the outstanding issues of a subjective reader and provide for more accurate assessment techniques for the locally treated lesions. Three-dimensional quantitative tumor assessment techniques are superior to one- and two-dimensional measurements. This allows for treatment alterations and more precise targeting, potentially resulting in improved patient outcome.     

Basis for molecular diagnostics and immunotherapy for esophageal cancer

Introduction: Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field’s most dire survival statistics.

Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC.

Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.     

Future applications of FGF/FGFR inhibitors in cancer

Introduction: Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors due to gene amplification, activating mutations, and oncogenic fusions. Thus, the development of FGF/FGFR-targeting therapies is the focus of several basic, preclinical, and clinical studies.

Areas covered: This review will recapitulate the status of current FGF/FGFR-targeted drugs.

Expert commentary: Non-selective FGF/FGFR inhibitors have been approved for cancer treatment but evidence highlights various complications affecting their use in the clinical practice. It appears mandatory to identify FGF/FGFR alterations and appropriate biomarkers that may predict and monitor response to treatment, to establish the contribution of the FGF/FGFR system to the onset of mechanisms of drug resistance, and to develop effective combinations of FGF/FGFR inhibitors with other targeted therapies.     

The current status of immunotherapy in peritoneal carcinomatosis

Introduction: Peritoneal carcinomatosis (PC) is a cancer disease with an urgent need for effective treatment. Conventional chemotherapy failed to show acceptable results. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) are only beneficial in few patients with resectable peritoneal metastasis. Immunotherapy could be attractive against PC, as all requirements for immunotherapy are available in the peritoneal cavity.

Areas covered: This review analyzes the present literature for immunotherapy of PC. Advances from immune stimulators, radionucleotide-conjugated- and bispecific antibodies to future developments like adoptive engineered T-cells with chimeric receptors are discussed. The clinical development of catumaxomab, which was the first intraperitoneal immunotherapy to be approved for clinical treatment, is discussed. The requirements for future developments are illustrated.

Expert commentary: Immunotherapy of peritoneal carcinomatosis is manageable, showing striking cancer cell killing. Improved profiles of adverse events by therapy-induced cytokine release, enhanced specific killing and optimal treatment schedules within multimodal treatment will be key factors.