Pharmacotherapy for squamous-cell carcinoma of the head and neck

Introduction: Squamous-cell carcinoma of the head and neck (HNSCC) is one of the most common malignancies, the treatment of which constitutes a therapeutic challenge.

Areas covered: The purpose of this review is to provide an update on the pharmacotherapy for the treatment of HNSCC focusing mainly on molecular-targeted therapies. An overview of the different novel therapeutic agents that can selectively inhibit signaling pathways and receptors that are involved in the development and progression of cancer especially in HNSCC is presented.

Expert opinion: The treatment of HNSCC is traditionally based on surgery and radiotherapy for early-stage HNSCC; however, chemotherapy is no longer used only for palliation, and individualized patient treatment assisted by molecular-targeted therapies represents a future therapeutic challenge.     

Emerging molecular targeted therapies in the treatment of head and neck cancer

Current development of molecular targeted therapies in oncology is particularly active. The aim of this study is to review recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). As EGFR signaling pathway and angiogenesis play a key role in the growth of HNSCC, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as VEGF and its receptors, represent the main targets of the new therapeutic agents now in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic diseases. Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors and with the development and evaluation of other molecular targeted therapies such as antiangiogenic drugs. As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue.     

An update: emerging drugs to treat squamous cell carcinomas of the head and neck

ABSTRACT

Introduction: Subsequent to the 2006 FDA approval of cetuximab, a variety of molecular targeting agents have been evaluated in head and neck squamous cell carcinoma (HNSCC). The treatment outcomes of recurrent and/or metastatic (R/M) HNSCC, in particular, remain dismal. The 2016 FDA approval of PD-1 immune checkpoint inhibitors has expanded the treatment options for R/M HNSCC and highlights the potential for immune-based therapies.

Areas covered: We will review the clinical application of EGFR-targeted agents, alone and in combination with other drugs. Molecular targeting agents directed against the IL6/PI3K/STAT3 signaling pathway will be covered. In addition, evaluation of immune checkpoint inhibitors in HNSCC, along with ongoing combination trials incorporating these agents, will be discussed. The expanded indications of emerging drugs and the potential clinical benefit of new drugs and treatment combinations will be summarized.

Expert opinion: In recent years, there has been a major shift toward immunotherapy-based approaches for the treatment of HNSCC, leading to significant improvements in outcomes for a subset of patients. Leveraging the increased understanding of the genetic alterations that characterize individual HNSCC tumors will facilitate precision medicine approaches using targeted agents, immunotherapies, as well as standard chemotherapy and radiation.     

EGFR targeting drugs in the treatment of head and neck squamous cell carcinoma

Importance of the field: Head and neck cancer is the sixth most common cancer worldwide. Despite intense efforts to improve different treatment modalities, mortality rates in advanced cases remain high.

Areas covered in the review: EGFR targeting mAb cetuximab (Erbitux) has been approved for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy and for recurrent or metastatic HNSCC. Here, we review recent scientific advances, as well as future research goals regarding EGFR inhibitors in the treatment of HNSCC. Information was compiled by searching the PubMed, Web of Knowledge and American Society of Clinical Oncology databases for articles published before October 2009. The search terms included ‘head and neck cancer’, ‘EGFR’, ‘cetuximab’, ‘panitumumab’, ‘zalutumumab’, ‘nimotuzumab’, ‘erlotinib’, ‘gefitinib’ and ‘lapatinib’. The National Institutes of Health registry of clinical trials (www.clinicaltrials.gov) was used to search for clinical trials in HNSCC.

What the reader will gain: The background scientific rationale, clinical efficacy and development of EGFR inhibitors in HNSCC are discussed.

Take home message: Cetuximab significantly improves survival of patients with locally advanced or metastatic HNSCC. Treatment strategies combining EGFR inhibitors with multimodality approaches may eventually increase cure rate in HNSCC.     

Pharmacotherapy for squamous-cell carcinoma of the head and neck

INTRODUCTION: squamous-cell carcinoma of the head and neck (HNSCC) is one of the most common malignancies, the treatment of which constitutes a therapeutic challenge. AREAS COVERED: the purpose of this review is to provide an update on the pharmacotherapy for the treatment of HNSCC focusing mainly on molecular-targeted therapies. An overview of the different novel therapeutic agents that can selectively inhibit signaling pathways and receptors that are involved in the development and progression of cancer especially in HNSCC is presented. EXPERT OPINION: the treatment of HNSCC is traditionally based on surgery and radiotherapy for early-stage HNSCC; however, chemotherapy is no longer used only for palliation, and individualized patient treatment assisted by molecular-targeted therapies represents a future therapeutic challenge.     

Pharmacotherapy of head and neck squamous cell carcinoma

Background: The clinical management of locally advanced head and neck squamous cell carcinoma (HNSCC) is a challenging problem and requires a multidisciplinary approach. Historically, locally advanced HNSCC has been primarily managed with surgery and radiation (RT). The integration of pharmacotherapy has rapidly expanded over the years into the multimodality treatment paradigm of locally advanced HNSCC. Objective: The studies leading to the adoption of the current standard of care for locally advanced HNSCC are discussed. In addition, the limitations of these various treatment approaches are presented. Methods: An extensive literature search was conducted using the PubMed database for studies published before January 2009. The keywords used for this search were: head and neck neoplasms, chemoradiation, adjuvant chemotherapy, induction chemotherapy, EGFR inhibitor, cisplatin, carboplatin, paclitaxel, docetaxel, 5-fluorouracil, and cetuximab. Publications of randomized clinical trials and other supporting references leading to the current standard of care were particularly selected and discussed in this review. Conclusions: Various single-agent and multi-agent chemotherapeutic regimens have been examined in the context of randomized clinical trials in locally advanced HNSCC for definitive, induction and adjuvant settings. Results from these clinical trials support the use of cisplatin-based chemoradiation as the standard of care for the definitive and adjuvant settings. Recent evidence indicates that cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is highly active as a single agent and in combination with standard chemotherapy and/or RT. Future studies should focus to determine the optimal pharmacotherapeutic regimens for use in locally advanced HNSCC.     

Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma

Introduction: Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment.

Areas covered: This review covers EGFR-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) signaling in HNSCC. The role of each pathway node in radioresistance is discussed. Preclinical and clinical innovative aspects of targeting EGFR-PI3K-AKT and mTOR are demonstrated. Ongoing clinical trials and future perspectives are presented.

Expert opinion: Different cellular signaling pathways seem to mediate radioresistance in advanced HNSCC and various molecular targeted therapies are currently being investigated to sensitize tumor cells to radiotherapy. Recently, new insights in the mutational landscape of HNSCC unraveled critical alterations in putative oncogenes and tumor suppressor genes and have emphasized the importance of PI3K and the corresponding upstream and downstream signaling pathways in pathogenesis and treatment response. The frequent activation of the EGFR-PI3K-AKT-mTOR pathway in HNSCC and its implication in the context of radiosensitivity make this pathway one of the most promising targets in the therapy of HNSCC patients. Clinical studies targeting EGFR and mTOR in combination with radiotherapy are under investigation.     

Capecitabine for treating head and neck cancer

Introduction: With an increasing incidence, over half a million cases of head and neck cancer (HNC) are diagnosed annually worldwide. Various chemotherapeutic agents are utilized to achieve adequate locoregional control. Cisplatin, fluorouracil (FU), and taxanes are often used to treat HNC but these regimens have shown high toxicity and poor patient compliance. Capecitabine is an orally administered prodrug that is preferentially converted to FU in tumor cells in comparison to normal cells.

Area covered: In this review, the authors evaluate the role of capecitabine in radical and palliative settings either alone or in combination with other chemotherapeutic drugs in the management of HNC. In addition, metabolic conversion, pharmacokinetics, pharmacodynamics, and toxicity profile of capecitabine are discussed.

Expert opinion: Various phase II trials conducted on capecitabine in the management of recurrent HNC have shown comparable results and tolerable toxic effects especially in pre-treated fragile patients. Capecitabine, used in induction or concurrent settings in the radical management of locoregionally advanced HNC, have also shown promising results. Randomized trials are needed to validate the role of capecitabine in the management of HNC.     

Management of advanced and/or metastatic carcinoid tumors: historical perspectives and emerging therapies

Introduction: Carcinoid tumors are uncommon neoplasms that offer unique therapeutic challenges to practicing physicians. Several chemotherapy combinations and IFN-α have been used for the treatment of unresectable carcinoid tumors over the last decades, but they have shown variable clinical results. Given the heterogeneity of these tumors, there is no clear therapeutic agent or combination that confers a significant advantage over others.

Areas covered: The authors provide a comprehensive evaluation of the existing therapies for advanced carcinoid tumors such as traditional agents, combination therapies and newer drugs.

Expert opinion: Somatostatin analogs are known to provide symptomatic relief in patients with carcinoid syndrome, but their antiproliferative effect has not been proven beyond the reasonable doubt. Traditional streptozocin-based regimens may offer a survival benefit in patients with advanced carcinoids, yet their toxicity is not negligible. Temozolomide has shown efficacy alone and in combination with other agents, and its further testing in advanced carcinoid tumors appears warranted. Efficacy of various tyrosine kinase inhibitors, VEGF inhibitors and mTOR inhibitors appears promising, and should be explored in patients with metastatic carcinoid tumors. In addition, use of these agents in combination with traditional chemotherapeutic agents should also be investigated.     

Programming the immune checkpoint to treat hematologic malignancies

Introduction: Hematologic malignancies manipulate the immune suppressive pathways involving CTLA-4, PD-1, and others to promote immune tolerance of cancer. New monoclonal antibodies targeting immune checkpoints are showing meaningful responses in the treatment of relapsed and refractory Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. The basis for success of anti-PD-1 therapy appears to be expression of PD-L1 on tumor cells and cells of the tumor microenvironment (TME). While adverse events associated with immune checkpoint inhibitors are capable of generating auto-immune phenomena, in general these therapies are well tolerated.

Areas covered: In this review, the authors discuss the development of immune checkpoint inhibitors and activators which hold promise as useful therapies in malignancies of hematologic origin, since many exploit endogenous pathways to induce tolerance. By programming the immune response to attack hematologic malignancies, unique regimens can be developed to optimally treat patients with curative potential.

Expert opinion: The utilization of immune checkpoint targeting agents to boost the innate and acquired immune systems to eradicate human malignancies represents a unique opportunity to develop novel therapies with increased clinical efficacy. Side effects of these therapies come with the price of auto-immune phenomena that require appropriate management.     

Management of colorectal cancer in elderly patients: focus on the cost of chemotherapy

The treatment of colorectal cancer has evolved dramatically over the last 15 years. Advances in surgery, radiotherapy and chemotherapy have enabled oncologists to cure more patients and offer improved quality of life to patients not amenable to cure. Specific knowledge of colorectal cancer care of the elderly, while lagging behind the treatment of younger patients, is beginning to emerge. Informed by recent trials, the approach towards elderly patients is shifting towards more aggressive treatment and multimodal therapy. Surgeons are operating on the elderly with greater frequency, less operative mortality and greater success; 5-year survival following potentially curative surgery has risen from 50% to 67%.Research of adjunctive therapy for colorectal cancer is enrolling more elderly patients, and with this has come an understanding of the role of chemotherapeutic agents in the treatment of the elderly, used individually and within multi-drug regimens. This research offers insight into how the elderly respond to chemotherapy, informing clinicians on anticipated benefits and toxicities of treatment. Fluorouracil-based regimens, which have long been the standard adjuvant chemotherapy, have been shown to offer benefits to the elderly compared with those not receiving adjuvant chemotherapy (71% versus 64% 5-year survival), and to cause similar toxicities as seen in younger patients. The role of novel chemotherapeutic agents in the treatment of elderly patients with colorectal cancer is also emerging, with studies finding that irinotecan, in combination with a fluorouracil-based regimen, can offer a further survival benefit of over 2 months compared with fluorouracil alone. While newer agents such as capecitabine, oxaliplatin, raltitrexed and tegafur/uracil (UFT) have been focused upon by clinical researchers, data on their use in the elderly remain unconvincing.Not only are we approaching a clearer understanding of the effectiveness of cancer care among the elderly, but research is also beginning to identify the cost effectiveness of both standard and emerging chemotherapeutic agents. Cost effectiveness of fluorouracil-based regimens, depending on delivery strategy, use of modulating agents and stage of cancer vary from US dollars 2000 per quality-adjusted life-year (QALY) to US dollars 20200 per QALY (1992 values). Irinotecan therapy has not been fully investigated from the perspective of cost effectiveness; the figure of US dollars 10000 per QALY (1998 values) for irinotecan monotherapy over fluorouracil regimens is likely an underestimate, while cost analysis of irinotecan and fluorouracil combination therapy has not yet been reported. Our understanding of cost effectiveness of other novel agents has lagged behind; further research on these agents is needed. Nonetheless, as the effects of these novel agents upon both outcomes and costs continue to be defined, both curative and palliative treatment of colorectal cancer in the elderly patient will become more sophisticated and effective.     

Pharmacotherapy of head and neck cancer

Introduction: There are over 55,000 new cases of head and neck cancer diagnosed annually in the United States. Historically surgical resection was the standard of care, but due to vital structures in the head and neck region this led to severe morbidity. The integration of pharmacotherapy has rapidly expanded over the years into a multimodality treatment paradigm for locally advanced head and neck cancer, allowing organ-sparing treatment approaches. Here we discuss the various approaches and settings in which chemotherapy can be incorporated into the management of head and neck squamous cell carcinoma (HNSCC).

Areas covered: Chemotherapy in HNSCC can be administered in several different treatment circumstances: in the metastatic setting for palliation of symptoms and prolongation of survival, before definitive local treatment (induction), as part of definitive treatment simultaneously with radiation (concurrent) or after definitive local therapy (adjuvant).

Expert opinion: The incorporation of chemotherapy into the management of patients with head and neck cancer has allowed organ preservation approaches and improved survival. Because of the toxicities of chemotherapy, it is imperative that chemotherapy is only administered to the appropriate patient population who are more likely to benefit. Cisplatin 100 mg/m² given in combination with radiation in the non-metastatic setting is the most widely tested regimen and remains the reference regimen. Cetuximab is also an alternative, but there is no data to support the use of cetuximab in a laryngeal preservation approach or in the postoperative setting.     

Emerging drugs for head and neck cancer

Head and neck squamous cell carcinoma is a devastating disease with poor outcomes in advanced stages. For patients with locally advanced disease, a multi-modality approach with chemotherapy and radiotherapy has been used. Despite advances in diagnosis and treatment, including improvements in radiation therapy, surgical techniques, chemotherapy and prevention strategies, survival rates for patients with recurrent head and neck cancer are poor. Several cytotoxic drugs with significant activities as single agents and/or combination regimens have shown high response rates, but over the past several years, significant improvement in survival has not been achieved. New drugs, including those that target the epidermal growth factor receptor, the p53 gene, RAS protein post-translational modification, the proteosome, vascular endothelial growth factor, cyclooxygenase-2 and other molecular pathways, are promising agents in the management of head and neck cancer. Their potential is being tested in various settings, including chemoprevention, recurrent and metastatic disease and combination with radiation therapy and/or cytotoxic agents.     

免疫治疗在头颈鳞癌中的研究进展

摘要： 尽管近年来外科手术和综合治疗手段在不断进步和发展， 但头颈鳞癌患者的5年生存率并未得到显著提高。因此， 提高头颈鳞癌治疗效率， 改善头颈鳞癌治疗手段迫在眉睫。作为一种颇具前景的新型疗法， 免疫治疗具有较低的毒性及高度特异性， 并且已逐渐被应用到包括头颈鳞癌在内的多种肿瘤的临床治疗之中。在头颈鳞癌的免疫治疗之中， 研究人员在单一细胞因子治疗的基础上进一步开发出了复合性系统疗法并取得了不错的疗效。另一方面， 包括蛋白/多肽-树突细胞疫苗在内的多种肿瘤疫苗治疗方法进入了大量临床试验研究中。此外， 针对PD-1 等免疫检查点的免疫疗法受到了广泛关注， 相关的抑制性抗体也已获批进行复发或转移性头颈鳞癌的治疗。本文旨在对以上多种免疫治疗手段在头颈鳞癌中的相关研究进展作一简要综述。     

Afatinib in squamous cell carcinoma of the head and neck

Introduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.

Areas covered: We searched the literature for published and ongoing studies with afatinib in HNSCC.

Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.

Expert opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.     

New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors,stromal modifiers and conjugated therapies

Introduction: Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options.

Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future.

Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.     

Novel targeted therapies for the treatment of penile cancer

Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival.

Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’.

Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade.     

Investigational multitargeted kinase inhibitors in development for head and neck neoplasms

Introduction: Despite advances in treatment, head and neck squamous cell carcinoma (HNSCC) survival rates remain stagnant. Current treatment is associated with significant toxicities and includes chemotherapy, radiation, surgery, and few targeted treatments. Targeted treatments, epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, and immune checkpoint inhibitors, pembrolizumab and nivolumab, show improved toxicity profiles and modestly improved survival in select patients. An urgent need remains to identify novel targeted treatments for single-agent or combined therapy use.

Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.

Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance.     

Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer

ABSTRACT

Introduction: The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities.

Areas covered: This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by ‘passively’ and ‘actively’ targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of ‘biologics’, antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated.

Expert opinion: Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.     

The radiosensitizing effect of β-Thujaplicin,a tropolone derivative inducing S-phase cell cycle arrest,in head and neck squamous cell carcinoma-derived cell lines

Investigational New Drugs - Resistance to radiotherapy is a common cause of treatment failure in advanced head and neck squamous cell carcinoma (HNSCC). ß-Thujaplicin, a natural tropolone...