Advances in pharmacotherapy of small cell lung cancer

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastatic dissemination and responsiveness to initial therapy. The incidence of SCLC has been declining over the past two decades. Limited-stage SCLC is a potentially curable disease with long-term survival of ～ 20% when treated with platinum-based chemotherapy plus concurrent thoracic radiation and prophylactic cranial irradiation. For patients with extensive-stage SCLC, survival can be increased with combination platinum-based chemotherapy, but the disease remains incurable.

Areas covered: This review looks at the current advances in pharmacotherapy for SCLC.

Expert opinion: Many chemotherapeutic strategies and newer cytotoxic agents have been evaluated in SCLC, and some had promising activity in early clinical trials. However, none have demonstrated consistent improvements in outcome over standard platinum-based treatment. Similarly, although many potential molecular targets have been identified in preclinical studies of SCLC, molecularly targeted therapy has yet to demonstrate any substantial activity in clinical trials. Nonetheless, future advances in this disease will undoubtedly depend on improvements in our understanding of the molecular mechanisms that drive the proliferation and survival of SCLC cells.     

Optimal drugs for second-line treatment of patients with small-cell lung cancer

Introduction: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed.

Areas covered: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials.

Expert opinion: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials.

Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients.

Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.     

Pharmacotherapeutic treatment of germ cell tumors: standard of care and recent developments

Introduction: Testicular germ cell tumors are the most common malignancy among men aged 40 and less. Since the introduction of cisplatin-based combination chemotherapy, germ cell tumors are among the most curable solid tumors with cure rates of 95% in all patients and > 80% in metastatic disease.

Areas covered: Current standards and future developments in GCT treatment, including adjuvant chemotherapy, first line treatment for metastatic disease, and salvage regimens in case of relapse and refractory disease.

Expert opinion: Maintaining therapeutic success while further reducing treatment-related toxicity is paramount. Cancer-specific survival in localized disease approximates 100%. Therefore, orchidectomy followed by active surveillance is the preferred approach for all seminomas and non-seminomas lacking lymphovascular invasion. Non-seminomas with lymphovascular invasion should be offered adjuvant treatment with one cycle of bleomycin, etoposide and cisplatin (BEP). The BEP regimen remains standard of care for metastatic disease, while the role of primary high-dose chemotherapy in case of inadequate tumor-marker decline or presence of high-risk features (i.e. mediastinal origin, non-pulmonary visceral metastases) remains to be elucidated. Several curative salvage chemotherapy combinations are available, i.e. TIP, VeIP, GIP or high-dose carboplatin and etoposide. GOP is the current option of choice in cisplatin-refractory patients. Novel targeted agents failed to improve treatment outcome so far.     

Opportunities and obstacles of targeted therapy and immunotherapy in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive malignant tumour which accounts for approximately 13–15% of all newly diagnosed lung cancer cases. To date, platinum-based chemotherapy are still the first-line treatments for SCLC. However, chemotherapy resistance and systemic toxicity limit the long-term clinical outcome of first-line treatment in SCLC. Recent years, targeted therapy and immunotherapy have made great breakthrough in cancer therapy, and researchers aim to exploit both as a single agent or in combination with chemotherapy to improve the survival of SCLC patients, but limited effectiveness and the adverse events remain the major obstacles in the treatment of SCLC. To overcome these challenges for SCLC therapies, prevention and early diagnosis for this refractory disease is very important. At the same time, we should reveal more information about the pathogenesis of SCLC and the mechanism of drug resistance. Finally, new treatment strategies should also be taken into considerations, such as repurposing drug, optimising of targets, combination therapy strategies or prognostic biomarkers to enhance therapeutic effects and decrease the adverse events rates in SCLC patients. This article will review the molecular biology characteristics of SCLC and discuss the opportunities and obstacles of the current therapy for SCLC patients.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

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.     

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens.

Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed.

Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.     

Targeted therapy and promising novel agents for the treatment of advanced soft tissue sarcomas

Introduction: Soft tissue sarcomas (STS) are a rare and difficult to treat malignancy. Efforts to utilize targeted therapy have been ongoing for the last decade and have resulted in the approval of pazopanib for treatment of advanced disease. Although several other agents have been investigated, the inability to predict responses remains a limiting factor to the incorporation of these agents into treatment.

Areas covered: The authors summarize recent clinical findings from studies focused on targeted agents in STS. The authors also discuss the potential approaches and ongoing clinical trials with novel agents.

Expert opinion: A major challenge in the treatment of advanced STS remains a lack of predictive biomarkers to guide therapy and the heterogeneity of response among different histologies of sarcoma. Incorporation of predictive biomarker analysis into clinical trials is warranted. Additionally, mechanisms of treatment resistance and parallel pathways of tumor growth pose challenges in how we treat these tumors. An active area of research in STS is the use of novel combinations of agents, such as chemotherapy combined with multi-targeted agents. The potential of immune check point inhibitors is being explored in advanced STS and is hoped to further expand our treatment armamentarium.     

Update on new drugs in small cell lung cancer

INTRODUCTION: Small cell lung cancer (SCLC) will account for 25,000 to 32,000 new lung cancer cases in the USA in 2010. Current treatmenta pproaches include platinum-based chemotherapy and etoposide with or without radiation therapy depending on stage and performance status. Five-year survival is approximately 25% for patients with limited stage disease and 1 -- 2% for patients with extensive stage disease and has noti mproved in almost two decades. AREAS COVERED: This article reviews the results of recent clinical trials that have evaluated targeted agents and novel cytotoxic agents alone or in combination with standard chemotherapy in the treatment of patients with SCLC. EXPERT OPINION: The lack of a targeted approach to the treatment of patients with SCLC has led investigators to evaluate a multitude of agents with overwhelmingly negative results. A more systematic approach to clinical trials in patients is needed to improve outcomes for patients with this disease.     

Emerging drugs in endometrial cancers

Importance of the field: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving.

Areas covered in this review: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers.

What the reader will gain: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents.

Take home message: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas.     

Advances in chemotherapy in advanced non-small-cell lung cancer

Importance of the field: Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers diagnosis, and the majority of people diagnosed with NSCLC have advanced disease.

Areas covered in this review: In this review the main advances achieved in the medical treatment of advanced NSCLC are discussed, regarding both targeted therapies and chemotherapy. Among targeted therapies, recent data on the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor tyrosyne kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib are described. Among chemotherapeutic agents, the role of pemetrexed is discussed.

What the reader will gain: The reader will gain up-to-date information on the main advances, achieved in the last 3 years in the medical treatment of advanced NSCLC.

Take home message: Some recent advances have changed the face of the first-line chemotherapy of advanced NSCLC, giving physicians more options to tailor choice in this challenging setting.     

Wnt signaling as potential therapeutic target in lung cancer

Introduction: Wingless-type (Wnt) signaling is tightly regulated at multiple cellular levels and is dysregulated in lung cancer. Therefore, it offers therapeutic targets for developing novel agents for lung cancer treatment.

Areas covered: In this article, we discuss the role of the Wnt signaling pathway in lung cancer, highlighting the aberrant activation of Wnt in lung cancer stem cells and its implication in resistance to radiotherapy, chemotherapy and targeted therapy. We also expound the regulatory roles of microRNAs in Wnt signaling, as well as the potential of the Wnt pathway to provide biomarkers and therapeutic targets in lung cancer. The potential use of small molecule and biological inhibitors targeting the Wnt pathway for lung cancer therapy and prevention is also discussed.

Expert opinion: Wnt signaling plays an important role in the development and metastasis of lung cancer; the pathway provides targets to develop agents towards for cancer prevention and therapy. A number of clinical trials have shown the effectiveness of Wnt pathway inhibitors in epithelial tumors. However, the side effects should be considered. Nevertheless, the results from clinical studies suggest that inhibitors targeting the Wnt signaling show promise against lung cancer.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

Optimization of genetics to create therapies for metastatic (stage IV) non-small-cell lung cancer

Importance of the field: Non-small-cell lung cancer (NSCLC) is a disseminated disease in 50% of cases, with a gloomy prognosis and median survivals of < 1 year.

Areas covered in this review: Based on substantial advances, cancer biology insights and novel biotechnology tools, customized treatment provides hints that cisplatin-based treatment can be optimized in favorable subgroups of patients according to gene expression DNA repair profiles. In 2004, it was discovered that 10 – 15% of NSCLC can harbor a new class of EGFR mutation conferring specific sensitivity to EGFR tyrosine kinase inhibitors.

What the reader will gain: The homologous recombination pathway provides information for customizing cisplatin-based chemotherapy. BRCA1 plays a central role in this pathway that can be used in tailoring chemotherapy. Patient subgroups can obtain significant increases in progression-free survival. For EGFR lung-addicted cancers, treatment with EGFR tyrosine kinase inhibitors like erlotinib provide impressive improvement in progression-free survival – up to 14 months with significant enhanced survival.

Take home message: Customized chemotherapy based on BRCA1 models can contribute to demonstrating this approach's clinical relevance, and the implementation of EGFR mutation assessment is warranted to identify EGFR-addicted lung cancers with a different prognosis that could benefit from a specifically targeted therapy approach.     

Cell cycle inhibitors for the treatment of NSCLC

Introduction: Lung cancer remains to be the leading cause of cancer-related death worldwide. Treatment of lung cancer still poses a significant challenge. Cell cycle is a tightly integrated process and is frequently aberrant in lung cancer. Cell cycle inhibitors have emerged as novel therapeutics, in anticipation of overcoming the unrestricted cell division and growth in lung cancer.

Areas covered: In this article, we first address the potential roles of cell cycle proteins and cell cycle deregulation in the development of lung cancer. The review then provides an overview for several major categories of cell cycle inhibitors with particular attention to their tolerability and disease control in early phases of lung cancer trials.

Expert opinion: Targeted agents against different components of cell cycle regulation, such as cyclin-dependent kinase, polo-like kinase, checkpoint kinase and aurora kinase, are currently in clinical development for lung cancer management. Their clinical benefits remain to be defined. When evaluated as single agents in lung cancer, cell cycle inhibitors are often associated with limited clinical activity and tolerable toxicities. The key challenges in the drug development are to understand resistance mechanisms and to identify predictive biomarkers that can potentially guide patient selection and optimize the utility of these targeted inhibitors.     

Emerging drugs for squamous cell lung cancer

Introduction: The management of advanced NSCLC has been shifted by histology-driven treatment and molecularly targeted therapy, especially in lung adenocarcinoma. However, as the second most common histology in NSCLC, the treatment options for squamous cell lung cancer (SQCLC) remain very limited.

Areas covered: The review first discusses the role of histology in management of NSCLC and new cytotoxic agents in SQCLC, and then addresses genomic characterization and potential molecular targets in SQCLC. The article then provides an overview for several major categories of novel molecularly targeted therapies and immune-based strategies with particular attention to ongoing SQCLC trials.

Expert opinion: The key challenges in drug development are to uncover novel actionable targets and to identify predictive biomarkers. Progress in genomic analysis has identified some promising targetable genes and oncogenic pathways in SQCLC with a wave of targeted agents being tested in clinical trials. Immunotherapy has also raised great interest in management of SQCLC, especially agents targeting immune check points, cytotoxic T-lymphocyte antigen-4, programmed death-1 receptor and its ligands. Better understanding of tumor biology and development of novel targeted therapies will help to facilitate more effective personalized therapy for patients with this devastating illness.