Considering adjuvant therapy for stage II melanoma

Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti–CTLA-4 and anti-PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti-PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node-negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma-specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk-stratification and treatment-benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma.     

A survey of treatments used in patients with metastatic melanoma: analysis of 189 patients referred to the National Cancer Institute.

BACKGROUND: Few effective treatments exist for patients with metastatic melanoma. The United States Food and Drug Administration has approved the use of interferon alfa-2b after the resection of locoregional disease, and dacarbazine or interleukin-2 for the treatment of patients with metastatic melanoma beyond the locoregional area, although many additional agents and combinations of agents are currently in use. METHODS: Between January 1997 and June 1998, the Surgery Branch of the National Cancer Institute conducted a prospective analysis of 226 consecutive patients with metastatic melanoma referred for protocol evaluation. The previous systemic treatments these patients received both before and after the development of metastatic disease were tabulated, along with the association of these treatments with formal institutional protocols. Only the identity of the agents and not the dose or the schedule of treatments was considered in this analysis. Complete information could be obtained from 189 of the 226 patients. RESULTS: Of the 189 patients evaluated for this study, 135 (71%) received some form of systemic therapy before referral to the National Cancer Institute. Before the development of metastatic disease, 80 patients were administered 25 different systemic treatments, including 23 different agents. After the development of metastatic disease, 53 patients were administered 57 different systemic and regional treatments, including 37 different agents. After the resection of all metastatic sites, 23 patients were administered nine different systemic adjuvant treatments. Overall, 78 different systemic treatments were administered to these patients. The majority of treatments in each group were not associated with formal institutional protocols. CONCLUSIONS: This study has demonstrated that a large number of agents and different combinations of agents are currently being administered to patients before and after the development of metastatic melanoma, and frequently not within the context of an approved institutional protocol. These results indicate a need for more formal evaluation of treatments in prospective protocols and greater standardization of the treatment of patients with melanoma.     

PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma

Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin''s lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.     

Implementing and evaluating shared decision making in oncology practice

Answer questions and earn CME/CNE Engaging individuals with cancer in decision making about their treatments has received increased attention; shared decision making (SDM) has become a hallmark of patient‐centered care. Although physicians indicate substantial interest in SDM, implementing SDM in cancer care is often complex; high levels of uncertainty may exist, and health care providers must help patients understand the potential risks versus benefits of different treatment options. However, patients who are more engaged in their health care decision making are more likely to experience confidence in and satisfaction with treatment decisions and increased trust in their providers. To implement SDM in oncology practice, physicians and other health care providers need to understand the components of SDM and the approaches to supporting and facilitating this process as part of cancer care. This review summarizes recent information regarding patient and physician factors that influence SDM for cancer care, outcomes resulting from successful SDM, and strategies for implementing SDM in oncology practice. We present a conceptual model illustrating the components of SDM in cancer care and provide recommendations for facilitating SDM in oncology practice. CA Cancer J Clin 2014;64:377–388. © 2014 American Cancer Society .     

Medikamentöse Systemtherapie des Melanoms

Context

Around 3000 melanoma patients are diagnosed with metastatic disease each year in Germany. For more than three decades no substantial therapeutic progress in the treatment of advanced melanoma was made; however, the use of targeted agents and immune modulating antibodies has changed the perception of melanoma as treatment-resistant tumor.

Objective

The aim of this article is to discuss the systemic treatment options for advanced metastatic melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma published in 2013 and other recent publications (PubMed and manual search).

Results

The CTLA-4 blocking antibody, ipilimumab, was the first medication to demonstrate an overall survival benefit in a prospective randomized clinical study of metastatic melanoma. Subsequently selective BRAF as well as MEK inhibitors were also shown to prolong overall survival leading to drug registration. Currently additional agents and antibodies, such as MEK inhibitors for NRAS mutations in melanoma and PD1 blocking antibodies are being tested in clinical phase III studies. Over the next years the combination and sequence of these new agents will further improve the treatment and prognosis of advanced melanoma. Treatment of metastatic melanoma always requires a multidisciplinary approach.

Conclusion

Therapy options for patients suffering from advanced metastatic melanoma have improved in recent years. Nevertheless, clinical studies still remain the best option to improve melanoma treatment and to offer patients innovative and promising treatment options despite the recently achieved progress.     

Ipilimumab,Vemurafenib, Dabrafenib,and Trametinib: Synergistic Competitors in the Clinical Management of BRAF Mutant Malignant Melanoma

There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T‐lymphocyte antigen‐4 blockade, with ipilimumab, and targeting of BRAF^V600, with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.     

Molecular targeted agents—where we are and where we are going

A total of 23 new cancer medicines or indication expansions were approved by the U. S. Food and Drug Administration in 2012. Among these, 12 are new molecular entities (NMEs)-new chemical or biological drugs approved for the first time for oncologic use-and 10 of these NMEs are molecular targeted agents. Among the 10 targeted agents, 4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors, targeting well established targets validated by previously approved agents such as bevacizumab (Avastin) or imatinib (Gleevec). Despite this progress, several questions remain: Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management, especially for tumor types uniquely prevalent in China? This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies, as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.     

Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma

Almost 50% of metastatic melanoma patients harbor a BRAF^V600 mutation andthe introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease.The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.     

Fertility preservation options in pediatric and adolescent patients with cancer

The incidence of childhood cancer has steadily increased since the 1950s, with approximately 16,000 children diagnosed each year. However, with the advent of more effective multimodal therapies, childhood cancer survival rates have continued to improve over the past 40 years, with >80% of patients now surviving into adulthood. Fertility preservation (FP) has become an important quality‐of‐life issue for many survivors of childhood cancer. As a result, the therapeutic options have become less gonadotoxic over time and more patients are being offered FP options. This review examines the indications for consultation, male and female FP options both in the prepubertal patient and adolescent patient, and the unique ethical issues surrounding FP in this vulnerable population. Cancer 2018;124:1867‐76 . © 2018 American Cancer Society.     

Integration of biologic agents with cytotoxic chemotherapy in metastatic colorectal cancer

Colorectal cancer (CRC) remains a leading cause of cancer death in the developed world. Metastatic disease eventually develops in nearly 50% of patients with CRC. Chemotherapy is the mainstay of treatment in metastatic CRC (mCRC); however the majority of patients remain incurable with current therapeutic options. Progress made in the field of surgery, locoregional treatment for low-volume metastatic disease, and systemic chemotherapy has created new treatment paradigms and improved survival in mCRC. Development of new cytotoxic drugs and the advent of targeted agents over the past decade have seen the median overall survival (OS) for mCRC increase from 9 months to > 2 years. Data from trials integrating targeted therapies appear to indicate that not all have efficacy as single agents and the choice of chemotherapy used in combination with these agents may impact results. Ongoing research is leading to identification of new biomarkers of response, further defining the subpopulations who achieve greatest benefit. Hence optimizing treatment for this group of patients has become increasingly complex, requiring a multidisciplinary approach not only to identify those who are curable with resectable disease but also to determine when it is best to incorporate targeted drugs, with which chemotherapy, and in whom. Currently bevacizumab, cetuximab, and panitumumab are the only approved biologic agents for use in mCRC. In this article we discuss the evidence supporting the use of biologic agents with chemotherapy and suggested strategies for their integration into the treatment armamentarium of mCRC.     

Sorafenib for the management of advanced renal cell carcinoma

The approval of sorafenib (Nexavar(?)) launched a new era of targeted therapy for advanced renal cell carcinoma (RCC). Sorafenib was the first oral multikinase inhibitor available for use in RCC, demonstrating a significant clinical benefit for patients living with this disease in the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). As other targeted agents have emerged and expanded options for patients with RCC, understanding the optimal role of targeted therapies in different treatment settings has become more important. This article reviews the expansive clinical evidence supporting the use of sorafenib in RCC, including analyses across a variety of subpopulations, and examines the impact of sorafenib on clinical practice and its future role in RCC.     

Management of patients with HER2‐positive metastatic breast cancer: Is there an optimal sequence of HER2‐directed approaches?

The successful development of therapies targeting the human epidermal growth factor receptor 2 (HER2) has altered the natural progression of disease among patients with HER2‐positive metastatic breast cancer. The monoclonal antibody trastuzumab was the first HER2‐directed agent and it was associated with significantly improved outcomes for patients. Subsequently, other HER2‐directed agents such as the monoclonal antibody pertuzumab, the tyrosine kinase receptor inhibitor lapatinib, and the immunoconjugate trastuzumab emtansine were developed to overcome resistance to trastuzumab and provide additional treatment options for patients. Recent data have demonstrated that the use of these HER2‐directed agents improves outcomes. However, with the emergence of new HER2‐targeted agents, the optimal sequencing of treatment remains unclear. Ongoing research is investigating new HER2 combinations, the role of sequencing, novel HER2‐directed agents, and combinations with other targeted agents to overcome resistance. Cancer 2015;121:17–24 . © 2014 American Cancer Society.     

Understanding biology to tackle the disease: Multiple myeloma from bench to bedside,and back

Answer questions and earn CME/CNE Multiple myeloma (MM) is a cancer of antibody‐producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease‐related end‐organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression‐free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration‐approved drugs in the past 15 years. These advances have resulted in more frequent long‐term remissions, transforming MM into a chronic illness for many patients. CA Cancer J Clin 2014;64:422–444. © 2014 American Cancer Society.     

Surgery for lymph node metastases of medullary thyroid carcinoma: A review

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells that occurs in hereditary and sporadic clinical settings. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation, and therefore surgery is the most effective option for curative therapy, reduction in tumor burden, or effective palliation. In patients undergoing preventative surgery for hereditary MTC, central lymph node dissection should be considered if the calcitonin level is elevated. Preservation of parathyroid function in these young patients is of paramount importance. In patients with established primary tumors, systematic surgical removal of lymph node basins (compartmental dissection) should be guided by ultrasound mapping of lymph node metastases and level of serum calcitonin. A “berry‐picking” approach is discouraged. Newly approved targeted molecular therapies offer wider treatment options for patients with progressive or metastatic disease. Cancer 2016;122:358–366. © 2015 American Cancer Society.     

Improving the outcome for children with cancer: Development of targeted new agents

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5‐year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short‐term and long‐term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome‐positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric‐specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra‐rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer. CA Cancer J Clin 2015;65: 212–220. © 2015 American Cancer Society.     

Newer medical therapies for metastatic soft tissue sarcoma

Introduction: Metastatic/advanced soft tissue sarcoma has a poor prognosis conventionally, treatment options have been limited. In recent years, this area has been a rich ground for research with many new drugs being approved and several more in the pipeline. With multiple new treatment options available, it is vital to keep up pace with this rapidly changing field.

Areas covered: Recent data regarding use of novel agents in advanced soft tissue sarcoma is reviewed with a focus on clinical applicability. The goal is to guide the clinician into choosing appropriate lines of therapy for the individual patient in light of recent availability of multiple new treatment options.

Expert commentary: Patients with advanced soft tissue sarcoma can expect to receive several lines of therapy in the modern era. Tumor histology should ideally guide the choice of therapy. The new FDA approved second line drugs viz, trabectedin, pazopanib and eribulin should be considered first after failure of doxorubicin-based chemotherapy. Additional options have become available, such as antiangiogenic agents, mTOR inhibitors, and several new molecules targeting specific oncogenic pathways. All these agents have a role in treating soft tissue sarcoma, and careful individualization of therapy can help achieve optimal outcomes in these challenging patients.     

Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts’ experience. Diagnosis is made clinically and staging is based upon the AJCC system. CMs are excised with one to two centimetre safety margins. Sentinel lymph node dissection is routinely offered as a staging procedure in patients with tumours more than 1 mm in thickness, although there is as yet no resultant survival benefit. Interferon-α treatment can be offered to patients with more than 1.5 mm in thickness and stage II to III melanoma as an adjuvant therapy, as this treatment increases the relapse-free survival. The lack of a clear survival benefit and the presence of toxicity however limit its use in practice. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic medical treatment is indicated, but with, to date, low response rates. Therapeutic decisions should be made by the melanoma team and the informed patient after full discussion of the options.     

Progress in emerging therapies for advanced prostate cancer

The landscape of prostate cancer treatment is rapidly changing as extensive research into potential therapies yields new options. In this article, the literature is reviewed to identify emerging therapies for advanced prostate cancer. Emphasis is placed on agents that have been approved in the United States of America (USA) and the European Union, or that have reached phase III clinical studies. Several new therapies have been approved in recent years across different stages of the natural history of the disease. Degarelix, a luteinizing hormone-releasing hormone antagonist, has been approved for reducing testosterone to castrate levels in hormone-sensitive disease. No new agents have been approved for use in combination with docetaxel chemotherapy, the current standard of care for metastatic castration-resistant prostate cancer. One immunotherapy, sipuleucel-T, has been approved (USA only) in the pre-docetaxel setting. Cabazitaxel, a next-generation taxane, and abiraterone acetate, an inhibitor of androgen biosynthesis, have both been approved as second-line agents following chemotherapy. Enzalutamide (MDV3100), an androgen receptor antagonist, has been shown to increase overall survival in the post-chemotherapy setting in metastatic disease. Denosumab, an antibody-based bone-targeted agent, has been approved for the prevention of skeletal-related events in patients with bone metastases. Radium-223 chloride, an α-emitting radiopharmaceutical, is likely to gain approval soon following promising results in a phase III trial. Clinical studies involving other promising agents are ongoing. The emergence of these therapies adds to the growing armamentarium against prostate cancer.