Current Treatment Options in Oncology

QT Interval Prolongation Associated With Cytotoxic and Targeted Cancer Therapeutics Opinion statement Cardiovascular toxicities are potentially serious treatment limiting complications of many different cancer therapeutics including traditional cytotoxic chemotherapies as well as targeted- and immunotherapies. As a result, there is increased monitoring for cancer treatment-related cardiotoxicities, ranging from heart failure to arrhythmias. Many anticancer treatments are known to prolong the QT interval through a variety of mechanisms including direct effects on ion channels and indirectly via intracellular signaling pathways. While QT prolongation increases the risk for the potentially life-threatening ventricular arrhythmia torsades de pointes, the incidence of this arrhythmia in the setting of most cancer treatments is quite rare, and the majority of patients can continue safely receiving these medications despite their QT prolonging potential. A multidisciplinary approach to the cardiovascular care of the cancer patient is essential to mitigate risk of cardiotoxicity while minimizing unnecessary treatment disruption of potentially life-saving cancer treatments.

Pediatric Cardio-Oncology: Development of Cancer Treatment-Related Cardiotoxicity and the Therapeutic Approach to Affected Patients Opinion statement The past 5 decades have seen significant improvements in outcomes for pediatric patients with cancer. Unfortunately, children and adolescents who have been treated for cancer are five to six times more likely to develop cardiovascular disease as a result of their therapies. Cardiovascular disease may manifest in a plethora of ways, from asymptomatic ventricular dysfunction to end-stage heart failure, hypertension, arrhythmia, valvular disease, early coronary artery disease, or peripheral vascular disease. A number of treatment modalities are implicated in pediatric and adult populations, including anthracyclines, radiation therapy, alkylating agents, targeted cancer therapies (small molecules and antibody therapies), antimetabolites, antimicrotubule agents, immunotherapy, interleukins, and chimeric antigen receptor T cells. For some therapies, such as anthracyclines, the mechanism of injury is elucidated, but for many others it is not. While a few protective strategies exist, in many cases, observation and close monitoring is the only defense against developing end-stage cardiovascular disease. Because of the variety of potential outcomes after cancer therapy, a one-size-fits-all approach is not appropriate. Rather, a good working relationship between oncology and cardiology to assess the risks and benefits of various therapies and planning for appropriate surveillance is the best model. When disease is identified, any of a number of therapies may be appropriate; however, in the pediatric and adolescent population supportive data are limited.

Diagnosis and Management of Subcutaneous Soft Tissue Sarcoma Opinion statement The proper diagnosis and treatment planning for subcutaneous soft tissue sarcoma is very important. Soft tissue tumors can occur anywhere in the body, but if they occur subcutaneously, patients can easily notice a subcutaneous soft tissue mass. Therefore, it is possible to determine through recording, the growth speed of the mass, which is often difficult to obtain with deep-situated soft tissue masses. Palpation can also provide information about the firmness and mobility of the mass. Thus, history taking and physical examinations are informative for subcutaneous soft tissue tumors, compared to tumors that occur deeply. Because subcutaneous soft tissue tumors are easily recognized, they are often resected, without sufficient imaging analyses or thorough treatment planning. An operation performed based on such an inadequate preoperative plan is called a "whoops surgery." In the case of "whoops surgeries," subsequent radical surgery is required to remove additional areas, including hematomas that result from the initial surgery, that require a wider range of resection and soft tissue reconstruction. Therefore, as with deep-seated soft tissue tumors, it is important to conduct careful imaging examinations and make appropriate preoperative plans for subcutaneous soft tissue tumors. Subcutaneous soft tissue sarcomas often show an invasive pattern, and such tumors require a more careful assessment to prevent local recurrence after surgery. During surgery, it is necessary to remove the entire infiltration area along the fascia. Sometimes, an adequately wide excision is necessary, which is considered the minimum necessary procedure to eradicate the lesion. As noted above, clinicians who see patients with subcutaneous soft tissue tumors are encouraged to have sufficient knowledge and experience regarding the diagnosis and treatment. This article is intended for all doctors who deal with subcutaneous soft tissue tumors and focuses on essential points regarding their diagnosis and management.

Correction to: Immunotherapy Advances in Urothelial Carcinoma In the original version of this article, which published in Current Treatment Options in Oncology, Volume 20, Issue 12, December 2018, the surname of the third author was captured incorrectly. The name shown above is correct.

The Role of CDK4/6 Inhibitors in Breast Cancer Opinion statement Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40–45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.

Multimodality Therapy of Patients with Refractory Meningiomas Opinion statement Recurrent and refractory meningiomas are a clinical challenge and treatment at the time of recurrence is not well delineated. Treatment with surgery and/or radiation remain the mainstay, but each has their limitations and risks. The search for an adjuvant systemic therapy continues and as many of the initially promising approaches have not had reproducible responses. Bevacizumab has shown some efficacy in controlling recurrent disease and could be useful in disease that is multifocal or in close proximity to critical structures. Other targeted therapies, as well as immunotherapy, are being studied and trials are in development. Though we are hopeful that these novel therapies will benefit patients with refractory meningiomas, we approach them with some trepidation. This is due to prior failures of immunotherapy and targeted therapy in central nervous system disease. In addition, there is known difficulty in developing trials and assessing response with these slow-growing tumors.

Cardiotoxicity of Contemporary Breast Cancer Treatments Opinion statement Treatment-related cardiotoxicity remains a significant concern for breast cancer patients undergoing cancer treatment and extends into the survivorship period, with adverse cardiovascular (CV) outcomes further compounded by the presence of pre-existing CV disease or traditional CV risk factors. Awareness of the cardiotoxicity profiles of contemporary breast cancer treatments and optimization of CV risk factors are crucial in mitigating cardiotoxicity risk. Assessment of patient- and treatment-specific risk with appropriate CV surveillance is another key component of care. Mismatch between baseline cardiotoxicity risk and intensity of cardiotoxicity surveillance can lead to unnecessary downstream testing, increased healthcare expenditure, and interruption or discontinuation of potentially life-saving treatment. Efforts to identify early imaging and/or circulating biomarkers of cardiotoxicity and develop effective management strategies are needed to optimize the CV and cancer outcomes of breast cancer survivors.

Cancer and Coronary Artery Disease: Common Associations, Diagnosis and Management Challenges Opinion statement Coronary artery disease (CAD) and cancer often occur in the same patients via common biological pathways and shared risk factors. A variety of chemotherapeutic agents and radiotherapy can influence the development and progression of CAD. The diagnosis of ischaemic heart disease may be challenging in certain cases such as premature CAD secondary to radiotherapy. The management of CAD in cancer patients in the stable, acute and chronic settings can often be complicated by issues related to ongoing or previous cancer treatment or the cancer itself. A multidisciplinary approach in the setting of a cardio-oncology service is often best-served to optimally treat such patients.

Pain in Cancer Survivors: How to Manage Opinion statement Managing pain in cancer survivors requires that oncologists understand the common painful syndromes that can occur from treatment or disease. Assessment no longer singularly focuses on pain characteristics (e.g., intensity, quality, location), now incorporating a strong focus on functional impairment and potential improvement that might occur with adequate treatment. Improvement in function is now the goal used to measure success. In addition, assessment must incorporate risk factors that might predispose patients to substance use disorder so that interventions can be implemented to mitigate this risk. Universal precautions are measures that help assess and ensure adherence to the treatment plan and may include the use of agreements, urine toxicology, and review of dispensing information derived from state prescription drug monitoring program (PDMP). These are generally obtained annually for all individuals, although some states have instituted mandatory review of the PDMP whenever prescribing an opioid. For patients at moderate to high risk for misuse of opioids, where opioids are warranted for the treatment of their pain syndrome, universal precautions are instituted more frequently. Other measures may include prescribing a 1- to 2-week supply of medications if compulsive use leads the patient to running out of drug early, and in some cases, family members may be employed to dispense daily allotments of the medication. When opioids are no longer indicated, gradual tapering of the drug by approximately 10% per month is generally sufficient to prevent withdrawal symptoms and ensure patient acceptance.

Malignant Melanoma: Autoimmunity and Supracellular Messaging as New Therapeutic Approaches Opinion statement Melanoma is one of the most aggressive forms of cancer, with a high mortality rate in the absence of a safe and curable therapy. As a consequence, several procedures have been tested over time, with the most recent (immunological and targeted) therapies proving to be effective in some patients. Unfortunately, these new treatment options continue to generate debate related to the therapeutic strategy (intended to maximize the long-term results of patients with melanoma), not only about the monotherapy configuration but also regarding association/succession between distinct therapeutic procedures. As an example, targeted therapy with BRAF inhibitors proved to be effective in advanced BRAF-mutant melanoma. However, such treatments with BRAF inhibitors lead to therapy resistance in half of patients after approximately 6 months. Even if most benign nevi incorporate oncogenic BRAF mutations, they rarely become melanoma; therefore, targeted therapy with BRAF inhibitors should be viewed as an incomplete or perfectible therapy. Another example is related to the administration of immune checkpoint inhibitors/ICIs (anti-CTLA-4 antibodies, anti-PD-1/PD-L1 antibodies), which are successfully used in metastatic melanoma. It is currently believed that CTLA-4 and PD-1 blockade would favor a strong immune response against cancer cells. The main side effects of ICIs are represented by the development of immune-related adverse events, which in some cases can be lethal. These ICI side effects would thus be not only therapeutically counterproductive but also potentially dangerous. Surprisingly, a subset of immune-related adverse events (especially autoimmune toxicity) seems to be clearly correlated with better therapeutic results, perhaps due to an additional therapeutic effect (currently insufficiently studied/exploited). Contrary to the classical approach of cancer (considered until now an uncontrolled division of cells), a very recent and comprehensive theory describes malignancy as a supracellular disease. Cancerous disease would therefore be a disturbed supracellular process (embryogenesis, growth, development, regeneration, etc.), which imposes/coordinates an increased rhythm of cell division, angiogenesis, immunosuppression, etc. Melanoma is presented from such a supracellular perspective to be able to explain the beneficial role of autoimmunity in cancer (autoimmune abortion/rejection of the melanoma-embryo phenotype) and to create premises to better optimize the newly emerging therapeutic options. Finally, it is suggested that the supracellular evolution of malignancy implies complex supracellular messaging (between the cells and host organism), which would be interfaced especially by the extracellular matrix and noncoding RNA. Therefore, understanding and manipulating supracellular messaging in cancer could open new treatment perspectives in the form of digitized (supracellular) therapy.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182