The Affordable Care Act (ACA) has reformed US health care delivery through insurance coverage expansion, experiments in payment design, and funding for patient-centered clinical and health care delivery research. The impact on cancer care specifically has been far reaching, with new ACA-related programs that encourage coordinated, patient-centered, cost-effective care. Insurance expansions through private exchanges and Medicaid, along with preexisting condition clauses, have helped more than 20 million Americans gain health care coverage. Accountable care organizations, oncology patient-centered medical homes, and the Oncology Care Model-all implemented through the Center for Medicare & Medicaid Innovation-have initiated an accelerating shift toward value-based cancer care. Concurrently, evidence for better cancer outcomes and improved quality of cancer care is starting to accrue in the wake of ACA implementation.

Unprecedented advances in the treatment of melanoma and the large number of investigational therapies entering clinical studies not only represent outstanding achievements, but also create major challenges for clinical research in melanoma. The challenges for accrual and for developing important new data in trials include the relatively low incidence of melanoma compared with other diseases, a shrinking pool of patients for trials because of the high efficacy of standard of care therapy, requirements for larger studies and longer duration of follow-up to detect signals of activity or establish efficacy, and suboptimal predictive biomarkers for the vast number of new combinations and new agents. The cost of new treatments remains a major concern, particularly because current standard of care involves doublets of targeted therapy or immune therapy, and clinically meaningful further increases in efficacy may require development of triplets or larger multidrug combinations. Toxicities of the current doublets, particularly for immune therapy, may limit development of some multidrug regimens or may require novel solutions such as sequencing or alternating schedules. The activity of first-line therapies may push development of new drugs or combinations into the second-line setting or into subgroups with suboptimal response to the first-line doublets as identified by predictive clinical variables or tissue biomarkers.

From the Department of Radiology and Biomedical Imaging, Yale Univesrity School of Medicine New Haven, CT. Reprints: Jean-Francois H. Geschwind, MD, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520. E-mail: [email protected]. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Stereotactic body radiation therapy (SBRT) has become a viable treatment option for the many patients who receive a diagnosis of localized prostate cancer each year. Technological advancements have led to tight target conformality, allowing for high-dose-per-fraction delivery without untoward normal tissue toxicity. Biochemical control, now reported up to 5 years, appears to compare favorably with dose-escalated conventionally fractionated radiotherapy. Moreover, toxicity and quality of life follow-up data indicate genitourinary and gastrointestinal toxicities are likewise comparable to conventional radiation therapy. Nevertheless, because of the long natural history of prostate cancer, extended follow-up will be necessary to confirm these impressive initial results. Within this prostate SBRT review, we explore the detailed rationale for SBRT treatment, the diverse SBRT techniques utilized and their unique technical considerations, and finally data for SBRT clinical efficacy and treatment-related toxicity.

Immunotherapy, particularly immune-checkpoint inhibition, is producing encouraging clinical responses and affecting the way numerous cancers are treated. Yet immune-checkpoint therapy is not effective for many patients, and even those who initially respond can experience relapse, fueling interest in finding new processes or tools to improve the effectiveness of these novel therapeutics. One such tool is radiation. Both preclinical and clinical studies have demonstrated that the systemic effects of immunotherapy can be amplified when it is used in combination with radiation and, conversely, that the immunogenic effects of local irradiation can be amplified and extended to distant sites when used with immunotherapy. We review how stereotactic ablative radiation therapy, a technique specifically indicated for tumors treated with immune-checkpoint inhibitors, can potentiate the effects of immune-checkpoint therapy. We further explore how these novel therapeutics may transform radiation, previously considered a local treatment option, into powerful systemic therapy.

The study of oncogenic RAS mutations has led to crucial discoveries regarding cancer molecular biology and behavior and has been integral in shaping the era of targeted cancer therapy. RAS mutations are one of the most common oncogenic drivers in human cancer, and intense efforts to find a clinically effective inhibitor are ongoing. Despite these efforts, targeting RAS mutations has remained elusive, so much so that some have termed oncogenic RAS mutations as "undruggable." In this review, we will summarize current understanding of RAS biology, explore strategies to inhibit RAS oncoproteins and its downstream effectors, and discuss recently described complexities that have shed new light on this pursuit.

Initial investigations of immune-checkpoint therapy targeting Programmed cell death protein 1/programed death ligand 1 in unselected colorectal cancer (CRC) has shown limited to no activity. However, a subset of CRC, characterized by mismatch deficiency or microsatellite instability high (MSI-high), has shown robust early signals of antitumor activity with PD1 targeting. It is now clear that MSI-high CRC represents a unique molecular and immunological tumor subset. Further study and understanding of the immunological microenvironment of these tumors will be critical to continued success with immune-based approaches in MSI-high CRC. This review discusses the current biological understanding of MSI-high CRC and outlines the current and ongoing clinical trials investigating immunotherapy.

The landscape of treatment for chronic lymphocytic leukemia is rapidly changing at present. Considerable improvement has been achieved with the introduction of the anti-CD20 antibodies, and chemoimmunotherapy has now become an established standard for patients without the high-risk features del(17p)/TP53 mutation. Also, the outcome of patients with these adverse genetic aberrations was dramatically improved with the introduction of the kinase inhibitors ibrutinib and idelalisib. Different combinations of these and additional novel agents are currently evaluated in clinical trials. The combination of the Bruton tyrosine kinase inhibitor ibrutinib with an anti-CD20 antibody is an attractive option, because both drugs act synergistically: ibrutinib redistributes the CLL cells from their homing organs to the peripheral blood, and obinutuzumab eliminates the leukemic cells in the blood with particular efficiency. Adding the Bcl-2 antagonist venetoclax could further intensify the treatment of CLL. This combination might hold the potential to achieve a deep remission with an eradication of residual CLL cells and thus lead to long-term remissions of CLL.

Autologous adoptive T-cell therapies have made tremendous strides over the last few years with excitement currently being generated by technologies that can reprogram T-cell specificities toward any desired antigen including chimeric antigen receptors and recombinant T-cell receptors. Time will tell whether these new genetically engineered T-cell technologies will be effective as advertised, especially in solid tumors, considering the limited availability of specific antigens and the difficulty in managing the unpredictable on-target, off-tissue toxicities. However, a form of T-cell therapy that has been utilized in patients more than any other and has left a lasting mark in the field is tumor-infiltrating lymphocytes (TILs). Tumor-infiltrating lymphocyte therapy has consistently yielded durable clinical responses in selected patients with metastatic melanoma and is now being increasingly applied to treat other solid tumors, including head and neck squamous cell carcinoma, cervical cancer, breast cancer, and lung cancer. Despite its long history in the clinic and key developments over the last few decades that have augmented response rates and have made TIL manufacturing more streamlined, a number of key outstanding conceptual questions remain to be answered in the TIL therapy field. In this review, we address critical questions, including the mechanism of action of TILs and active T-cell subsets, the current need for lymphoablative preconditioning, predictive biomarkers, the role of combination therapy such as checkpoint blockade, new excitement over the recognition of mutated antigens (the "mutanome") by TILs, and issues in developing TILs for nonmelanoma indications. In each case, we will critically discuss the main issues and concerns and how they can affect the eventual positioning of TIL therapy in the mainstream of cancer care.

Abnormal tumor vasculature is a potent mediator of treatment resistance because it results in heterogeneous perfusion, hypoxia, increased interstitial fluid pressure, and incomplete penetration of cytotoxic chemotherapies. Targeting this abnormal tumor vasculature is a promising therapeutic strategy, but results with antiangiogenic drugs in brain cancer have been mixed. Vasculature's response to treatment is a dynamic physiological process that can change rapidly throughout treatment, so it requires noninvasive techniques to serially monitor these changes in order to improve outcome. We review the role of vascular magnetic resonance imaging to measure tumor response to treatment and highlight opportunities and future avenues for expanding these promising techniques.