Amanda J. Walker

Tumor immunology and cancer immunotherapy: Summary of the 2013 SITC primer

Knowledge of the basic mechanisms of the immune system as it relates to cancer has been increasing rapidly. These developments have accelerated the translation of these advancements into medical breakthroughs for many cancer patients. The immune system is designed to discriminate between self and non-self, and through genetic recombination there is virtually no limit to the number of antigens it can recognize. Thus, mutational events, translocations, and other genetic abnormalities within cancer cells may be distinguished as “altered-self” and these differences may play an important role in preventing the development or progression of cancer. However, tumors may utilize a variety of mechanisms to evade the immune system as well. Cancer biologists are aiming to both better understand the relationship between tumors and the normal immune system, and to look for ways to alter the playing field for cancer immunotherapy. Summarized in this review are discussions from the 2013 SITC Primer, which focused on reviewing current knowledge and future directions of research related to tumor immunology and cancer immunotherapy, including sessions on innate immunity, adaptive immunity, therapeutic approaches (dendritic cells, adoptive T cell therapy, anti-tumor antibodies, cancer vaccines, and immune checkpoint blockade), challenges to driving an anti-tumor immune response, monitoring immune responses, and the future of immunotherapy clinical trial design.

Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression?

A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms--acute, subacute and late--and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem.

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer.

Correlation of Clinical Stage and Performance Status With Quality of Life in Patients Seen in a Pancreas Multidisciplinary Clinic

INTRODUCTION The objectives of this study were to evaluate quality of life (QoL) in patients presenting to the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC), and to examine associations between disease status, performance status, and QoL in order to identify patient subgroups that are most at risk for reduced QoL. PATIENTS AND METHODS Data from 77 patients were evaluated. At initial presentation, disease and performance status were assessed, as well as QoL, which was obtained with the European Organisation for Research and Treatment of Cancer QLQ-PAN26 questionnaire. Statistical analyses examined associations between QoL, disease status, and performance status. RESULTS Digestive symptoms (P < .003) significantly differed by pancreatic disease status (resectable, resected, locally advanced, and metastatic). Patients with a worse performance status, defined as Eastern Cooperative Oncology Group ≥ 1, were more likely to report symptomatic pancreatic pain (P = .001), digestive symptoms (P = .017), cachexia (P = .004), and ascites (P < .001) compared with patients with a performance status of 0. The majority (92%) of patients reported a significant fear of future health problems, regardless of disease status or performance status. CONCLUSION Although several measures of QoL have been observed in all patients, certain measures appear to correlate specifically with worse disease status. Therefore, routine assessment of QoL is suggested in order to guide treatment decisions. Further investigation on optimizing the use of QoL measures and patient-reported outcomes to better tailor management is warranted.

Use of standardized uptake value thresholding for target volume delineation in pediatric Hodgkin lymphoma

PURPOSE A limitation of [(18)F] 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDGPET) in radiation planning for Hodgkin lymphoma (HL) is significant variability in delineation of tumor volume. One approach to reduce variability is to apply automatic or semiautomatic segmentation methods such as thresholding based on a percent tumor maximum standardized uptake value (SUVmax). Here, we apply various tumor SUVmax thresholds and examine their effects in involved field radiation therapy (IFRT) and involved site radiation therapy (ISRT) target volumes. METHODS AND MATERIALS PET/computed tomography data sets were reviewed for 16 pediatric and young adult patients treated with IFRT. The following percent tumor SUVmax thresholds were applied to the prechemotherapy PET: 15%, 20%, 25%, 30%, 35%, and 40%. Clinical target volumes for IFRT and ISRT plans were manually generated based on these threshold volumes (CTVPET) and compared with clinical target volumes generated using the standard qualitative visual method (CTVQVM). Treatment plans were generated, doses to normal structures were compared, and the optimum threshold, defined as the CTVPET that corresponded to the percent overlap closest to 100% when compared with the CTVQVM, was determined. RESULTS On average, there was a 7.6-fold increase in PET volume between 40% and 15% SUVmax. When the 6 SUVmax thresholds were applied in the design of target volumes for IFRT, 2 of 16 patients had a change in treatment volume. There was a 2.4-fold increase in ISRT CTVs generated based on the 15% and 40% SUVmax, which translated into a clinically significant decrease in dose to normal structures when the ISRT plans that were generated using the 15% SUVmax volumes were compared with the 40% SUVmax. In most patients, the optimum threshold was SUVmax 15%. CONCLUSIONS Accurate target volume delineation with [(18)F] 2-fluoro-2-deoxy-d-glucose PET in HL is challenging and may require more precise and reproducible segmentation methods as we move toward more conformal therapies.

Analysis of fiducials implanted during EUS for patients with localized rectal cancer receiving high-dose rate endorectal brachytherapy

Colorectal cancer is the third most common malignancy and the third leading cause of cancer-related death in the United States, with more than 40,000 rectal cancer cases diagnosed each year.1 Standard treatment for localized (ie, resectable) rectal cancer includes 5-fluorouracil (5-FU)-based chemoradiation therapy followed by surgery. Improved radiation technology including image-guided radiation therapy (RT) and brachytherapy (contact therapy) can allow for the delivery of higher doses of RT to the rectal tumor over a shorter time period. These treatments may result in improved outcomes; however, they require fiducial markers to allow better localization and targeting of the rectal tumor. In this retrospective study, we evaluated the role of gold fiducial markers in patients receiving neoadjuvant endorectal brachytherapy in patients with localized rectal tumors.

Patterns of failure after involved field radiation therapy for pediatric and young adult Hodgkin lymphoma

Involved field radiation therapy (IFRT) is integral in curative therapy for Hodgkin lymphoma (HL), although primarily used in patients with intermediate/high‐risk HL. We present failure patterns and clinical outcomes in a cohort of pediatric and young adult patients with HL treated with IFRT at the Johns Hopkins Hospital.

PET/CT in RT Planning

Radiation therapy is a key component of combined modality therapy for Hodgkin’s lymphoma. In an effort to improve the therapeutic ratio and prevent late effects, radiation fields designed to encompass entire lymph node regions have recently been replaced with conformal methods of target volume delineation, known as involved-site radiation therapy (ISRT) and involved-node radiation therapy (INRT). Due to an increased risk of marginal misses with these new approaches, FDG-PET has become a critical aspect of modern radiation therapy planning, given its ability to identify areas of disease overlooked on CT. However, there are many challenges inherent to using PET for radiation planning. The current standard is a qualitative visual method, whereby PET/CT images are fused to the planning CT and the radiation oncologist contours target volumes using information from both image sets. Although not always possible, this method is best applied with input from an experienced radiologist or nuclear medicine physician given the complex nature of PET imaging and high rates of false positives. Due to a significant degree of inter- and intra-observer variability with this method, an effort has been made to explore the use of automated segmentation methods, which vary from simple standardized uptake value (SUV) cutoffs to more complex algorithms that incorporate signal-to-background ratios and sophisticated edge detection methodologies. This chapter covers the role of PET/CT in radiation planning for HL including automated and semiautomated contouring methods and the common pitfalls and artifacts in PET that are relevant when applied to radiation planning.

Radiosensitizers in pancreatic cancer—Preclinical and clinical exploits with molecularly targeted agents

Radiotherapy (RT) is an integral part of both definitive and palliative cancer management, which is estimated to be indicated in the treatment of 52% of patients with cancer. Although RT can afford local control, the addition of systemic therapy may manage occult distant disease and, in some cases, also offer radiosensitization benefit. Yet, the use of conventional cytotoxic chemotherapy as a means of radiosensitization may lead to increased toxicity owing to the lack of specificity for tumor cells. Therefore, there has been evolving interest in identifying agents that selectively target tumor-specific pathways important in RT-induced cell death with the goal of augmenting the effects of RT while minimizing sensitization of normal tissues. Many of the targeted agents, currently studied as potential radiosensitizers, are cytostatic; although unlike conventional cytotoxic chemotherapies, these agents may avoid or reduce normal tissue toxicity by exploiting molecular differences between malignant and nonmalignant cells. Yet, despite the potential benefit of using novel targeted agents as radiosensitizers, there have been relatively few clinical trials involving the combination of such agents and RT. Although there are an estimated 400 phase I non-RT oncology trials per year, there were only approximately 30 phase I and I/II trials utilizing RT in 2009, which may be due in part to several limitations specific to combination radiosensitizer and RT trials. Moreover, despite success in phase III clinical trials, agents such as the hypoxic tumor cell radiosensitizer, nimorazole, may not be adopted into standard clinical practice. Overgaard and colleagues provide a review of multiple factors contributing to lack of implementation of this and other hypoxic radiosensitizers. To address the lack of formal guidelines for the development of such agents, recommendations and strategies for radiosensitizer development in preclinical and clinical trials have been suggested. This review provides a brief summary of these recommendations.