Seminars in Radiation Oncology

Magnetic resonance image guided radiation therapy (MRIgRT) is a relatively new technology that has already shown outcomes benefits but that has not yet reached its clinical potential. The improved soft-tissue contrast provided with MR, coupled with the immediacy of image acquisition with respect to the treatment, enables expansion of on-table adaptive protocols, currently at a cost of increased treatment complexity, use of human resources, and longer treatment slot times, which translate to decreased throughput...

The introduction of MR-guided treatment machines into the radiation oncology clinic has provided unique challenges for the radiotherapy QA program. These MR-linac systems require that existing QA procedures be adapted to verify linac performance within the magnetic field environment and that new procedures be added to ensure acceptable image quality for the MR system. While both high and low-field MR-linac options exist, this chapter is intended to provide a structure for implementing a QA program within the low-field MR environment...

The recent introduction of a commercial 1.5 T MR-linac system has considerably improved the image quality of the patient acquired in the treatment unit as well as enabling online adaptive radiation therapy (oART) treatment strategies. Quality Assurance (QA) of this new technology requires new methodology that allows for the high field MR in a linac environment. The presence of the magnetic field requires special attention to the phantoms, detectors, and tools to perform QA. Due to the design of the system, the integrated megavoltage imager (MVI) is essential for radiation beam calibrations and QA...

Recognizing the potential of quantitative imaging biomarkers (QIBs) in radiotherapy, many studies have investigated the prognostic value of quantitative MRI (qMRI). With the introduction of MRI-guided radiotherapy systems, the practical challenges of repeated imaging have been substantially reduced. Since patients are treated inside an MRI scanner, acquisition of qMRI can be done during each fraction with limited or no prolongation of the fraction duration. In this review paper, we identify the steps that need been taken to move from MR as an imaging technique to a useful biomarker for MRI-guided radiotherapy (MRgRT)...

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Optimal management of cancer patients relies heavily on late-phase oncology randomized controlled trials. A comprehensive understanding of the key considerations in designing and interpreting late-phase trials is crucial for improving subsequent trial design, execution, and clinical decision-making. In this review, we explore important aspects of late-phase oncology trial design. We begin by examining the selection of primary endpoints, including the advantages and disadvantages of using surrogate endpoints...

The paradigm of oligometastatic disease (OMD), characterized by a limited number of metastases potentially amenable to local therapies, presents unique opportunities and challenges in clinical trial design and implementation. Although local ablative therapies, such as stereotactic body radiation therapy, have shown promise in improving outcomes for patients with OMD, there is a lack of large-scale randomized phase III trials supporting their widespread use. This paper outlines the key challenges in trial design and implementation in the oligometastatic setting, including appropriate patient selection, the definition of the oligometastatic state, trial design considerations, endpoint selection, and logistical considerations related to enrollment and follow-up...

Advances in proton therapy have garnered much attention and speculation in recent years as the indications for proton therapy have grown beyond pediatric, prostate, spine, and ocular tumors. To achieve and maintain consistent access to this cancer treatment and to ensure the future viability and availability of proton centers in the United States, a call for evidence has been heard and answered by proton radiation oncologists. Answers provided in this review include the evolution of proton therapy research, rationale for proton clinical trial design, challenges in and barriers to the conduct of proton therapy research, and other unique considerations for the study of proton therapy...

Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes...

The practice of oncology requires analyzing and synthesizing abundant data. From the patient's workup to determine eligibility to the therapies received to the post-treatment surveillance, practitioners must constantly juggle, evaluate, and weigh decision-making based on their best understanding of information at hand. These complex, multifactorial decisions have a tremendous opportunity to benefit from data-driven machine learning (ML) methods to drive opportunities in artificial intelligence (AI). Within the past 5 years, we have seen AI move from simply a promising opportunity to being used in prospective trials...

Randomized controlled trials (RCTs) are the gold standard for comparative-effectiveness research (CER). Since the 1980s, there has been a rise in the creation and utilization of large national cancer databases to provide readily accessible "real-world data" (RWD). This review article discusses the role of RCTs in oncology, and the role of RWD from the national cancer database in CER. RCTs remain the preferred study type for CER because they minimize confounding and bias. RCTs have challenges to conduct, including extensive time and resources, but these factors do not impact the internal validity of the result...

Growing evidence has demonstrated significant, persistent, and widespread disparities in cancer clinical trial enrollment across myriad disease sites and target populations. Although mechanisms underlying such disparities are complex and multifactorial, clinical trial eligibility criteria may serve as a key structural barrier to equitable and diverse trial enrollment. In this review, we provide an overview of the data describing historical and current disparities in cancer clinical trial enrollment and subsequently describe several patient-, institution-, and trial-related factors which appear to be key drivers of enrollment inequity, with specific discussion regarding the impact of eligibility criteria...

Underreporting of patient symptoms by clinicians is a common and well-documented phenomenon that has led to integrating patient-reported outcomes (PROs) as endpoints into clinical trials. While PROs are often used to measure disease symptoms, cancer therapy toxicities, and quality of life, they can also assess patients' general experiences and preferences. With the increasing use of electronic medical records and the digital health revolution in oncology, conversion from paper to electronic PROs (ePROs) has also facilitated the integration of PROs into routine care...

The concept of informed consent has evolved considerably over the course of the 20th century, leading to its establishment as a foundational ethical principle for the conduct of biomedical research in the United States. Even though it is now a highly regulated part of cancer research, the process of obtaining informed consent is often impeded by systemic, clinician, and patient factors that require both small- and large-scale intervention. New challenges and considerations continue to emerge due to innovations in clinical trial design, increases in utilization of genomic sequencing, and advances in genomic editing and artificial intelligence...

Head and neck cancer is notoriously challenging to treat in part because it constitutes an anatomically and biologically diverse group of cancers with heterogeneous prognoses. While treatment can be associated with significant late toxicities, recurrence is often difficult to salvage with poor survival rates and functional morbidity.1 , 2 Thus, achieving tumor control and cure at the initial diagnosis is the highest priority. Given the differing outcome expectations (even within a specific sub-site like oropharyngeal carcinoma), there has been growing interest in personalizing treatment: de-escalation in selected cancers to decrease the risk of late toxicity without compromising oncologic outcomes, and intensification for more aggressive cancers to improve oncologic outcomes without causing undue toxicity...

There is significant rationale for combining radiation therapy (RT) and immuno-oncology (IO) agents, but the optimal radiation parameters are unknown. This review summarizes key trials in the RT and IO space with a focus on RT dose. Very low RT doses solely modulate the tumor immune microenvironment, intermediate doses both modulate the tumor immune microenvironment and kill some fraction of tumor cells, and ablative doses eliminate the majority of target tumor cells and also possess immunomodulatory effects...

Radiopharmaceutical therapy (RPT) is an invigorated form of cancer therapy that systemically delivers targeted radioactive drugs to cancer cells. Theranostics is a type of RPT that utilizes imaging, either of the RPT drug directly or a companion diagnostic, to inform whether a patient will benefit from the treatment. Given the ability to image the drug onboard theranostic treatments also lends itself readily to patient-specific dosimetry, which is a physics-based process that determines the overall absorbed dose burden to healthy organs and tissues and tumors in patients...

Improvements in radiotherapy delivery have enabled higher therapeutic doses and improved efficacy, contributing to the growing number of long-term cancer survivors. These survivors are at risk of developing late toxicity from radiotherapy, and the inability to predict who is most susceptible results in substantial impact on quality of life and limits further curative dose escalation. A predictive assay or algorithm for normal tissue radiosensitivity would allow more personalized treatment planning, reducing the burden of late toxicity, and improving the therapeutic index...

Hypoxia (oxygen deprivation) occurs in most solid malignancies, albeit with considerable heterogeneity. Hypoxia is associated with an aggressive cancer phenotype by promotion of genomic instability, evasion of anti-cancer therapies including radiotherapy and enhancement of metastatic risk. Therefore, hypoxia results in poor cancer outcomes. Targeting hypoxia to improve cancer outcomes is an attractive therapeutic strategy. Hypoxia-targeted dose painting escalates radiotherapy dose to hypoxic sub-volumes, as quantified and spatially mapped using hypoxia imaging...

PET imaging with 2'-deoxy-2'-[18F]fluoro-D-glucose ([18F]FDG) has become one of the pillars in the management of malignant diseases. It has proven value in diagnostic workup, treatment policy, follow-up, and as prognosticator for outcome. [18F]FDG is widely available and standards have been developed for PET acquisition protocols and quantitative analyses. More recently, [18F]FDG-PET is also starting to be appreciated as a decision aid for treatment personalization. This review focuses on the potential of [18F]FDG-PET for individualized radiotherapy dose prescription...