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...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. Progress over the last 10 years has shown that the etiology of late clinical radiotoxicity is multifactorial and informs development of predictive models that combine information on treatment (eg, dose, adjuvant treatment), demographic and health behaviors (eg, smoking, age), co-morbidities (eg, diabetes, collagen vascular disease), and biology (eg, genetics, ex vivo functional assays). AI has emerged as a useful tool and is facilitating extraction of signal from large datasets and development of high-level multivariable models. Some models are progressing to evaluation in clinical trials, and we anticipate adoption of these into the clinical workflow in the coming years. Information on predicted risk of toxicity could prompt modification of radiotherapy delivery (eg, use of protons, altered dose and/or fractionation, reduced volume) or, in rare instances of very high predicted risk, avoidance of radiotherapy. Risk information can also be used to assist treatment decision-making for cancers where efficacy of radiotherapy is equivalent to other treatments (eg, low-risk prostate cancer) and can be used to guide follow-up screening in instances where radiotherapy is still the best choice to maximize tumor control probability. Here, we review promising predictive assays for clinical radiotoxicity and highlight studies that are progressing to develop an evidence base for clinical utility.
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-cance...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. This therapeutic approach could overcome hypoxia-induced radioresistance and improve patient outcomes without the need for hypoxia-targeted drugs. This article will review the premise and underpinning evidence for personalized hypoxia-targeted dose painting. It will present data on relevant hypoxia imaging biomarkers, highlight the challenges and potential benefit of this approach and provide recommendations for future research priorities in this field. Personalized hypoxia-based radiotherapy de-escalation strategies will also be addressed.
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 prognosti...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. This includes dose painting, gradient dose prescription, and [18F]FDG-PET guided response-adapted dose prescription. The current status, progress, and future expectations of these developments for various tumor types are discussed.
Semin Radiat Oncol
· 2023 Jul · PMID 37331782
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Patient-derived cancer models have been used for decades to improve our understanding of cancer and test anticancer treatments. Advances in radiation delivery have made these models more attractive for studying radiation...Patient-derived cancer models have been used for decades to improve our understanding of cancer and test anticancer treatments. Advances in radiation delivery have made these models more attractive for studying radiation sensitizers and understanding an individual patient's radiation sensitivity. Advances in the use of patient-derived cancer models lead to a more clinically relevant outcome, although many questions remain regarding the optimal use of patient-derived xenografts and patient-derived spheroid cultures. The use of patient-derived cancer models as personalized predictive avatars through mouse and zebrafish models is discussed, and the advantages and disadvantages of patient-derived spheroids are reviewed. In addition, the use of large repositories of patient-derived models to develop predictive algorithms to guide treatment selection is discussed. Finally, we review methods for establishing patient-derived models and identify key factors that influence their use as both avatars and models of cancer biology.
Earland N, Chen K, Semenkovich NP
… +3 more, Chauhan PS, Zevallos JP, Chaudhuri AA
Semin Radiat Oncol
· 2023 Jul · PMID 37331781
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Recent breakthroughs in circulating tumor DNA (ctDNA) technologies present a compelling opportunity to combine this emerging liquid biopsy approach with the field of radiogenomics, the study of how tumor genomics correla...Recent breakthroughs in circulating tumor DNA (ctDNA) technologies present a compelling opportunity to combine this emerging liquid biopsy approach with the field of radiogenomics, the study of how tumor genomics correlate with radiotherapy response and radiotoxicity. Canonically, ctDNA levels reflect metastatic tumor burden, although newer ultrasensitive technologies can be used after curative-intent radiotherapy of localized disease to assess ctDNA for minimal residual disease (MRD) detection or for post-treatment surveillance. Furthermore, several studies have demonstrated the potential utility of ctDNA analysis across various cancer types managed with radiotherapy or chemoradiotherapy, including sarcoma and cancers of the head and neck, lung, colon, rectum, bladder, and prostate . Additionally, because peripheral blood mononuclear cells are routinely collected alongside ctDNA to filter out mutations associated with clonal hematopoiesis, these cells are also available for single nucleotide polymorphism analysis and could potentially be used to detect patients at high risk for radiotoxicity. Lastly, future ctDNA assays will be utilized to better assess locoregional MRD in order to more precisely guide adjuvant radiotherapy after surgery in cases of localized disease, and guide ablative radiotherapy in cases of oligometastatic disease.
Semin Radiat Oncol
· 2023 Jul · PMID 37331780
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Quantitative image analysis, also known as radiomics, aims to analyze large-scale quantitative features extracted from acquired medical images using hand-crafted or machine-engineered feature extraction approaches. Radio...Quantitative image analysis, also known as radiomics, aims to analyze large-scale quantitative features extracted from acquired medical images using hand-crafted or machine-engineered feature extraction approaches. Radiomics has great potential for a variety of clinical applications in radiation oncology, an image-rich treatment modality that utilizes computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) for treatment planning, dose calculation, and image guidance. A promising application of radiomics is in predicting treatment outcomes after radiotherapy such as local control and treatment-related toxicity using features extracted from pretreatment and on-treatment images. Based on these individualized predictions of treatment outcomes, radiotherapy dose can be sculpted to meet the specific needs and preferences of each patient. Radiomics can aid in tumor characterization for personalized targeting, especially for identifying high-risk regions within a tumor that cannot be easily discerned based on size or intensity alone. Radiomics-based treatment response prediction can aid in developing personalized fractionation and dose adjustments. In order to make radiomics models more applicable across different institutions with varying scanners and patient populations, further efforts are needed to harmonize and standardize the acquisition protocols by minimizing uncertainties within the imaging data.
Rydzewski NR, Helzer KT, Bootsma M
… +4 more, Shi Y, Bakhtiar H, Sjöström M, Zhao SG
Semin Radiat Oncol
· 2023 Jul · PMID 37331779
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Developing radiation tumor biomarkers that can guide personalized radiotherapy clinical decision making is a critical goal in the effort towards precision cancer medicine. High-throughput molecular assays paired with mod...Developing radiation tumor biomarkers that can guide personalized radiotherapy clinical decision making is a critical goal in the effort towards precision cancer medicine. High-throughput molecular assays paired with modern computational techniques have the potential to identify individual tumor-specific signatures and create tools that can help understand heterogenous patient outcomes in response to radiotherapy, allowing clinicians to fully benefit from the technological advances in molecular profiling and computational biology including machine learning. However, the increasingly complex nature of the data generated from high-throughput and "omics" assays require careful selection of analytical strategies. Furthermore, the power of modern machine learning techniques to detect subtle data patterns comes with special considerations to ensure that the results are generalizable. Herein, we review the computational framework of tumor biomarker development and describe commonly used machine learning approaches and how they are applied for radiation biomarker development using molecular data, as well as challenges and emerging research trends.
Sutera P, Skinner H, Witek M
… +8 more, Mishra M, Kwok Y, Davicioni E, Feng F, Song D, Nichols E, Tran PT, Bergom C
Semin Radiat Oncol
· 2023 Jul · PMID 37331778
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Histopathology and clinical staging have historically formed the backbone for allocation of treatment decisions in oncology. Although this has provided an extremely practical and fruitful approach for decades, it has lon...Histopathology and clinical staging have historically formed the backbone for allocation of treatment decisions in oncology. Although this has provided an extremely practical and fruitful approach for decades, it has long been evident that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. As efficient and affordable DNA and RNA sequencing have become available, the ability to provide precision therapy has become within grasp. This has been realized with systemic oncologic therapy, as targeted therapies have demonstrated immense promise for subsets of patients with oncogene-driver mutations. Further, several studies have evaluated predictive biomarkers for response to systemic therapy within a variety of malignancies. Within radiation oncology, the use of genomics/transcriptomics to guide the use, dose, and fractionation of radiation therapy is rapidly evolving but still in its infancy. The genomic adjusted radiation dose/radiation sensitivity index is one such early and exciting effort to provide genomically guided radiation dosing with a pan-cancer approach. In addition to this broad method, a histology specific approach to precision radiation therapy is also underway. Herein we review select literature surrounding the use of histology specific, molecular biomarkers to allow for precision radiotherapy with the greatest emphasis on commercially available and prospectively validated biomarkers.
The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for cli...The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding cytotoxic chemotherapy, targeted agents and immunotherapy. In contrast, clinical decisions regarding radiation therapy (RT) remain uninformed about the genomic heterogeneity of tumors. In this review, we discuss the clinical opportunity to utilize genomics to optimize RT dose. Although from the technical perspective, RT has been moving towards a data-driven approach, RT prescription dose is still based on a one-size-fits all approach, with most RT dose based on cancer diagnosis and stage. This approach is in direct conflict with the realization that tumors are biologically heterogeneous, and that cancer is not a single disease. Here, we discuss how genomics can be integrated into RT prescription dose, the clinical potential for this approach and how genomic-optimization of RT dose could lead to new understanding of the clinical benefit of RT.
Individuals with cancer experience a host of symptoms, especially when the malignancy is advanced. Pain occurs from the cancer itself or related treatments. Undertreated pain contributes to patient suffering and lack of...Individuals with cancer experience a host of symptoms, especially when the malignancy is advanced. Pain occurs from the cancer itself or related treatments. Undertreated pain contributes to patient suffering and lack of engagement in cancer-directed therapies. Adequate pain management includes thorough assessment; treatment by radiotherapists or anesthesia pain specialists; anti-inflammatory medications, oral or intravenous opioid analgesics, and topical agents; and attention to the emotional and functional effects of pain, which may involve social workers, psychologists, speech therapists, nutritionists, physiatrists and palliative medicine providers. This review discusses typical pain syndromes arising in cancer patients undergoing radiotherapy and provides concrete recommendations for pain assessment and pharmacologic treatment.
Iocolano M, Langi A, Dharmarajan KV
… +1 more, Jones J
Semin Radiat Oncol
· 2023 Apr · PMID 36990638
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Radiotherapy (RT) plays a critical role in the palliation of symptoms in patients with advanced or metastatic cancer. To address the growing need for these services, multiple dedicated palliative RT programs have been es...Radiotherapy (RT) plays a critical role in the palliation of symptoms in patients with advanced or metastatic cancer. To address the growing need for these services, multiple dedicated palliative RT programs have been established. This article serves to highlight the novel ways in which palliative RT delivery systems support patients with advanced cancer. Through early integration of multidisciplinary palliative supportive services, rapid access programs facilitate best practices for oncologic patients at the end of life.
In patients with advanced cancer, radiation therapy is considered at various time points in the patient's clinical course from diagnosis to death. As some patients are living longer with metastatic cancer on novel therap...In patients with advanced cancer, radiation therapy is considered at various time points in the patient's clinical course from diagnosis to death. As some patients are living longer with metastatic cancer on novel therapeutics, radiation oncologists are increasingly using radiation therapy as an ablative therapy in appropriately selected patients. However, most patients with metastatic cancer still eventually die of their disease. For those without effective targeted therapy options or those who are not candidates for immunotherapy, the time frame from diagnosis to death is still relatively short. Given this evolving landscape, prognostication has become increasingly challenging. Thus, radiation oncologists must be diligent about defining the goals of therapy and considering all treatment options from ablative radiation to medical management and hospice care. The risks and benefits of radiation therapy vary based on an individual patient's prognosis, goals of care, and the ability of radiation to help with their cancer symptoms without undue toxicity over the course of their expected lifetime. When considering recommending a course of radiation, physicians must broaden their understanding of risks and benefits to include not only physical symptoms, but also various psychosocial burdens. These include financial burdens to the patient, to their caregiver and to the healthcare system. The burden of time spent at the end-of-life receiving radiation therapy must also be considered. Thus, the consideration of radiation therapy at the end-of-life can be complex and requires careful attention to the whole patient and their goals of care.
Adrenal glands represent a common site of metastases from several primary tumors, including lung cancer, breast cancer and melanoma. Surgical resection is considered the standard of care, but surgery is not always feasib...Adrenal glands represent a common site of metastases from several primary tumors, including lung cancer, breast cancer and melanoma. Surgical resection is considered the standard of care, but surgery is not always feasible given the challenges related to anatomical site and/or due to patient and/or disease characteristics. Stereotactic body radiation therapy (SBRT) represents a promising treatment for oligometastases, though the literature on its role for adrenal metastases is still heterogeneous. Herein are summarized the most relevant published studies on the efficacy and safety of SBRT for adrenal gland metastases. The preliminary data suggests that SBRT yields high local control rates and symptom relief with a mild pattern of toxicity. Advanced radiotherapy techniques including IMRT and VMAT, a BED10 > 72 Gy and the use of 4DCT for motion control should be considered for a high quality ablative treatment of adrenal gland metastases.
The liver is a common site for metastatic spread for various primary tumor histologies. Stereotactic body radiation therapy (SBRT) is a non-invasive treatment technique with broad patient candidacy for the ablation of tu...The liver is a common site for metastatic spread for various primary tumor histologies. Stereotactic body radiation therapy (SBRT) is a non-invasive treatment technique with broad patient candidacy for the ablation of tumors in the liver and other organs. SBRT involves focused, high-dose radiation therapy delivered in one to several treatments, resulting in high rates of local control. Use of SBRT for ablation of oligometastatic disease has increased in recent years and emerging prospective data have demonstrated improvements in progression free and overall survival in some settings. When delivering SBRT to liver metastases, clinicians must balance the priorities of delivering ablative tumor dosing while respecting dose constraints to surrounding organs at risk (OARs). Motion management techniques are crucial for meeting dose constraints, ensuring low rates of toxicity, maintaining quality of life, and can allow for dose escalation. Advanced radiotherapy delivery approaches including proton therapy, robotic radiotherapy, and real-time MR-guided radiotherapy may further improve the accuracy of liver SBRT. In this article, we review the rationale for oligometastases ablation, the clinical outcomes with liver SBRT, tumor dose and OAR considerations, and evolving strategies to improve liver SBRT delivery.
The lung parenchyma and adjacent tissues are one of the most common sites of metastatic disease. Traditionally, the approach to treatment of a patient with lung metastases has been with systemic therapy, with radiotherap...The lung parenchyma and adjacent tissues are one of the most common sites of metastatic disease. Traditionally, the approach to treatment of a patient with lung metastases has been with systemic therapy, with radiotherapy being reserved for palliative management of symptomatic disease. The concept of oligo metastatic disease has paved the way for more radical treatment options, administered either alone or as local consolidative therapy in addition to systemic treatment. The modern-day management of lung metastases is guided by a number of factors, including the number of lung metastases, extra-thoracic disease status, overall performance status, and life expectancy, which all help determine the goals of care. Stereotactic body radiotherapy (SBRT) has emerged as a safe and effective method in locally controlling lung metastases, in the oligo metastatic or oligo-recurrent setting. This article outlines the role of radiotherapy in multimodality management of lung metastases.
Progress in biological cancer characterization, targeted systemic therapies and multimodality treatment strategies have shifted the goals of radiotherapy for spinal metastases from short-term palliation to long-term symp...Progress in biological cancer characterization, targeted systemic therapies and multimodality treatment strategies have shifted the goals of radiotherapy for spinal metastases from short-term palliation to long-term symptom control and prevention of compilations. This article gives an overview of the spine stereotactic body radiotherapy (SBRT) methodology and clinical results of SBRT in cancer patients with painful vertebral metastases, metastatic spinal cord compression, oligometastatic disease and in a reirradiation situation. Outcomes after dose-intensified SBRT are compared with results of conventional radiotherapy and patient selection criteria will be discussed. Though rates of severe toxicity after spinal SBRT are low, strategies to minimize the risk of vertebral compression fracture, radiation induced myelopathy, plexopathy and myositis are summarized, to optimize the use of SBRT in multidisciplinary management of vertebral metastases.
"True" malignant epidural spinal cord compression (MESCC) is used here to describe a lesion compressing of infiltrating the spinal cord associated with neurologic deficits. Radiotherapy alone is the most common treatment..."True" malignant epidural spinal cord compression (MESCC) is used here to describe a lesion compressing of infiltrating the spinal cord associated with neurologic deficits. Radiotherapy alone is the most common treatment, for which several dose-fractionation regimens are available including single-fraction, short-course and longer-course regimens. Since these regimens are similarly effective regarding functional outcomes, patients with poor survival are optimally treated with short-course or even single-fraction radiotherapy. Longer-course radiotherapy results in better local control of malignant epidural spinal cord compression. Since most in-field recurrences occur 6 months or later, local control is particularly important for longer-term survivors who, therefore, should receive longer-course radiotherapy. It is important to estimate survival prior to treatment, which is facilitated by scoring tools. Radiotherapy should be supplemented by corticosteroids, if safely possible. Bisphosphonates and RANK-ligand inhibitors may improve local control. Selected patients can benefit from upfront decompressive surgery. Identification of these patients is facilitated by prognostic instruments considering degree of compression, myelopathy, radio-sensitivity, spinal stability, post-treatment ambulatory status, and patients' performance status and survival prognoses. Many factors including patients' preferences must be considered when designing personalized treatment regimens.
Bone is a common site for metastases, which may cause pain and other skeletal-related events (SRE) in patients with advanced cancer. Since the 1980s, prospective clinical trials have demonstrated the high efficacy of ext...Bone is a common site for metastases, which may cause pain and other skeletal-related events (SRE) in patients with advanced cancer. Since the 1980s, prospective clinical trials have demonstrated the high efficacy of external beam radiotherapy (EBRT) for pain relief from focal, symptomatic lesions. In uncomplicated bone metastases, which include those without pathologic fracture, evidence of cord compression, or prior surgical intervention, improvement or complete pain relief with radiotherapy is as high as 60%, with no difference in efficacy when radiotherapy is delivered in a single or multiple fractions. The ability to treat with a single fraction makes EBRT an attractive therapy even for patients with poor performance status and/or life expectancy. Even in patients with complicated bone metastases (eg cord compression), several randomized trials have demonstrated similar rates of pain relief in addition to improved functional outcomes such as ambulation. In this review, we summarize the role of EBRT for alleviating painful bone metastases and explore its role for other endpoints including functional outcomes, recalcification, and prevention of SREs.