A Review of the Mechanisms and Clinical Implications of Precision Cancer Therapy-Related Toxicity: A Primer for the Radiologist.

OBJECTIVE. The purpose of this review is to elucidate the mechanisms, types, and clinical significance of molecular targeted therapy (MTT) and immune checkpoint inhibitors (ICIs) and their related toxicity, emphasizing the radiologic manifestations. CONCLUSION. The related toxicities of MTT and ICIs can have acute, recurrent, chronic, and delayed presentations. These toxicities may serve as markers of response and survival. By understanding the clinical significance of drug toxicities, radiologists can play an important role in personalized cancer therapy.

A Review of the Spectrum of Imaging Manifestations of Epithelioid Hemangioendothelioma.

OBJECTIVE. The purpose of this article is to review the spectrum of imaging manifestations of epithelioid hemangioendothelioma across different organ systems and briefly describe its current treatment strategies. CONCLUSION. Epithelioid hemangioendothelioma is a rare, locally invasive neoplasm with metastatic potential. Although most commonly occurring in liver, lungs, and bones, it can also present at multiple other sites. Because of its nonspecific clinical and imaging manifestations, it is often misdiagnosed. The possibility of epithelioid hemangioendothelioma must be considered in the presence of a slowly growing mass that invades adjacent structures. Imaging can help plan percutaneous biopsy, detect sites of disease, and identify poor prognostic factors.

Imaging of Metastatic Germ Cell Tumors in Male Patients From Initial Diagnosis to Treatment-Related Toxicities: A Primer for Radiologists.

OBJECTIVE. This review describes the influence of histology and metastatic sites on prognosis in male patients with metastatic germ cell tumors (GCTs) and explains the role imaging in assessing therapeutic response, residual disease, recurrence, sand treatment-related toxicities. CONCLUSION. Seminomatous and nonseminomatous GCTs differ in imaging appearance, pattern of spread, and prognosis, and an organ-based approach is helpful in prognostication. Multimodality imaging aids in accurate staging, prognostication, characterization of treatment response, and identification of therapy-related toxicity.

Imaging of Waldenström Macroglobulinemia: A Comprehensive Review for the Radiologist in the Era of Personalized Medicine.

OBJECTIVE. We describe the range of organ systems involved and the spectrum of imaging findings seen in Waldenström macroglobulinemia (WM). CONCLUSION. Although imaging is not mandatory in the initial workup of a patient with WM, a multimodality imaging approach can lead toward the diagnosis of a lymphoproliferative disorder, establish the tumor burden, identify sites of involvement, and thus explain the clinical presentation, help in determining prognosis and monitoring response to therapy, and help identify treatment-induced toxicity.

Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine.

For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.

Patterns and Prognostic Importance of Hepatic Involvement in Patients with Serous Ovarian Cancer: A Single-Institution Experience with 244 Patients.

Purpose To evaluate the frequency, patterns, and prognostic importance of metastatic hepatic involvement in serous ovarian cancer. Materials and Methods This institutional review board-approved retrospective study, with waived informed consent, included 244 patients with pathologically proven serous ovarian cancer (mean age ± standard deviation, 59 years ± 10.7; range 19-93 years). Electronic medical records and all available imaging studies over a median follow-up of 44 months (interquartile range [IQR], 27-70) were reviewed to identify the frequency of liver parenchymal invasion (LPI) from perihepatic peritoneal metastasis and hematogenous liver metastases. The associations and prognostic importance of LPI and hematogenous metastases were studied by using univariate and multivariate Cox proportional analysis. Results Eighty-four of 244 patients (34%) developed perihepatic metastases, of whom 55 (23%) developed LPI after median of 43 months (IQR, 25-63). Hematogenous hepatic metastases developed in 38 of 244 patients (16%) after median of 42 months (IQR, 26-64). At multivariate analysis, age (P = .008; hazard ratio [HR]: 1.03; 95% confidence interval [CI]: 1.009, 1.07) and suboptimal cytoreduction (P = .03; HR, 2.13; 95% CI: 1.12, 4.07) were associated with LPI. Increasing age (P = .01; HR, 1.04; 95% CI: 1.008, 1.08), high-grade tumor (P = .01; HR, 6.75; 95% CI: 1.44, 120.5), and advanced stage (P = .03; HR, 3.16; 95% CI: 1.94, 4.56) were associated with hematogenous metastases. Overall survival with and without LPI was similar (median, 80 months; IQR, 50-not reached vs 123 months; IQR, 49-279; P = .6). Hematogenous metastases were associated with significantly shorter survival at univariate (median 63 months, IQR 43-139 vs 145 months, IQR 50-not reached; P = .006) and multivariate analyses (P = .03; HR, 1.88; 95% CI: 1.14, 3.28). Conclusion Differentiating hematogenous metastases and LPI is important for radiologists; hematogenous metastases are associated with shorter survival, while LPI does not adversely affect survival and prognostically behaves like peritoneal disease. © RSNA, 2016.

Sunitinib-associated Pancreatic Atrophy in Patients with Gastrointestinal Stromal Tumor: A Toxicity with Prognostic Implications Detected at Imaging.

Purpose To evaluate the effect and clinical importance of sunitinib on pancreatic volume in patients with gastrointestinal stromal tumor (GIST). Materials and Methods This retrospective study was approved by the institutional review board and compliant with HIPAA. The requirement to obtain informed consent was waived. The authors evaluated 65 patients with GIST treated with oral sunitinib and a control group of 30 patients with GIST who did not receive any therapy (mean age: 56 years [range, 29-75 years] vs 60 years [range, 27-78 years], respectively; P = .11) seen at their institution from January 2002 through December 2008. Segmented pancreatic volumes of study and control groups were measured with computed tomography by using commercial software by two independent readers who were blinded to study group and the timing of the scan at a median of 6.2 and 6.1 months, respectively. Pre- and posttreatment volumes (Wilcoxon signed rank test) and rate of volume change per month (Wilcoxon rank sum test) were compared. Interobserver agreement was calculated. Associations and prognostic importance of pancreatic atrophy were studied by using multivariate linear regression and Cox proportional analysis, respectively. Results Both readers recorded significant pancreatic volume loss in the study group (respective median pre- and posttreatment volume: 76.1 cm(3) and 58.4 cm(3) for reader 1 and 67.7 cm(3) and 59.0 cm(3) for reader 2; P < .0001 for both) but not in the control group (respective median pre- and posttreatment volume: 79.9 cm(3) and 83.8 cm(3) for reader 1 [P = .43] and 79.9 cm(3) and 84.8 cm(3) for reader 2 [P = .50]). The rate of volume loss per month was greater in the study group than in the control group (reader 1: -2.1% vs -0.1%, respectively, P = .003; reader 2: -2.0% vs -0.3%, P < .0001). Twenty-three of the 65 patients who received sunitinib (35%) showed at least 3% pancreatic volume loss per month, compared with only one of the 30 patients in the control group (3%). The concordance correlation coefficient for pre- and posttreatment measurements was 0.83 (95% confidence interval [CI]: 0.75, 0.89) and 0.91 (95% CI: 0.86, 0.94), respectively, and the mean relative difference was 0.04% and 1.2%. Sunitinib treatment was independently associated with pancreatic atrophy (P = .03; risk estimate: 2.64; 95% CI: 0.17, 5.11). At Cox proportional analysis within the study group, more than 3%, more than 5%, and more than 7% loss per month were independently associated with worse survival (P < .001, hazard ratio: >1.00 for all). Conclusion Pancreatic atrophy is a sunitinib-associated toxicity detected at imaging. It may be a clinically important biomarker because a higher rate of pancreatic atrophy was independently associated with shorter survival. (©) RSNA, 2016.

A New Look at Toxicity in the Era of Precision Oncology: Imaging Findings, Their Relationship With Tumor Response, and Effect on Metastasectomy.

OBJECTIVE: As cancer care becomes increasingly personalized and patients with metastatic disease live longer, oncologists' approach to drug toxicity is also evolving. CONCLUSION: This article aims to broaden the radiologist's understanding of imaging-evident toxicity by describing how oncologists grade toxicity, exploring toxicity as a biomarker of treatment response, discussing the effect of toxicity in patients who are candidates for metastasectomy, and illustrating how combining drugs of varying classes amplifies toxicity.

Current Concepts in the Molecular Genetics and Management of Thyroid Cancer: An Update for Radiologists.

Substantial improvement in the understanding of the oncogenic pathways in thyroid cancer has led to identification of specific molecular alterations, including mutations of BRAF and RET in papillary thyroid cancer, mutation of RAS and rearrangement of PPARG in follicular thyroid cancer, mutation of RET in medullary thyroid cancer, and mutations of TP53 and in the phosphatidylinositol 3'-kinase (PI3K)/AKT1 pathway in anaplastic thyroid cancer. Ultrasonography (US) and US-guided biopsy remain cornerstones in the initial workup of thyroid cancer. Surgery is the mainstay of treatment, with radioactive iodine (RAI) therapy reserved for differentiated subtypes. Posttreatment surveillance of thyroid cancer is done with US of the thyroid bed as well as monitoring of tumor markers such as serum thyroglobulin and serum calcitonin. Computed tomography (CT), magnetic resonance imaging, and fluorine 18 fluorodeoxyglucose positron emission tomography/CT are used in the follow-up of patients with negative iodine 131 imaging and elevated tumor markers. Certain mutations, such as mutations of BRAF in papillary thyroid carcinoma and mutations in RET codons 883, 918, and 928, are associated with an aggressive course in medullary thyroid carcinoma, and affected patients need close surveillance. Treatment options for metastatic RAI-refractory thyroid cancer are limited. Currently, Food and Drug Administration-approved molecularly targeted therapies for metastatic RAI-refractory thyroid cancer, including sorafenib, lenvatinib, vandetanib, and cabozantinib, target the vascular endothelial growth factor receptor and RET kinases. Imaging plays an important role in assessment of response to these therapies, which can be atypical owing to antiangiogenic effects. A wide spectrum of toxic effects is associated with the molecularly targeted therapies used in thyroid cancer and can be detected at restaging scans. (©)RSNA, 2016.

Role of Imaging in Management of Desmoid-type Fibromatosis: A Primer for Radiologists.

Desmoid-type fibromatosis (DF) is a locally aggressive fibroblastic neoplasm that has variable clinical and biologic behaviors ranging from indolent tumors that can undergo spontaneous regression to aggressive tumors with a tendency toward local invasion and recurrence. The management of DF has evolved considerably in the last decade from aggressive first-line surgery and radiation therapy to systemic treatment (chemotherapy, hormonal therapy, and targeted therapy) and symptomatic local control (surgery and radiation therapy). Imaging plays an important role in each of these treatment settings. In surgical candidates, computed tomography (CT) and magnetic resonance (MR) imaging are the modalities of choice for assessing resectability and surgical planning. For evaluating recurrence, MR imaging is the modality of choice for extra-abdominal recurrence, whereas CT is the preferred modality for intra-abdominal recurrence. Signal intensity changes at MR imaging can be used to monitor the biologic behavior of certain DFs chosen for expectant management. Response to systemic treatment with anti-inflammatory agents, hormonal therapy (eg, tamoxifen), cytotoxic chemotherapy (eg, doxorubicin, vinblastine, methotrexate), and targeted therapy (eg, sorafenib), as well as to radiation therapy, can be assessed at CT by monitoring size and attenuation changes or at MR imaging by monitoring size, T2 signal intensity, and degree of enhancement. Several patterns of response can be seen at imaging. Imaging also helps in detecting complications associated with systemic therapy and radiation therapy. (©)RSNA, 2016.

Imaging response assessment for oncology: An algorithmic approach.

Treatment response assessment by imaging plays a vital role in evaluating changes in solid tumors during oncology therapeutic clinical trials. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is the reference standard imaging response criteria and provides details regarding image acquisition, image interpretation and categorical response classification. While RECIST 1.1 is applied for the majority of clinical trials in solid tumors, other criteria and modifications have been introduced when RECIST 1.1 outcomes may be incomplete. Available criteria beyond RECIST 1.1 can be explored in an algorithmic fashion dependent on imaging modality, tumor type and method of treatment. Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) is available for use with PET/CT. Modifications to RECIST 1.1 can be tumor specific, including mRECIST for hepatocellular carcinoma and mesothelioma. Choi criteria for gastrointestinal stromal tumors incorporate tumor density with alterations to categorical response thresholds. Prostate Cancer Working Group 3 (PCWG3) imaging criteria combine RECIST 1.1 findings with those of bone scans. In addition, multiple response criteria have been created to address atypical imaging responses in immunotherapy.

A radiologist's guide to novel anticancer therapies in the era of precision medicine.

Novel anticancer agents have replaced conventional chemotherapy as first line agents for many cancers, with continued new and expanding indications. Small molecule inhibitors act on cell surface or intracellular targets and prevent the downstream signaling that would otherwise permit tumor growth and spread. Anticancer antibodies can be directed against growth factors or may be immunotherapeutic agents. The latter act by inhibiting mechanisms that cancer cells use to evade the immune system. Hormonal agents act by decreasing levels of hormones that are necessary for the growth of certain cancer cells. Cancer therapy protocols often include novel anticancer agents and conventional chemotherapy used successively or in combination, in order to maximize survival and minimize morbidity. A working knowledge of anti-cancer drug classification will aid the radiologist in assessing response on imaging.

Teaching cancer imaging in the era of precision medicine: Looking at the big picture.

The role of imaging in cancer diagnosis and treatment has evolved at the same rapid pace as cancer management. Over the last twenty years, with the advancement of technology, oncology has become a multidisciplinary field that allows for researchers and clinicians not only to create individualized treatment options for cancer patients, but also to evaluate patients' response to therapy with increasing precision. Familiarity with these concepts is a requisite for current and future radiologists, as cancer imaging studies represent a significant and growing component of any radiology practice, from tertiary cancer centers to community hospitals. In this review we provide the framework to teach cancer imaging in the era of genomic oncology. After reading this article, readers should be able to illustrate the basics cancer genomics, modern cancer genomics, to summarize the types of systemic oncologic therapies available, their patterns of response and their adverse events, to discuss the role of imaging in oncologic clinical trials and the role of tumor response criteria and to display the future directions of oncologic imaging.

Imaging features of toxicities associated with immune checkpoint inhibitors.

The past decade has witnessed a change in landscape of cancer management with the advent of precision oncology. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and have played an important role in improving patient survival. While the patients are living longer, treatment with ICIs are sometimes associated with adverse effects, some of which could be fatal. Radiologists can play a crucial role by early identification of some of these adverse effects during restaging scans. Our paper focuses on the imaging features of commonly occurring ICI toxicities based on organ system.

Importance of tumor subtypes in cancer imaging.

Cancer therapy has evolved from being broadly directed towards tumor types, to highly specific treatment protocols that target individual molecular subtypes of tumors. With the ever-increasing data on imaging characteristics of tumor subtypes and advancements in imaging techniques, it is now often possible for radiologists to differentiate tumor subtypes on imaging. Armed with this knowledge, radiologists may be able to provide specific information that can obviate the need for invasive methods to identify tumor subtypes. Different tumor subtypes also differ in their patterns of metastatic spread. Awareness of these differences can direct radiologists to relevant anatomical sites to screen for early metastases that may otherwise be difficult to detect during cursory inspection. Likewise, this knowledge will help radiologists to interpret indeterminate findings in a more specific manner.

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in CTNNB1 or APC: A Multi-institutional Retrospective Study.

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments. EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan-Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen. RESULTS: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or "other" therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations. CONCLUSIONS: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated. See related commentary by Greene and Van Tine, p. 3911.

A Primer on RECIST 1.1 for Oncologic Imaging in Clinical Drug Trials.

Drug discovery and approval in oncology is mediated by the use of imaging to evaluate drug efficacy in clinical trials. Imaging is performed while patients receive therapy to evaluate their response to treatment. Response criteria, specifically Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at different time points to classify response into the categories of complete response, partial response, stable disease, or disease progression. At the trial level, categorical responses for all patients are summated into image-based trial endpoints. These outcome measures, including objective response rate (ORR) and progression-free survival (PFS), are characteristics that can be derived from imaging and can be used as surrogates for overall survival (OS). Similar to OS, ORR and PFS describe the efficacy of a drug. U.S. Food and Drug Administration (FDA) regulatory approval requires therapies to demonstrate direct evidence of clinical benefit, such as improved OS. However, multiple programs have been created to expedite drug approval for life-threatening illnesses, including advanced cancer. ORR and PFS have been accepted by the FDA as adequate predictors of OS on which to base drug approval decisions, thus substantially shortening the time and cost of drug development (1). Use of imaging surrogate markers for drug approval has become increasingly common, accounting for more than 90% of approvals through the Accelerated Approval Program and allowing for use of many therapies which have altered the course of cancer. Keywords: Oncology, Tumor Response RSNA, 2021.

Spectral detector CT applications in advanced liver imaging.

OBJECTIVE: Spectral detector CT (SDCT) has many applications in advanced liver imaging. If appropriately utilized, this technology has the potential to improve image quality, provide new diagnostic information, and allow for decreased radiation dose. The purpose of this review is to familiarize radiologists with the uses of SDCT in liver imaging. CONCLUSION: SDCT has a variety of post-processing techniques, which can be used in advanced liver imaging and can significantly add value in clinical practice.