Vol. 6, Issue 3 : Imaging and Monitoring Tumor Response in Clinical Trials

The use of imaging has gained an increased role in monitoring tumor response to therapy. For many years, assessment of tumor response has relied on non-standardized bi-dimensional measurements (World Health Organization criteria) and now standardized technique measurements (Response Evaluation Criteria in Solid Tumors). However, growing numbers of clinical trials are now using both diameter and volumetric measurements to assess treatment response, with the two kinds of measurements at times producing strikingly different results. In addition, we are now introducing metabolic and functional information from molecular imaging methods. Molecular imaging provides critical additional information for treatment follow-up of individual patients when used as a supplement to anatomic imaging.

Functional CT/MRI Imaging
Transcatheter intra-arterial and molecular targeted therapies have proven to be valuable against primary and secondary hepatic malignancies. The rationale for regional chemotherapy is to maximize drug concentrations and tumor drug uptake in the target organ and minimize systemic toxicity. These therapies, which include transarterial embolization, intra-arterial chemoinfusion, transarterial chemoembolization with or without drug-eluting beads, and radioembolization with use of yttrium 90, inflict lethal insult to tumors while preserving normal hepatic parenchyma. This is possible because hepatic neoplasms preferentially derive their blood supply from an arterial source while the majority of noncancerous liver is supplied by the portal vein. Evaluation of treatment efficacy for all transcatheter based therapies has been traditionally performed with radiologic measurement of tumor size as proposed by the WHO or RECIST Version 1.0 and 1.1 guidelines. Local therapies such as radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and transcatheter arterial radio embolization (TARE) with yttrium 90 induce cell death or necrosis. They may lead to stability of tumor size or even an increase in hepatic tumor size after therapy, a feature that limits the role of size-based criteria for assessing tumor response in this setting.

Similarly, molecular-targeted therapies may not change hepatic tumor size but cause alteration of cell growth signaling or alter the morphology of the tumor by affecting tumor angiogenesis. To evaluate the response of hepatic malignancies to therapy, quantitative functional criteria that are specific to tumor type and therapy have been developed. Examples include the Modified CT Response Evaluation Criteria for Gastrointestinal Stromal Tumors (Choi criteria), the European Association for Study of the Liver (EASL) guidelines, modified RECIST, and Response Evaluation Criteria in Cancer of the Liver (RECICL). Unlike anatomic imaging biomarkers, many functional imaging biomarkers demonstrate hepatic tumor response on the basis of tumor viability, which is assessed by measuring the residual enhancing tissue. Advanced cases of gastrointestinal stromal tumor (GIST) had limited therapeutic options until the introduction of Imatinib, a tyrosine kinase inhibitor, which affects tumor cell growth signaling and has improved the prognosis of patients with this tumor. Studies have shown that use of tumor size alone to assess tumor response in patients with advanced GIST who undergo Imatinib therapy results in a significant underestimation, especially in the early stage of treatment.

In 2007, Choi et al. proposed new GIST-specific criteria that included evaluation of changes in CT attenuation in lesions after Imatinib therapy. They demonstrated good correlation between attenuation change seen at CT and tumor response seen at FDG PET. They also showed that some GIST lesions could even increase in size, despite clinical and FDG PET results indicating favorable patient response, a finding that emphasizes the limitation of size-based criteria.

In 2010, a modified RECIST system was proposed. Modified RECIST quantifies the longest diameter of the enhancing part of hepatocellular carcinoma, which is assessed in the arterial phase of CT or magnetic resonance (MR) imaging and measured to avoid any major areas of intervening necrosis.

Positron Emission Tomography 
PET Response Criteria in Solid Tumors (PER¬CIST) is a new criterion that may serve as a useful tool for assessing treatment response in FDG-avid malignancies, particularly those treated with cytostatic therapies. PERCIST is based on the change of SUV measurement within the tumor and the assumption that it provides a reproducible and reliable quantification of tumor metabolism. SUV should be measured within a 1-cm3 spherical ROI and be corrected for lean body mass (SUL). PERCIST adapts the RECIST 1.1 principles and measures the SUL peak in up to five index lesions (up to two per organ) with the highest FDG uptake. Response to therapy is expressed as a percentage change in SUL peak (or sum of the lesions’ SULs) between the pretreatment and post treatment scans. PERCIST classifies objective response in four categories: complete metabolic response, partial metabolic response, stable metabolic disease, and progressive metabolic disease.

Molecular imaging is useful in assessment of not only chemotherapy/ biologic therapies, but also the monitoring of changes after image-guided intervention or radiation therapy. For example, PET/CT with fluorine 18 L-thymidine (FLT), a cell proliferation tracer, is being used in clinical trials to assess response to single-dose image-guided radiation therapy (IGRT). In a patient with metastatic squamous cell cancer of the oropharynx treated with IGRT, serial CT scans may show no change in the size of the metastasis. But just 1 day after treatment, FLT PET/CT scanning shows a decrease in the standardized uptake value and 3 weeks later there is a further dramatic response, and decrease in the standardized uptake value.

Tc99 MDP bone scanning, which was for many years the main stay for the evaluation of bone metastasis, can greatly underestimate the extent of such metastasis. In patients with metastatic prostate cancer, three different studies are currently performed for evaluation of bone metastasis: Tc 99MDP scan, FDG PET/CT, and PET/CT with fluorodihydrotestosterone (FDHT), an androgen receptor tracer. The manifold increase in extent of bone metastasis and lymph node involvement that is detected at FDHT PET/ CT but not at either FDG PET/CT or bone scanning shows the tremendous potential of modern molecular imaging for advancing cancer detection and follow-up post therapy.

On The Horizon 
Newer methods to assess tumor response based on volumetry, tumor vascularity, tumor cellular-ity, and tumor metabolism are on the horizon. Some examples of these newer methods include volumetric quantification of the whole tumor and necrotic component, diffusion-weighted imaging, tumor perfusion, MR spectroscopy, ultrasound (US) and MR elastography. Quantification by volumetry can be a more accurate reflection of the actual tumor size than uni- or bi-dimensional measurements. Linear tumor measurement has also demonstrated more inter-observer variation than volumetry in patients with hepatocellular carcinoma.

Apparent Diffusion Coefficient 
The apparent diffusion coefficient (ADC) value, a diffusion-weighted imaging parameter, has been correlated with the tumor proliferation index and tumor grade before therapy, as well as with the presence of necrosis and tumor cell apoptosis after successful treatment. Studies have shown a potential to characterize malignant lesions and to differentiate viable tissue from necrosis on the basis of ADC cut-off values, because necrosis has higher ADC values. For patients with hepatocellular carcinoma treated with sorafenib, a transient decrease in tumor ADC value approximately 1 month after treatment has been reported to suggest hemorrhagic necrosis; however, a sustained decrease in ADC at 3-month follow-up may indicate viable tumor or tumor progression. ADC values in patients with hepatocellular carcinoma treated with transhepatic chemoembolization have been shown to increase ADC, a finding suggestive of cellular necrosis, and in such cases may be an early marker of treatment response before changes in tumor size are observed. More recently, use of volumetric ADC measurements to assess response to locoregional therapies in patients with hepatic metastases of neuroendocrine tumor and cholangiocarcinoma have shown good correlation with prognosis.

MR Spectroscopy
MR spectroscopy is a technique in which different metabolites and their relative concentration in tissue can be determined on the basis of chemical shift phenomenon. Hepatocellular carcinomas tended to have higher choline levels compared with those in uninvolved liver parenchyma. Use of proton MR spectroscopy to assess response of hepatocellular carcinoma after TACE has also been evaluated, and responsive tumors showed a decrease in the choline peak; thus, this biomarker may have potential prognostic value as an indicator of treatment efficacy.

MR Elastography 
In MR elastography, low-frequency mechanical waves are propagated, and the resulting tissue displacements are measured and used to evaluate shear or mechanical properties. This assessment provides additional information about the mechanical properties of hepatic masses that may help to differentiate malignant from benign hepatic lesions. In a preliminary study that used MR elastography, malignant liver tumors demonstrated significantly higher stiffness than did benign tumors.

In Conclusion 
In addition to size changes, various biologic and functional parameters can be quantified by using new imaging technologies. Measurement of these parameters is especially important for the evaluation of tumor response to newer targeted therapies, in which change in functional status sometimes precedes anatomic changes.

To download a PDF version of this article click here.

About the Author

Dr. Ashwin Shetty is a Board-Certified, Fellowship trained Interventional Radiologist at Intrinsic Imaging. He completed his residency in Diagnostic Radiology at Allegheny General Hospital, Pittsburgh,PA. Dr. Shetty sub-specialized in Interventional Radiology with Fellowship training at Albany Medical Center, NY followed by an academic appointment. He has been a member of the Society of Interventional Radiology since 1986.

About Intrinsic Imaging LLC

Located in Bolton, Massachusetts and San Antonio, Texas, Intrinsic Imaging is an FDA audited, ISO 9001:2008 and ISO 13485:2003 certified, GAMP® 5 compliant medical imaging core lab specializing in providing imaging core lab services for clinical trials. Its comprehensive medical imaging core lab services include, but are not limited to, expert radiologist consultation, protocol and charter development, site qualification, training and management, as well as image acquisition, processing and detailed radiologic analysis.

Intrinsic Imaging has more than sixty full-time, board-certified diagnostic radiologists on staff that have sub-specialization in all therapeutic areas including, but not limited to, Cardiovascular, Central Nervous System, Gastrointestinal & Genitourinary, Medical Device, Musculoskeletal and Oncology.