Ashwin Shetty, MD

	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, bidimensional measurements-World Health Organization (WHO) criteria-and now standardized technique measurements-Response Evaluation Criteria in Solid Tumors (RECIST). 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.

	Transcatheter intra-arterial and molecular targeted therapies have proven to be valuable against primary and secondary hepatic malignancies. 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. 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 radioembolization (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.

	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.

	PET Response Criteria in Solid Tumors (PERCIST) 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 the standardized uptake value (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 region of interest (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.

	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.


	Perfusion MRI imaging of a malignant brain tumor.

	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. Tumor size may remain constant on CT, but nodules with increased uptake may be seen on PET scanning indicating residual tumor. Intra-therapy appearance of hot spots on PET indicate emergence of secondary resistance to therapy. Response to therapy can be seen as quick as 24 hours and this has shortened many clinical trials (e.g., sunitinib was brought to market six months ahead of schedule).

	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 one day after treatment, FLT PET/CT scanning shows a decrease in the standardized uptake value and three weeks later there is a further dramatic response, and decrease in the standardized uptake value. A series showed uptake of FLT in all cases of head and neck squamous cell cancers and significant decrease in the first four weeks of chemoradiotherapy or radiotherapy. A greater decrease in 18F-FLT in the second week of treatment predicted a more favorable long term outcome.

 Follow up with CT scanning on the other hand is usually done three to six months after radiation to differentiate recurrent or persistent tumor from radiation changes.

	Tc99 MDP bone scanning, which was for many years the mainstay 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. The most successful application for 18F-FDHT is a Phase I-II trial of the androgen receptor antagonist enzalutamide for castration-resistant prostate cancer (CRPC) reported by Scher et al. In a cohort of 22 patients, there was reduced 18F-FDHT binding after four weeks of therapy compared with baseline. This rapid evaluation of treatment is the power of molecular imaging agents and brings us closer to personalized medicine.

	Newer methods to assess tumor response based on volumetry, tumor vascularity, tumor cellularity, 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, and MR elastography. Quantification by volumetry can be a more accurate reflection of the actual tumor size than uni- or bidimensional measurements. Linear tumor measurement has also demonstrated more inter-observer variation than volumetry in patients with hepatocellular carcinoma.

 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 one month after treatment has been reported to suggest hemorrhagic necrosis; however, a sustained decrease in ADC at three-month follow-up may indicate viable tumor or tumor progression.

	Imaging has secured a central role in evaluating the impact of devices and drugs in clinical trials. As the biomarkers described earlier evolve and become more specific and more sensitive, the impact on assessing changes in disease processes improves. This allows a new level of drug and device evaluation both at a functional and physiologic level. Specifically, for example, the utilization of the mRECIST criteria has allowed for a better understanding of response after interventional oncology treatments. Prior to the advent of these modified criteria, patients would have been disqualified after transarterial chemoembolization as their tumor size would often be unaffected after treatment. Under the new modified criteria, these patients would now be considered to have a positive response as the necrosis of their tumor would be properly characterized. As we continue to learn and evolve these methodologies, it will assist in ensuring novel therapies are evaluated appropriately.

	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.

, is Interventional Radiologist at Intrinsic Imaging LLC. 

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	6. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. 

	7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). 

	8. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference-European Association for the Study of the Liver. 

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