Current Clinical Practice of Tumor Response Assessment David M. Panicek, MD Department of Radiology Memorial Sloan-Kettering Cancer Center, New York, NY Learning Objectives Review various response assessment criteria used in clinical trials Illustrate some limitations of response assessment at imaging Discuss how response assessment often is performed in daily clinical care Evolving Concept of "Response" Cytotoxic chemotherapy o Response = tumor shrinkage o No size change = drug failure Targeted therapies o Response = no size change, or tumor shrinkage o No size change = drug success Immunotherapy o Response = tumor shrinkage, or initial enlargement then shrinkage, or shrinkage despite new lesion(s) o No size change, or shrinkage with new lesions = drug success Locoregional ablative techniques o Response = ablation zone larger than tumor o No size change = treatment failure Paradigm shift - from "curing cancer" to making cancer a "chronic disease" Common response criteria used in clinical research trials General criteria o WHO (World Health Organization) Largest tumor diameter x largest perpendicular tumor diameter Measurable disease CR [Complete Response] Disappearance of all known disease, observed at least 4 weeks apart PR [Partial Response] >50% decrease in sum of products of perpendicular diameters; no new lesion NC (SD) [No Change Neither PR nor PD (Stable Disease)]
PD [Progressive Disease] >25% increase in product of perpendicular diameters of lesion(s); or appearance of new lesion Non-measurable disease CR Disappearance of all known disease, for at least 4 weeks PR >50% estimated decrease in size NC (SD) Neither PR nor PD PD >25% estimated increase in size, or appearance of new lesion Overall response (measurable disease + non-measurable disease) Progression anywhere = PD Persistence anywhere despite substantial improvement elsewhere = PR o RECIST (Response Evaluation Criteria In Solid Tumors), versions 1.0, 1.1 Largest tumor diameter In clinical trial, use the criteria version specified in the protocol; do not automatically switch from RECIST 1.0 to RECIST 1.1 for trials in progress Some major changes in RECIST 1.1 (compared to RECIST 1.0) include: Maximum of 5 measurable lesions per patient, up to 2 per organ Minimum target lesion size (long axis) at CT or MRI is 10 mm, except 15 mm (short axis) for lymph node Short axis measurement used for lymph nodes o Normal: <10 mm o Non-measurable: 10 to <15 mm o Measurable (Target): 15 mm Soft tissue component of a lytic or a mixed lytic and blastic bone metastasis can be measurable disease PET may be used as a complement to CT, particularly for PD Target lesions CR Disappearance of all target lesions. Any pathological lymph nodes must have short axis <10 mm PR >30% decrease in sum of diameters since baseline; no new lesion SD neither PR nor PD PD >20% increase in sum of diameters of target lesions since nadir AND absolute increase >5 mm; or appearance of new lesion Non-target lesions CR Non-CR/Non-PD Disappearance of all non-target lesions. All lymph nodes <10 mm (short axis) Persistence of non-target lesion(s)
PD Unequivocal progression of existing non-target lesions, or new lesion o NOTE: The WHO and RECIST articles explicitly state that the response criteria were designed for use in clinical trials, not for guiding decisions in the care of an individual patient. Disease-specific criteria o Hepatocellular carcinoma EASL (European Association for the Study of the Liver) Response criterion: Reduction in viable tumor estimated visually as extent of contrast uptake at arterial-phase CT or MRI mrecist (modified RECIST) Assessment of intratumoral arterial enhancement in target lesions CR: Disappearance of any intratumoral arterial enhancement in all target lesions RECICL (Response Evaluation Criteria In Cancer of the Liver) Proposed by the Liver Cancer Study Group of Japan Criteria address adequacy of ablative margins after locoregional therapies such as radiofrequency ablation and transcatheter arterial chemoembolization o Gastrointestinal Stromal Tumor (GIST) Choi PR: >10% decrease in unidimensional size, or >15% decrease in CT attenuation measurement (HU) PD: New or enlarging intratumoral nodules o Renal cell carcinoma SACT (Size and Attenuation CT) PD if marked central fill-in of previously centrally necrotic metastasis, or new enhancement in homogeneously hypoattenuating, nonenhancing mass Requires 3D analysis (proprietary) MASS (Morphology, Attenuation, Size, and Structure) Favorable response: No new lesion, AND 20% decrease in tumor size, or predominantly solid enhancing lesion with marked central tumor necrosis or 40 HU decrease in CT attenuation Indeterminate response: Neither Favorable nor Unfavorable response Unfavorable response: 20% increase in tumor size in absence of marked central necrosis or marked decreased CT attenuation; or new metastasis; or marked central fill-in or new enhancement of previously homogeneously hypoattenuating, nonenhancing mass
o Lymphoma Cheson Abnormal lymph node: Long axis >1.5 cm, or long axis 1.1-1.5 cm AND short axis >1.0 cm Nodes: CR if any nodal mass becomes PET negative, or if nodes initially were variably FDG-avid or PET negative but regressed to normal size on CT Nodes: PR if >50% decrease in sum of products of diameters of up to 6 largest dominant nodal masses, with no increase in size of other nodes Hepatic or splenic nodules: PR if >50% decrease in sum of products of diameters of nodules (for single nodule in greatest transverse diameter) o Bone tumors Huvos criteria Good response: >90% necrosis in resected tumor specimen at histopathologic analysis Modality-specific criteria o PET EORTC (European Organization for Research and Treatment of Cancer) Progressive Metabolic Disease (PMD): >25% increase in [ 18 F]-FDG tumor SUV relative to baseline scan; or visible increase >20% in longest dimension of tumor uptake; or new uptake Stable Metabolic Disease (SMD): <25% increase or <15% decrease in [ 18 F]-FDG tumor SUV; no visible increase in uptake extent Partial Metabolic Response (PMR): >15-25% decrease in [ 18 F]-FDG tumor SUV after 1 cycle of chemotherapy, and >25% decrease after >1 treatment cycle Complete Metabolic Response (CMR): Complete resolution of [ 18 F]- FDG uptake within tumor (same uptake as normal surrounding tissue) PERCIST (PET Response Criteria In Solid Tumors) Assess normal reference tissue values in a 3-cm-diameter ROI in liver Use a fixed, small ROI (1.2-cm diameter [corresponding to approximately 1 cm 3 ]) in most active region of metabolically active tumors Assess SUV lean measurements in the most metabolically active tumor focus as a continuous variable Response: >30% decline in SUV
Treatment-specific criteria o Immunotherapy Delay in appearance of radiologic changes after successful immunotherapy, due to time required for T-cell expansion and subsequent infiltration of the tumor irrc (immune-related Response Criteria) Largest tumor diameter x largest perpendicular tumor diameter Tumor burden: Sum of diameter products of all measurable lesions, including baseline and new lesions Four favorable response patterns: Conventional patterns Novel patterns o Immediate response - Rapid resolution of tumor o Durable stable response - Stable disease with possible continued slow decrease in tumor burden o Increase followed by response - Tumor initially enlarges, then decreases in size o Response despite new lesions - New lesions that contribute <25% to total tumor burden do not alone imply PD Limitations in response assessment Intra- and inter-reader variability Ambiguous or absent criteria o Enlargement of tumor due to extensive internal hemorrhage o Increase in amount of solid tumor within a cystic mass, despite interval decrease in size of mass Which lesions to select o Response assessment classification in patients with renal cell carcinoma is affected by exclusion or inclusion of the primary renal tumor (which may not be resected) in the calculations Primary tumor is often much larger than its metastases, and thus mathematically dominates the sum of lesion diameters How many lesions to select o Selecting 6 lesions (bidimensional measurements) or 4 lesions (unidimensional measurement) results in 90% decrease in variance of summed diameters Technical variations o On repeat lung CT scans taken 15 minutes later, 84% of lung tumor measurements were + 10% of earlier measurement 3% were sufficiently different that an apparent PD would be recorded
Response criteria in daily clinical practice Clinical signs and symptoms - e.g., decreased swelling, decreased pain Laboratory data - e.g., decreased serum alkaline phosphatase level Radiologic findings - e.g., decreased bidimensional measurements, sclerosis of lytic lesion, reduced perfusion References Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: Conclusions of the Barcelona-2000 EASL Conference. J Hepatol 2001; 35:421-430. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579-586. Choi H, Charnsangavej C, Faria SC, et al. Correlation of Computed Tomography and Positron Emission Tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new Computed Tomography response criteria. J Clin Oncol 2007; 25:1753-1759. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247. Hoos A, Eggermont AMM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 2010; 102:1388-1397. Kudo M, Kubo S, Takayasu K, et al for The Liver Cancer Study Group of Japan (Committee for Response Evaluation Criteria in Cancer of the Liver, Liver Cancer Study Group of Japan). Response evaluation criteria in cancer of the liver (RECICL) proposed by the Liver Cancer Study Group of Japan (2009 revised version). Hepatol Res 2010; 40:686-692. Lencioni R, Llovet JM. Modified RECIST (mrecist) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52-60. Maitland ML, Bies RR, Barrett JS. A time to keep and a time to cast away categories of tumor response. J Clin Oncol 2011; 29:3109-3111. Maksimovic O, Schraml C, Hartmann JT, et al. Evaluation of response in malignant tumors treated with the multitargeted tyrosine kinase inhibitor sorafenib: A multitechnique imaging assessment. AJR 2010; 194:5-14. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-214. Nishino M, Jagannathan JP, Ramaiya NH, Van den Abbeele AD. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. AJR 2010; 195:281-289. O Regan KN, Jagannathan JP, Ramaiya N, Hodi FS. Radiologic aspects of immunerelated tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy. AJR 2011; 197:W241-W246. Oxnard GR, Zhao B, Sima CS, et al. Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes. J Clin Oncol 2011; 29:3114-3119.
RECIST website. http://www.recist.com Schwartz LH, Mazumdar M, Brown W, Smith A, Panicek DM. Variability in response assessment in solid tumors: Effect of number of lesions chosen for measurement. Clin Cancer Res 2003; 9:4318-4323. Schwartz LH, Mazumdar M, Wang L, et al. Response assessment classification in patients with advanced renal cell carcinoma treated on clinical trials. Cancer 2003; 98:1611-1619. Shanbhogue AKP, Karnad AB, Prasad SR. Tumor response evaluation in oncology: Current update. J Comput Assist Tomogr 2010; 34:479-484. Smith AD, Shah SN, Rini BI, Lieber ML, Remer EM. Morphology, attenuation, size, and structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR 2010; 194:1470-1478. Sullivan DC, Gatsonis C. Response to Treatment series: Part 1 and introduction, Measuring tumor response Challenges in the era of molecular medicine. AJR 2011; 197:15-17. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-216. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009; 50:122S 150S. Yaghmai V, Miller FH, Rezai P, Benson AB III, Salem R. Response to Treatment series: Part 2, Tumor response assessment Using new and conventional criteria. AJR 2011; 197:18-27. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [ 18 F]-fluorodeoxyglucose and Positron Emission Tomography: Review and 1999 EORTC recommendations. Eur J Cancer 1999; 35:1773-1782. Author has no relevant financial interests or relationships to disclose.