Fatima, Nosheen

Sajid, Mahwish

Zaman, Maseeh Uz

English

eCommons@AKU

eCommons@AKUDepartment of Radiology Medical College, PakistanJuly 2017Tumor Response Evaluation Criteria:Standardization Ensures SuccessMaseeh Uz ZamanAga Khan University, maseeh.uzzaman@aku.eduNosheen FatimaAga Khan University, nosheen.fatima@aku.eduMahwish SajidFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_radiolPart of the Radiology CommonsRecommended CitationZaman, M. U., Fatima, N., Sajid, M. (2017). Tumor Response Evaluation Criteria: Standardization Ensures Success. Journal of theCollege of Physicians and Surgeons Pakistan, 27(7), 389-391.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_radiol/275Cancer-related mortality is growing rapidly. It is expectedthat in years to come, cancer will become the mostcommon cause of death worldwide. Cancer-relatedtherapies are not only expensive but associated withmorbidities; and the tumor shrinkage with recentlyintroduced therapies is seen in only 10-15% patients.1However, in recent days various therapies haveimproved survival rate and outcome of patients withcertain cancers like childhood malignancy andlymphomas. Imaging plays an important role by helpingthe oncologists and guides them whether to continue,change or abandon a treatment, depending upon theresponse of the tumor. Response could be evaluated byphysical examination or by using anatomical orfunctional imaging, and it could be assessed eitherqualitatively like the visual analysis or quantitativelyusing digital images and computer algorithms.In early 70's when computerized tomography (CT) wasnot freely available, Moertel and Henley2 presented astudy in which they employed 16 experiencedoncologists and assessed the consistency in palpationof 12 pairs of fake masses. For 50% reduction inperpendicular diameter of tumor as response, the inter-observer variability was 7-8%. However, for a cut-off of25% reduction in tumor size as response, they observedan inter-observer variability of 19-25%. Therefore, theyrecommended that greater than 50% decline in theperpendicular tumor diameter should be considered asresponse. In late 70’s with the wider availability of CTscan, the World Health Organization (WHO) presentedtumor response criteria based on the product of2 perpendicular diameters (bi-dimensional criteria).3According to these criteria, the tumor responses werecategorized as complete response when there wasdisappearance of tumor at least 4 weeks after treatment;partial response when ≥ 50% decrease in some ofproducts; and no change when neither partial norcomplete response. Progressive disease was defined as≥ 25% increase in sum of product with or withoutappearance of new lesion. However, WHO criteria hadsevere limitation of overestimation of the progressivedisease because an increase of 11% in each dimensiongives a product of 25% (false positive). Other limitationswere that there was no mention of the number of lesionsthat should be measured or the smallest lesion thatshould be considered as a measurable one.In the year 2000, a comprehensive response evaluationcriteria in solid tumor (RECIST) was published whichwas revised (RECIST 1.1) in 2009.4,5 These criteria incontradistinction to WHO criteria recommended usingthe single longest diameter of tumor (uni-dimensional)and sum of longest dimensions was recommended tocategorize response evaluation. RECIST and RECIST1.1 have addressed most of the limitations of WHOcriteria as well. RECIST 1.1 recommends measuringmaximal 5 target lesions and 02 lesions per organ(target non-nodal lesion: ≥ 10 mm in the longestdimension; target node: ≥ 15 mm short axis dimension);and ≥30% declining the sum of the longest dimension isconsidered as partial response. Revised RECIST 1.1criteria also recommend an increase in 20% in sum ofthe longest dimension with at least 5 mm absoluteincrease in size of a lesion to qualify for progressivedisease.The basic limitations of RECIST criteria are variability inthe measurement of tumor sizes by various readers andits application in non-measurable diseases likemesothelioma or bone marrow metastasis. Furthermore,with the introduction of the cytostatic therapy (Imatinib inGIST and Sorafenib in Hepatoma) tumor shrinkage isnot expected in the early phase of the treatment. Havinga residual mass at completion of the chemotherapy isnot an unusual finding and poses difficulty to assess theresponse solely on anatomical criteria.Histopathologically, these residual tumor masses maybe composed of non-viable fibrotic tissue or havingsubclinical viable tumor tissue. This has opened vista formetabolic response criteria. History of metabolicresponse assessment dates back to 1988 when Israelet al. claimed disappearance of Gallium-67 as anindicator of remission of Non-Hodgkin lymphoma(NHL).6 In 1993, Richard Wahl shared his experience ofusing serial 18-fluorodeoxyglucose (18FDG) in a patientwith breast cancer who responded to chemo-hormonetherapy with a progressive decline in 18FDG uptake.7Based on these evidences, it was found that there is astrong correlation between 18FDG uptake and metabolictumor burden and, therefore, changes in the 18FDGuptake rather than the tumor size must be considered asJournal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (7): 389-391 389EDITORIALTumor Response Evaluation Criteria: Standardization Ensures SuccessMaseeh uz Zaman1, Nosheen Fatima1 and Mahwish Sajid21 Section of PET/CT and NM Imaging, Department of Radiology,The Aga Khan University Hospital, Karachi, Pakistan.2 Department of Radiotherapy, KIRAN, Karachi, Pakistan.Correspondence: Dr. Maseeh uz Zaman, Associate Professorand Section Head NM and PET/CT Imaging, Department ofRadiology, AKUH, Karachi.E-mail: maseeh.uzzaman@aku.eduReceived: March 29, 2017;   Accepted: May 27, 2017.a metabolic indicator for tumor response. Presently,18FDG because of its wider availability is the mostcommonly used agent for evaluation of metabolic tumorresponse. 18FDG based assessment could be madeeither visually or qualitatively, which requires staticimage but no blood sampling; or quantitatively, whichneeds acquisition of the dynamic imaging and arterialblood sampling (cumbersome); and despite beingaccurate, is not used by most of the clinical centersworldwide. Another method, is the semiquantitativemethod which requires static whole body imagingwithout blood sampling and the ratio of tumor 18FDGuptake with injected 18FDG dose normalized to the bodyweight (BW) or lean body mass (LBM) or body surfacearea (BSA) is calculated. This ratio is calledstandardized uptake value (SUV), which along withqualitative (visual) assessment is the most commonlyused strategy for assessment of metabolic tumorresponse.The first metabolic response criteria were published byEuropean Organization of Research and Treatment ofCancer (EORTC), which was published by Young et al.8These criteria emphasized upon the patient preparation,time of scans after the last chemotherapy and use ofSUV normalized to the BSA; and for tumor sampling,SUVmax and SUVmean were recommended to be used.Complete metabolic response (CMR) was defined ascomplete disappearance of tumor activity to thebackground level while the partial metabolic response(PMR) was defined as >15% decline in SUVmax after thefirst or more >25% decline after 2nd chemotherapy whilethe reduction in the extent of the uptake is not required.Stable metabolic disease (SMD) was defined asincrease in SUVmax <25% or declining in SUVmax >15%decline but no increase in extent of uptake. Progressivemetabolic disease (PMD) was defined as increase inSUVmax >25%, increase in extent >20%, or appearanceof a definite new 18FDG avid lesion. However, thelimitation of EORTC criteria included significant changesin the individual tumor SUVs and the use of theretrospective data having limited number of patients,tumor types and treatment strategies.Richard Wahl presented a comprehensive PositronEmission Response Criteria In Solid Tumor (PERCIST)in 2009.1 PERCIST criteria stress upon the utilization ofSUV which is normalized to LBM (SUVlbm = SUL) anduse SULpeak (measured over 1.3 cm3 circle) for tumorsampling and not SUVmax (calculated upon single pixeland subject to image noise) as recommended byEORTC criteria. PERCIST also defined the measurablelesion having a SULpeak >1.5 x Liver SULmean +2standard deviation. It recommends measuring the singlehottest lesion for response evaluation. However,measurement up to 5 lesions may be performed to builda prospective data. PERCIST strongly emphasized uponstandardization of imaging protocol and recommendsthat hepatic SULmean, uptake time and injected 18FDGdoses of 2 studies must be ±20%, ±15 minute and ±10%,respectively. It also stresses upon the utilization of thesame scanner as difference between calibrations of twoscanners could result in variation in SULpeak values.CMR is defined as visual disappearance of all ofmetabolically active tumors; PMR as decline of >30%(0.8 unit) of SULpeak between intensities of hottest lesionspre- and post-therapy (which may not be the samelesion) and no new lesion; SMD as no CMR/PMR/RMD;PMD as increase of >30% (0.8 unit) of SULpeak orappearance of a definite 18FDG avid malignant lesion.Limitations of PERCIST include getting SULpeak (ascalculation of LBM is difficult) and lack of standardizationof imaging protocols. According to one study publishedin 2011, <50% the studies could not meetstandardization criteria due to the use of differentscanners at Johns Hopkins University. Because of theselimitations, PERCIST has been struggling to gainpopularity in oncological functional imaging.However, in 18FDG-avid lymphomas, metabolic responsecriteria have been widely used worldwide. Because ofthe high diagnostic accuracy of 18FDG PET/CT inHodgkin's lymphoma and many diffuse large B-celllymphomas (DLBCL), bone marrow biopsy can beavoided. 18FDG PET/CT is used for staging and interimPET [iPET] (after 2 cycles) and end of treatment [ePET]18FDG PET/CTs are used for response evaluation.However, routine surveillance scan is not recommendeddue to high incidence of false positive findings resultingin unjustified investigations. Although there are manyresponse evaluation criteria published by manysocieties, Deauville-5-point score (D-5PS) is the mostcommonly used criteria worldwide.9 Score 1 means nouptake and score 2 defined as uptake equal or less thanmediastinal blood pool activity. Score 1 and 2 areconstrued as CMR for both iPET and ePET. Score 3 isdefined as uptake greater than mediastinal blood poolactivity but equal or less than liver. For iPET, it isinterpreted as CMR but for ePET good response. Score4 is defined as activity moderately greater than liver(1 liver SUVmax) and score 5 as markedly greater thanliver (>2 liver SUVmax) uptake with or without a newdefinite lesion. If uptake is less than baseline scan,score 4 and 5 are interpreted as PMR for iPET and RMDfor ePET. If uptake is greater than baseline or no changeor appearance of a new lesion, then score 4 and 5 areinterpreted as PMD and/or treatment failure.Tumor response may be evaluated on the basis ofanatomical or metabolic metrics. Anatomical changesalthough appear late and having limitation ofreproducibility, RECIST is the most commonly usedcriteria globally. Metabolic changes which appear quiteearly in phase of the treatment are more sensitive thanmorphological changes. 18FDG uptake has a strongcorrelation with viable tumor burden; and change inMaseeh uz Zaman, Nosheen Fatima and Mahwish Sajid390 Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (7): 389-39118FDG uptake has significantly high diagnostic accuracyfor predicting tumor response. PERCIST criteria must beused for a precise and early prediction of tumorresponse. However, lack of standardization in PET/CTimaging protocols is the fundamental reason of dearth ofits popularity. For 18FDG avid lymphomas, Deauville5-PS is the most reliable response evaluation criteriawhich are being used for both Hodgkin and Non-Hodgkinlymphomas worldwide. It is imperative that all existingPET/CT facilities must work together to adopt sameimaging protocols to make subtle changes in 18FDGtumor uptake more meaningful for better diseaseoutcome.REFERENCES1. Wahl R, Jacene H, Kasamon Y, Lodge M. From RECIST toPERCIST: Evolving considerations for PET response criteria insolid tumors. J Nucl Med 2009; 50:122S-50S.2. Moertel CG, Hanley JA. The effect of measuring error on theresults of therapeutic trials in advanced cancer. Cancer 1976;38:388-94.3. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reportingresults of cancer treatment. Cancer 1981; 47:207-14.4. Therasse P, Arbuck SG, Eisenhauer EA. New guidelines toevaluate the response to treatment in solid tumors. EuropeanOrganization for Research and Treatment of Cancer, NationalCancer Institute of the United States, National Cancer Instituteof Canada. J Natl Cancer Inst 2000; 92:205-16.5. Eisenhauer EA, Therasse P, Bogaerts J. New responseevaluation criteria in solid tumours: revised RECIST guideline(version 1.1). Eur J Cancer 2009; 45:228-47.6. Israel O, Front D, Lam M. Gallium 67 imaging in monitoringlymphoma response to treatment. Cancer 1988; 61:2439-43.7. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R.Metabolic monitoring of breast cancer chemohormono-therapyusing positron emission tomography: initial evaluation. J ClinOncol 1993; 11:2101-11.8. Young H, Baum R, Cremerius U. Measurement of clinical andsubclinical tumour response using [18F]-fluorodeoxyglucoseand positron emission tomography: review and 1999 EORTCrecommendations. European Organization for Research andTreatment of Cancer (EORTC) PET Study Group. Eur J Cancer1999; 35:1773-82.9. Barrington SF, Mikhaeel NG, Kostakoglu L. Role of imaging inthe staging and response assessment of lymphoma: consensusof the international conference on malignant lymphomasimaging working group. J Clin Oncol 2014; 32: 3048-58.Tumor response evaluation criteria: standardization ensures successJournal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (7): 389-391 391

Tumor Response Evaluation Criteria: Standardization Ensures Success

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Tumor Response Evaluation Criteria: Standardization Ensures Success

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