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1、“REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMAJ Clin Oncol 25:579-586. 2007 by American Society of Clinical OncologyCheson et al, J Clin Oncol 17:1244, 1999In 1999, an International Working Group (IWG) of clinicians, radiologists, and pathologists with expertise in the evaluation and management o

2、f patients with Lymphoma published guidelines for response assessment and outcomes measurement.Response Criteria for LymphomaReappearance New or increased New or increased Enlarging liver/spleen; new sites Relapse/progression Irrelevant 50% decrease 50% decrease Decrease in liver/spleen Irrelevant 5

3、0% decrease 50% decrease Normal Positive NormalNormal Normal PRNormal or indeterminate 75% decrease Normal Normal Indeterminate Normal Normal Normal CRuNormal Normal Normal Normal CRBone Marrow Lymph Node Masses Lymph Nodes Physical Examination Response Category Definitions of End Points for Clinica

4、l Trials DeathDeath related to NHLAll patientsCause-specific death Entry onto trialTime when new treatment is neededAll patientsTime to next treatment First documentation of responseTime to relapse or progressionCR, CRu, PRResponse duration First documentation of responseTime to relapseCR, CRuDiseas

5、e-free survival Entry onto trialDisease progression or death from NHLAll patientsProgression-free survival Entry onto trialFailure or death from any causeCR, CRu, PREvent-free survival Entry onto trialDeath from any causeAll patientsOverall survival Point of Measurement Definition Response Category

6、End Point Standardized response criteria provide uniform end points for clinical trials:Allowing for comparisons among studiesFacilitating the identification of more effective therapiesThe widely used IWG criteria for response assessment of lymphoma are based predominantly on CT.It became clear that

7、 the International Working Group criteria warranted revision, because of identified limitations and the increased use of :18F fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC),flow cytometry,molecular biology “REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMAJ Clin Onc

8、ol 25:579-586. 2007 by American Society of Clinical OncologyThe Competence Network Malignant Lymphoma convened an International Harmonization Project at which 5 subcommittees were formed: Response Criteria End Points for Clinical Trials Imaging Clinical Features Pathology/BiologyUse of Positron Emis

9、sion Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in LymphomaJ Clin Oncol 25:571-578. 2007 by American Society of Clinical OncologyPET- PET/CT PET using 18Ffluorodeoxyglucose (FDG, a radioactive derivative of glucose, is

10、 an advanced imaging tool, based on the increased glucose consumption of cancer cells), has emerged as a powerful functional imaging tool for staging, restaging, and response assessment of lymphomas. The advantage of PET over conventional imaging techniques, such as TC or RMN, is its ability to dist

11、inguish between viable tumor and necrosis or fibrosis in residual mass(es) often present after treatment. A recently developed integrated PET/CT system, which combines a PET camera and CT scanner in a single session, has overcome these drawbacks by providing both anatomical and functional imaging at

12、 the same position. PET/CT has become the new standard approach to imaging in the diagnosis and management of many cancer patients. Standardization of PET and CT Imaging ParametersPatients undergoing PET imaging should receive an FDG dose of 3.5 to 8 MBq/kg of body weight, with a minimum dose of 185

13、 MBq in adults (5 mCi) and 18.5 MBq (0.5 mCi) in children. Patients should have fasted for at least 4 hours before FDG injection.Blood glucose level should not exceed 200 mg/dL at the time of FDG injection. If the blood glucose exceeds this level, the FDG-PET study should be rescheduled and an attem

14、pt made to control the blood sugar.Whole-body acquisition using a PET or PET/CT system should encompass at least the region between the base of the skull and themed thigh, and can be acquired in either two- or three-dimensional mode.Whole-body imaging should begin 50-70 minutes after the administrat

15、ion of FDG. The reconstructed PET or PET/CT images must be displayed on a computer workstation so that transaxial, sagittal, and coronal images can be viewed simultaneously.PET False-positive: - Thymic hyperplasia - Infection- Inflammation - Sarcoidosis- Brown fatOther causes of false-positive scans

16、 should be ruled out. False-negative: - Resolution of the equipment and technique - Variability of FDG avidity among histologic subtypesJuweid et al. evaluated the impact of integrating PET into the IWG criteria in a retrospective study of 54 patients with diffuse large B-cell NHL who had been treat

17、ed with an anthracycline-based regimen. PET:Increased the number of complete remission (CR) patients, Eliminated the CRu categoryEnhanced the ability to discern the difference in progression-free survival (PFS) between patients experiencing CR and PRRecommendations for the use of PET or PET/CTPET is

18、 strongly recommended before treatment for patients with routinely FDG-avid, potentially curable lymphomas (eg, diffuse large B-cell lymphoma DLBCL, Hodgkins lymphoma) to better delineate the extent of disease. 2. PET is essential for the post-treatment assessment of DLBCL and Hodgkins lymphoma beca

19、use a complete response is required for a curative outcome. Based on the “meta-analysis by Zijlstra et al, pooled sensitivity and specificity of FDG-PET for detection of residual disease after completion of first-line therapy were 84% and 90%, respectively, for HL, and 72% and 100%, respectively, fo

20、r aggressive NHL. Recommendations for the use of PET or PET/CT3. However, PET is recommended in the other, incurable histologies only if they were PET positive before treatment and if response rate is a primary end point of a clinical study. 4. Numerous studies have demonstrated that PET performed a

21、fter 1 to 4 cycles of multiagent chemotherapy predicts therapeutic outcome; however, no currently available data demonstrate improvement in results by altering treatment based on this information. The role of PET for response assessment of aggressive NHL subtypes other than DLBCL and of indolent and

22、 mantle-cell lymphomas, is less clear. For these generally incurable NHLs, progression-free or overall survival is usually the primary end point in clinical trials evaluating their response to treatment. Requirement for Pretherapy PET Scan for Response Assessment of Lymphoma at the Conclusion of The

23、rapynot obligatory for assessment of response after treatment of patients with HL, DLBCL, follicular lymphoma, or mantle-cell lymphoma because these lymphomas routinely are FDG avid. However, it is strongly encouraged for these subtypes because it can facilitate the interpretation of post-therapy PE

24、T.mandatory for variably FDG-avid lymphomas, if PET is used to assess their response to treatment.These include aggressive NHL subtypes other than DLBCL, such as T-cell lymphomas, and all subtypes of indolent NHL other than follicular lymphoma, such as extranodal marginal zone lymphoma of mucosa ass

25、ociated lymphoid tissue and small lymphocytic lymphoma.If PET is to be used for response assessment of patients with these histologic subtypes, there needs to be documentation that PET was positive at all disease sites 1.5 cm in diameter noted by CT.Timing of PET Performed for Response Assessmentat

26、the Conclusion of TherapyPET should not be performed before at least 3 weeks after chemotherapy and preferably 8 to 12 weeks after completion of radiotherapy.REVISED RESPONSE CRITERIA, 2007New or recurrent involvement50%increase from nadir in the SPD of any previous lesionsAppearance of a new lesion

27、(s)1.5 cm in any axis, 50% increase in SPD of more than one node, or 50% increase in longest diameter of a previously identifed node1 cm in short axisLesion PET positive if FDG-avid lymphoma or PET positive prior therapyAny new lesion or increase by 50% of previously involved sites from nadirPD(a)FD

28、G-avid or PET positive prior to therapy; PET positive prior sites of disease and no new sites on CT or PET(b) Variably FDG-avid or PET negative; no change in size of previous lesions on CTFailure to attain CR/PR or PDSDIrrelevant if positive prior to therapy; cell type should be specified 50% decrea

29、se in SPD of nodules; no increase in size of liver or spleen 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes(a)FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site(b) Variably FDG-avid or PET negative; regression o

30、n CTRegression of measuable disease and no new sitesPRInfiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negativeNot palpable, nodules disappeared- FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative- Variably FDG-avi

31、d or PET negative; regression to normal size on CTDisappearance of all evidence of diseaseCRBONE MARROWSPLEEN, LIVERNODAL MASSESDEFINITIONRESPONSEEnd pointOverall Survival is defined as the time from entry onto the clinical trial until death as a result of any cause. Progression Free Survival is def

32、ined as the time from entry onto a study until lymphoma progression or death as a result of any cause. PFS is often considered the preferred end point in lymphoma clinical trials, it reflects tumor growth, and therefore is interpretable earlier than the end point of overall survival. Event-Free Surv

33、ival is measured from the time from study entry to any treatment failure including disease progression, or discontinuation of treatment for any reason (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death). It may be useful in th

34、e evaluation of some therapies such as those that are highly toxic. Time to Progression is defined as the time from study entry until documented lymphoma progression or death as a result of lymphoma. Disease-Free Survival is measured from the time of occurrence of disease-free state or attainment of

35、 a CR to disease recurrence or death as a result of lymphoma or acute toxicity of treatment. End pointResponse Duratio is from the time when criteria for response (ie, CR or PR) are met, for which the event is the first documentation of relapse or progression.Lymphoma-Specific Survival (eg, disease-

36、specific survival, cause specific survival) is defined as time from study entry to death as a result of lymphoma. Time to Next Treatment is defined as the time to next lymphoma treatment may be of interest, and is defined as time from the end of primary treatment until the institution of the next th

37、erapy.Clinical Benefit is one of the most important end points for patients as well as for drug approval by regulatory agencies has been evidence of clinical benefit. Clinical benefit may reflect improvement in:quality of life, reduction in patient symptoms, transfusion requirements, frequent infect

38、ions, other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.Follow-Up Evaluation- Good clinical judgment and a careful history - Physical examination- CBC and serum chemistries There is no evidence to support regular surveillance CT sca

39、ns, given that the patient or physician identifies the relapse more than 80% of the time without the need for imaging studies. Data with PET are also insufficient to recommend routine procedures at this time. In a clinical trial, uniformity of reassessment is necessary to ensure comparability among

40、studies with respect to the major end points of: event-free survival,disease-free survival progression free survivalOne recommendation has been to assess patients on clinical trials after completion of treatment at a minimum of every 3 months for 2 years, then every 6 months for 3 years, and then an

41、nually for at least 5 years.These intervals may vary with: - specific treatments- duration of treatment - protocols- unique drug characteristicsFollow-Up EvaluationRecently, the National Comprehensive Cancer Network published recommendations for follow-up of patients with Hodgkins and NHL: for patients with Hodgkins lymphoma in an initial CR, an interim history and physical examination every 2 to 4 months for 1 to 2 years, then ever