International Harmonization Project Research Articles

Interim [18F]fluorodeoxyglucose positron emission tomography imaging in stage I–II non-bulky Hodgkin lymphoma: would using combined positron emission tomography and computed tomography criteria better predict response than each test alone?

Our objective was to validate the International Harmonization Project (IHP) positron emission tomography (PET) response criteria and correlate with the Deauville criteria and diagnostic computed tomography-based (dCT) lesion size changes. All patients were recruited prospectively to the Cancer and Leukemia Group B (CALGB) 50203 trial for the treatment of stage I–II, non-bulky Hodgkin lymphoma (HL). [18F]Fluorodeoxyglucose (FDG) PET and dCT were performed at baseline and after two doxorubicin, vinblastine and gemcitabine (AVG) cycles (PET-2, dCT-2) in 88 patients. IHP and Deauville criteria and percent decrease in the sum of the products of the perpendicular diameters (%SPPD) after two cycles were correlated with progression-free survival (PFS). After a median follow-up of 3.3 years, 23.9% of patients relapsed/progressed (3-year PFS 77%). By IHP, the 2-year PFS was 88% and 54% for PET-2 negative and positive groups, respectively (p = 0.0009). Similar results were obtained for Deauville criteria. In a univariate analysis, PET-2 predicted PFS better than %SPPD, and in a combinatorial analysis, in the PET-2 positive group, a negative dCT-2 increased PFS by 27–35%. However, some confidence intervals were large due to small sample sizes. In conclusion, IHP and Deauville criteria-based interpretation of PET-2 was strongly associated with 2-year PFS. The combined analysis of PET-2 with dCT-2 suggested a better predictive value for PFS compared to either test alone. Further studies are under way to confirm these findings.

Comparison of various criteria in interpreting end of therapy F-18 labeled fluorodeoxyglucose positron emission tomography/computed tomography in patients with aggressive non-Hodgkin lymphoma

Various interpretation criteria exist to assess end of therapy F-18 labeled fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in lymphoma. This study was carried out to compare these criteria. Data of 69 patients with aggressive non-Hodgkin lymphoma (AGR-NHL) who underwent FDG PET/CT at the end of therapy and were followed up for a minimum period of 1 year (median follow-up period 17 months) were evaluated. Twenty-eight of the 69 patients were found to have residual/recurrent disease during follow-up. The accuracy for predicting residual disease of International Harmonization Project (IHP) criteria, London criteria and Gallamini criteria was 71.0%, 84.0% and 88.4%, respectively. Gallamini and London criteria had greater accuracies in predicting residual disease than IHP criteria (p = 0.0001). The major difference in accuracy was due to the low positive predictive value of IHP criteria. Positive predictive values (PPVs) of both London and Gallamini criteria (79.3% and 88.5%, respectively) were high when compared with that of IHP criteria (60.5%) (p = 0.001). Negative predictive values (NPVs) were similar for all the criteria. In conclusion, Gallamini and London criteria had higher accuracy when interpreting end of therapy FDG PET/CT studies in AGR-NHL. London criteria can be used preferentially over Gallamini criteria because of simplicity in interpretation and reproducibility.

Early Interim PET Scans in Diffuse Large B-Cell Lymphoma: Can There Be Consensus About Standardized Reporting, and Can PET Scans Guide Therapy Choices?

The prognosis value of interim positron emission tomography (PET) remains controversial in diffuse large B-cell lymphoma (DLBCL) patients because of the absence of consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation, was related to a low positive predictive value of treatment failure. The 5-point scale (5PS) that refers the residual uptake to the liver as background tissue was shown to slightly reduce false-positive interim PET interpretations compared to IHP criteria. Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV (SUVmax) between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis. This latter approach is feasible in a multicenter setting and allows clinicians to design a risk-adapted therapeutic strategy based on early PET response assessment.

Interim FDG PET Imaging in CALGB 50203 Trial of Stage I/II Non-Bulky Hodgkin Lymphoma: Would Using Combined PET and CT Criteria Better Predict Response Than Each Test Alone?,

Abstract 3644Use of interim PET in Hodgkin Lymphoma (HL) for risk-adapted treatment has been confounded by a lack of standardized criteria for interpretation. The International Harmonisation Project (IHP) criteria (JCO 2007;25:571) have been validated and are widely used for restaging following therapy. Our objective was to validate the IHP criteria for response evaluation based on PET after two cycles and correlate with the “London”criteria and diagnostic CT-based (dCT) lesion size changes. Methods:Pts were accrued prospectively to CALGB 50203, a trial of doxorubicin, vinblastine and gemcitabine (AVG) for initial treatment of stage I-II non-bulky Hodgkin lymphoma (HL). All had FDG PET or PET/CT and a separate high-resolution dCT scan at baseline, after two cycles of AVG (PET-2 and dCT-2) and at the end of therapy. No treatment change was made based on the PET-2 results. Of 99 assessable pts, 88 had both PET-2 and dCT-2. The primary PET-2 interpretation was based on IHP criteria (uptake > mediastinal blood pool/background is positive), a secondary interpretation was performed using the 5 point London criteria (uptake > liver is positive). The percent decrease in the sum of the products of the diameter (%SPPD) was determined between baseline dCT and dCT-2. A receiver operator curve (ROC) analysis was performed to determine the best cut-off for %SPPD to define a positive and negative CT result. The PET-2 and dCT-2 (%SPPD change) data were correlated with progression free survival (PFS). Results:Sixty-four pts (73%) achieved a complete remission (CR)/CR unconfirmed (CRu), 23.9% a partial response (PR), and 3% had stable disease. After a median follow-up of 3.3 years (1.8–5.0 years), 23.9% of patients relapsed/progressed with an estimated 3-year PFS of 0.77 [CI 68,84]. Eleven of 24 (45.8%) PET-2 positive patients relapsed vs. 10 of 64 (15.6%) PET-2 negative patients (p=0.0004). The best cut-off determined from ROC analysis for %SPPD change was 65%. The comparative results for individual evaluation criteria are displayed in the Table. In the PET-2 positive group, a negative dCT-2 increased PFS by 27–35%, suggesting an influence from dCT-2 results. However, in the combinatorial analysis, some of the confidence intervals are large due to small number of patients in each individual group, particularly, when both PET-2 and dCT-2 were positive as well as when PET-2 was positive and dCT-2 was negative. Conclusions:Interim PET/CT after two cycles of chemotherapy using either IHP or London criteria has a high NPV in early stage non-bulky HL. However, the PPV of interim PET needs to be improved to guide clinical management. Combining PET-2 with %SPPD decrease after 2 cycles improves prediction of PFS compared to each test alone. These data provide a proof of concept for risk-adapted clinical trials and further studies are underway to confirm these findings in a larger population.TableFDG PET Evaluation with IHP and London Criteria, Dedicated CT and Combined AnalysisPatients N, (%)Progression N, (%)PPV [95%CI]NPV [95%CI]2-year PFS [95%CI]PET by IHP45.8% [26,67]84.4% [73,92]PET2−64 (72.7%)10 (15.6%)88% [77,93]PET2+24 (27.3%)11 (45.8%)54% [33,71]PET by London50.0% [25,75]81.9% [71,90]PET2−72 (81.8%)13 (18.1%)85% [74,91]PET2+16 (18.2%)8 (50.0%)50% [25,71]%SPPD change42.9% [26,61]88.5% [77,95]≥65% (negative)52 (59.8%)6 (11.5%)88% [76,95]<65% (positive)35 (40.2%)15 (42.9%)63% [45,76]Combined AnalysisNANAPET2−/≥ 65%42 (48.3%)3 (7.1%)93% [79,98PET2−/< 65%21 (24.1%)7 (33.3%)76% [52,89]PET2+/≥ 65%10 (11.5%)3 (30.0%)70% [33,89]PET2+/< 65%14 (16.1%)8 (57.1%)43% [18,66]NA: not done, small samples Disclosures:Bartlett:seattle genetics: Research Funding. Cheson:Celphalon: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.

Role of FDG-PET As Prognostic Indicator in Patients with Follicular Lymphoma(FL) After Immunochemotherapy Induction. A Retrospective Study From the Fondazione Italiana Linfomi

Abstract 2636 Background and objectives:Quality of response assessed with [18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a strong independent prognostic factor in patients with Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Recently the prognostic role of response assessment with PET was also shown in patients with Follicular Lymphoma (FL) (Trotman et al JCO 2011). We conducted a retrospective analysis to investigate the role of FDG-PET after immunochemotherapy in FL. Patients and methods:The study was designed as a retrospective unplanned analysis of newly diagnosed FL patients randomized among R-CVP, R-CHOP, R-FM in the FOLL05 clinical trial (NCT00774826). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. As mandatory patients should have undergone staging and restaging at the end of treatment with FDG-PET. Local PET interpretation was used to identify clearly positive and clearly negative cases. For this phase of the study uncertain cases were not analyzed for study endpoints: centralized review is ongoing. Contrast enhanced computed tomography (CECT) scans were also collected to confirm quality of response: in particular a cut off of 1.5 cm for the maximum transverse diameter of residual lymph nodes was considered to separate Complete vs. Partial remissions according to International Workshop Criteria (IWC) (Cheson et al JCO 1999). The primary study endpoint was Progression Free Survival. Results:Among 534 patients enrolled in the FOLL05 trial, 114 cases fulfilled eligibility criteria for this study. Baseline patients characteristics did not differ from the overall FOLL05 patient population. In particular FLIPI was 0–1 in 23%, 2 in 42% and 3–5 in 35%. First-line immunochemotherapy, included R-CHOP (36 pts.), R-CVP (33), and R-FM (45). No maintenance therapy with Rituximab was given. Overall response rate at the end of therapy, defined according to IWC, was 97% including a 78% complete remissions (CR) rate. Baseline PET scan was positive in all patients. In 16 cases an interim PET was also available and resulted clearly positive in 6 patients (38%). At the end of treatment 10 cases had inconclusive final PET results and were excluded from subsequent analyses; a clearly positive PET scan was recorded in 26 out of the remaining 104 (25%). In univariate logistic analysis number of nodal sites (>4) was predictive of final positive PET. Although a trend towards a higher rate of PET positive scans was observed with increasing FLIPI and FLIPI2 this difference was not statistically significant. The rate of patients with negative final PET was 81%, 57%, and 60% for those in CR, PR, and less than PR (Fisher exact test: P=0.021). Assessing response with International Harmonization Project (IHP) criteria (Cheson et al JCO 2007), that also consider PET, 14/74 (19%) of patients previously defined in CR according to IWC were changed to PR and 13/23 (57%) of those in PR were switched to CR. The CR rate changed from 78% to 75% with an agreement rate of 70% between IWC and IHP. With a median follow up of 28 months (range 9–56), 3 year PFS was 68% (95% IC 54%–79%). In univariate analysis a shorter 3yr PFS was observed in post-treatment PET+ vs. PET- patients: 48% vs 84% (log rank p=0.036, HR 2.34, 95% CI 1.03–5.3). A positive final PET was confirmed as a poor prognostic factor when adjusted by FLIPI and FLIPI2 (HR 2.33 P=0.048, and HR 2.41 P=0.039, respectively). Prognostic role of final PET was not affected by treatment arm or by any of analyzed prognostic factors. Finally a trend toward a prolonged duration of remission was observed for patients who achieved a PET negative CR, compared with PET+ CRs and and both PET+/− PRs. Conclusions:This FOLL05 ancillary study confirms that post-treatment PET-CT can modify response allocation and is a predictor of PFS after first line immunochemotherapy in patients with FL. If the prognostic role of PET assessment of response will be confirmed in a larger series and in prospective studies a response adapted treatment strategy could be tested also in FL. Disclosures:Di Raimondo:Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

SUVmax reduction improves early prognosis value of interim positron emission tomography scans in diffuse large B-cell lymphoma

AbstractThe prognostic value of interim positron emission tomography (PET) interpreted according to visual criteria is a matter of debate in diffuse large B-cell lymphoma (DLBCL). Maximal standardized uptake value reduction (ΔSUVmax) may better predict outcome. To compare the prognostic value of both methods, we analyzed PET done at baseline (PET0) and after 2 (PET2) and 4 (PET4) cycles in 85 patients with high-risk DLBCL enrolled on a prospective multicenter trial. All images were centrally reviewed and interpreted visually according to the International Harmonization Project criteria and by computing ΔSUVmax between PET0 and PET2 (ΔSUVmaxPET0-2) or PET4 (ΔSUVmaxPET0-4). Optimal cutoff to predict progression or death was 66% for ΔSUVmaxPET0-2 and 70% for ΔSUVmaxPET0-4. Outcomes did not differ significantly whether PET2 and PET4 were visually positive or negative. Inversely, ΔSUVmaxPET0-2 analysis (> 66% vs ≤ 66%) identified patients with significantly different 2-year progression-free survival (77% vs 57%; P = .0282) and overall survival (93% vs 60%; P < .0001). ΔSUVmaxPET0-4 analysis (> 70% vs ≤ 70%) seemed even more predictive for 2-year progression-free survival (83 vs 40%; P < .0001) and overall survival (94% vs 50%; P < .0001). ΔSUVmax analysis of sequential interim PET is feasible for high-risk DLBCL and better predicts outcome than visual analysis. The trial was registered at http://clinicaltrials.gov as NCT00498043.

Prognostic Significance of FDG-PET in Relapsed or Refractory Classical Hodgkin Lymphoma Treated with Standard Salvage Chemotherapy and Autologous Stem Cell Transplantation

Positron emission tomography using [(18)F]fluorodeoxyglucose (FDG-PET) has emerged as the standard response assessment tool in frontline therapy for classical Hodgkin lymphoma (cHL). The ability of FDG-PET to predict outcomes in patients with relapsed cHL treated with modern standard salvage chemotherapy and autologous stem cell transplantation (ASCT) remains uncertain. Forty-six patients with relapsed/refractory cHL treated from 2001 to 2007 with standard salvage/ASCT therapy had FDG-PET available for blinded review. The results of pre-ASCT FDG-PET interpreted by the international harmonization project (IHP) criteria were compared with published prognostic models for prediction of event-free survival (EFS) and overall survival (OS). Overall, 3-year EFS was 62% and OS was 78%, with a median follow-up of 38 months. Pre-ASCT FDG-PET response significantly predicted 3-year EFS in FDG-PET-negative (82%) versus FDG-PET-positive (41%) patients (P = .02). A trend was observed for 3-year OS comparing FDG-PET-negative (91%) versus -positive (64%) patients (P = .08). Multivariate analysis demonstrated the independent prognostic significance of pre-ASCT FDG-PET for EFS with a hazard ratio (HR) of 3.2 (confidence interval [CI] 1.1-9.0, P = .03). Pre-ASCT FDG-PET scans predict EFS in patients with relapsed cHL patients treated with modern salvage/ASCT therapy and warrant prospective evaluation.

18F-FDG PET/CT for early response assessment in diffuse large B-cell lymphoma: poor predictive value of international harmonization project interpretation.

PET using (18)F-FDG has prognostic value when performed at the completion of initial chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). (18)F-FDG PET may also be predictive of outcome when performed during the treatment course of DLBCL, but robust prospective studies and standardization of (18)F-FDG PET interpretation in this setting are lacking. In this prospective study, patients with advanced-stage DLBCL were treated with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and (18)F-FDG PET/CT was performed after cycle 2 or 3 and at the end of therapy. The (18)F-FDG PET/CT scans were interpreted according to the International Harmonization Project for Response Criteria in Lymphoma, and the maximum standardized uptake value (SUV) of the most (18)F-FDG-avid lesions was recorded. Fifty patients were enrolled, and all underwent interim (18)F-FDG PET/CT. At a median follow-up of 33.9 mo, the positive predictive value (PPV) of interim (18)F-FDG PET/CT for relapse or progression was 42%, and the negative predictive value (NPV) was 77%. Interim (18)F-FDG PET/CT was significantly associated with event-free survival (P = 0.017) and with progression-free survival (P = 0.04) but not with overall survival (P = 0.08). End-of-therapy (18)F-FDG PET/CT had high PPV and NPV (71% and 80%, respectively) and was significantly associated with event-free survival, progression-free survival, and overall survival (P < 0.001). SUV measurements did not discriminate patients who relapsed or progressed from those who remained in remission. When performed after 2 cycles of immunochemotherapy and interpreted according to International Harmonization Project criteria, early response assessment with PET/CT has a high NPV but low PPV in patients with advanced-stage DLBCL. Prospective trials are required to validate different criteria for the interpretation of interim (18)F-FDG PET/CT and establish the role of interim (18)F-FDG PET/CT in the management of patients with DLBCL.

Prognostic value of interim FDG PET/CT in Hodgkin’s lymphoma patients treated with interim response-adapted strategy: comparison of International Harmonization Project (IHP), Gallamini and London criteria

Interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) has shown to be an accurate predictor of prognosis in Hodgkin's lymphoma (HL). However, FDG PET response criteria are a matter of ongoing debate. The aim of this study was to confirm the prognostic value of interim PET/CT in HL patients treated with an interim response-adapted strategy and to compare the respective performances of different published criteria. Newly diagnosed patients with HL underwent interim PET/CT after four courses of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). The treatment strategy was adapted according to prognostic factors at diagnosis and interim PET/CT and CT results. PET images were prospectively interpreted visually: a negative result was defined as no residual uptake above local background. All other findings were considered as positive. Retrospectively, interim PET/CT was analysed according to International Harmonization Project (IHP), Gallamini and London criteria The analysis included 90 patients; 6 of 31 patients with positive interim PET/CT and 7 of 59 patients with negative interim result presented treatment failure. The negative predictive value (NPV) and positive predictive value (PPV) for predicting 2-year progression-free survival (PFS) was 95 and 16%, respectively. With the other criteria, NPV remained very high (from 95 to 96%). The PPV increased from 19 to 45% according to the threshold used. Interim PET/CT was significantly correlated with PFS with Gallamini (p = 0.01) and London criteria (p < 0.0001). Our study confirms the high NPV of interim PET/CT for predicting treatment outcome in HL and a probably better prognostic value using a higher threshold for positivity even after four cycles of chemotherapy as used in Gallamini and London criteria.

Évaluation de la réponse au traitement du lymphome avec la TEP 18F-FDG : existe-t-il un consensus dans l’évaluation de la réponse ?

The concept of risk-adapted therapy in lymphoma is increasingly accepted as a way to achieve higher cure rates with a lower or equal risk of treatment-related morbidity and mortality. Tailoring and individualizing therapy according to the need of the patient is a therapeutic option which could maybe soon become the standard of care. However, it is still not proven that modifying therapy based on interim-PET can improve patient outcomes. Therefore, this issue must be analyzed in appropriately designed clinical trials. 18F-FDG PET enables evaluation of the early metabolic changes rather than the morphologic changes which occur later during therapy. In lymphoma these early metabolic changes are highly predictive of the final treatment response. PET performed after a few courses of standard chemotherapy is a reliable prognostic tool to identify poor responders to therapy. Interim-PET is a powerful prognostic tool when compared to other well-established clinical parameters in lymphoma. However, the major drawback in the literature appeared to be related to the lack of uniform and reliable criteria for interim-PET scan interpretation. Therefore, in April 2009 an international meeting took place in Deauville (France), where uniform criteria were established for interim-PET scan interpretation. On the other hand, when PET is used to assess treatment response after completion of therapy, the criteria established in the International Harmonization Project in 2007 must be applied. These recommendations were designed to standardize the interpretation of interim PET and PET at the conclusion of therapy of patients with lymphoma both in clinical practice and clinical trials.

Évaluation de la réponse au traitement des lymphomes : rôle de la TEP-FDG

Positron emission tomography (PET) with FDG has a prominent role in the staging of lymphoma, including Hodgkin's lymphoma and aggressive non Hodgkin's lymphoma. Its value in the assessment of end therapy response is also well established, especially with residual masses on CT scan to differentiate between fibrosis (scar) and active tissue. International experts with the International Harmonization Project of lymphoma have proposed a set of interpretation criteria. Finally, FDG-PET looks very promising in the early response assessment; it has shown to be predictive of chemosensitivity and of therapy response. Interpretation criteria have been improved and proposed. FDG-PET usefulness is being evaluated in national and international research protocols where therapeutic strategies are based on FDG-PET results.

IHP Interpretation Criteria of Interim-PET Scan Confirms Prognostic Impact In Early Stage Hodgkin Lymphoma Patients without Bulky Disease

AbstractAbstract 3890 Introduction:Early stage classical Hodgkin lymphoma (cHL) is highly curable with a combination of chemotherapy and radiotherapy. Nevertheless a small proportion of patients with localized stage do not respond to therapy and progressed. We want to explore the predictive value on therapy outcome of an early evaluation of treatment response by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed after two corses of ABVD in pts with localized Hodgkin's disease. Patients and methods:From 2002, 246 new localized stage cHL pts were consecutively admitted to twelve Italian hematological centers on behalf of Intergruppo Italiano Linfomi. Pts with stage I-IIA according to Ann Arbor stage, independent of presence of bulky disease, were considered for the study. FDG-PET was mandatory at baseline, after two cycles and at the end of therapy. International Harmonization Project (IHP) interpretation criteria were recommended to define PET positivity. We evaluated the progression free survival of pts starting from the time of diagnosis to relapse or progression of disease or last follow-up. No treatment variation based only on PET-2 results was allowed. All bulky-disease pts reports were centrally reviewed. Results:The median age was 33 years (13-78), 133 pts were female, 225 pts were stage II, bulky was reported in 76 pts, 231pts were treated with combined modality and 15 pts were treated with chemotherapy alone. The FDG-PET performed after two cycles (PET2) was positive in 32 pts (13%). Seventeen non-bulky pts were PET2 positive: 10 (59%) progressed or relapsed and 7 remained in CR. By contrast 152/153 (99%) non-bulky pts with a negative PET2 remained in CR. Thus the PPV value of a PET2 in non-bulky pts was 59% and the NPV was 99%, moreover the sensitivity and specificity of PET2 were 91% and 96%, respectively. In bulky disease pts we performed a revision of all reports according to Deauville criteria and 3 cases were converted from PET2 positive to PET2 negative. In revised bulky disease pts 15 were PET2 positive: 6 (40%) progressed or relapsed and 9 remained in CR. In this group of pts the PPV was 40%, the NPV 93% and sensitivity and specificity were 60% and 90% respectively. In univariate analysis negative FDG-PET performed after two cycles (p .0000), absence of bulky disease at diagnosis (.005) were statistically correlated with a better progression free survival. In multivariate analysis only PET2 was independently predictive of relapse/progression probability (p .000). With a median follow-up of 35 months (range 4–87), the 2-yr FFS probability for PET2 negative and for PET2 positive non-bulky patients were 98% and 29% respectively (p: .000) for patients with bulky-disease were 99% and 45% respectively (p: .002). Conclusion:This multicentric study confirms that FDG-PET scan performed after two courses of conventional standard dose chemotherapy was able to predict treatment outcome in early stage non-bulky cHL. In bulky disease we suggest new interpretation criteria to define interim PET results. Disclosures:Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Respective PROGNOSTIC Value of the International Harmonization PROJECT (IHP), Gallamini and London Criteria for Interim FDG PET-CT Performed AFTER 4 Courses of ABVD IN HODGKIN'S LYMPHOMA

AbstractAbstract 3889During the last decade, the role of Interim 2-[18F]fluoro-2-deoxy-D-glucose emission positron tomography (FDG PET-CT) has increased for Hodgkin's lymphoma (HL) evaluation and it is strongly recommended for both staging and post treatment evaluation. Early treatment response assessment is a challenge for risk-adapted therapy and interim PET-CT has emerged as a powerful prognostic tool to predict treatment outcome, a negative exam predicting a favorable disease-free survival while a positive study a worse prognosis. However, FDG PET response criteria are a matter of ongoing debate. So, the aim of our study was to confirm the prognostic value of interim FDG PET-CT performed after 4 courses of chemotherapy (ABVD) but also to compare the respective performances of the different published criteria: International Harmonization Project (IHP), Gallamini criteria, 5-point scale (Gallamini A et al. Haematologica 2006; 91: 475–481; Juweid ME et al. J Clin Oncol 25:571-578, 2007; Barrington SF et al. Eur J Nucl Med Mol Imaging 2009;36(Suppl. 2):S252; Meignan M et al. Leukemia & Lymphoma, August 2009; 50(8): 1257–1260; Gallamini A, et al. Leuk Lymphoma. 2009 Nov;50(11):1761-4.) Design and methods:From 2002 to 2006, newly diagnosed patients with HL who underwent interim PET-CT after 4 courses of ABVD were eligible for the purpose of the present study. Treatment strategy after 4 courses of ABVD was then adapted according to prognostic factors at diagnosis and interim PET-CT result. PET images were interpreted prospectively visually by at least two nuclear medicine physicians with expertise in lymphoma imaging with the criteria used before 2005: negative result was defined as no residual uptake above local background. All other findings were considered as positive. Using these evaluation criteria, interim PET positive patients who were not in CR on CT underwent autologous stem cell transplantation. Interim PET positive patients who reached CR on CT and interim PET negative patients received additional courses of ABVD (patients with advanced HD or bulky disease at diagnosis) or radiotherapy alone (stage I or II without bulky disease). Retrospectively and for the purpose of the present study, interim PET results were interpreted using the more recent criteria (Gallamini criteria, IHP criteria and 5-point scale method) Results:90 patients were included. Median age at diagnosis was 34.4 (16-71). 49% of the patients presented with B-symptoms and 50% had stage III-IV disease. According to initial criteria, 31 patients had a positive interim PET result. Among these patients, 28 underwent ASCT. Fifty-nine patients had a negative interim PET-CT. Six of 31 patients with positive interim PET-CT and 7 of 59 patients with negative interim result presented treatment failure. Thus, the negative predictive value (NPV) and positive predictive value (PPV) for predicting 2 years progression free survival (PFS) was 95% and 16%, respectively. Retrospectively, interim PET-CT was analyzed according to different recent published criteria using mediastinum and liver background as threshold for positivity. With these criteria, NPV remained very high (from 95% to 96%). However, the PPV increased from 25% to 55% according to the threshold used. Taken together, the statistical analysis revealed that Interim PET-CT was significantly correlated with PFS only for two methods: the Gallamini criteria and the 5-point scale method. Conclusion:The first part of our study using the criteria used before 2005 shows the high NPV of interim PET-CT for predicting treatment outcome in HL. However, better prognostic values are obtained by using higher threshold for positivity such as liver background even after 4 cycles of ABVD. Indeed, our analysis underscores the better results reached by the Gallamini criteria and 5-point scale methods. The better method to predict PFS was obtained by the 5-point scale (scores 1, 2, 3 and 4 were classified as negative while only score 5 was classified as positive) showing a PPV and NPV of 55% and 96%, respectively. Disclosures:No relevant conflicts of interest to declare.

Post-Treatment (not interim) PET-CT Scan Status Is Highly Predictive of Outcome In Mantle Cell Lymphoma Treated with R-Hypercvad or ASCT

AbstractAbstract 3131 Introduction:Although MCL is reported to be an FDG-avid NHL subtype, PET-CT is not currently recommended in the modified IWG criteria (Chesen et al, JCO 2007) to stage, survey and assess treatment response in MCL. PET-CT is however frequently used for these purposes in clinical practice in MCL. Although convincing data exists regarding the prognostic utility of PET-CT imaging in Hodgkin Lymphoma (interim & post treatment) and DLBCL (post treatment), its prognostic utility both during treatment and immediately following treatment have not systematically been evaluated in a large MCL patient cohort to support its use in clinical practice. Methods:We conducted a two-center (JTCC & UPenn), retrospective cohort study to examine the prognostic utility of pre-treatment (PET-1), interim-treatment (PET-2 after 2–3 treatment cycles) and post-treatment PET-CT (PET-3) imaging in a uniform MCL patient cohort undergoing dose-intensive chemotherapy (R-HCVAD) or high-dose chemotherapy followed by autologous stem (ASCT) cell rescue in the 1st line setting. The primary study endpoints were PFS and OS. PET-CT images were centrally reviewed for the purposes of this study using standardized response criteria proposed by the Imaging Subcommittee of International Harmonization Project in Lymphoma (Juweid et al, JCO 2007). Radiologists were blinded to clinical outcomes at the time of PET-CT review and results were dichotomized at each time point and their concomitant SUV max at a suspected site of disease was recorded. Result:82 pts (median age 61, range 35–95) with advanced stage (98% stage IV) MCL with PET-CT data were identified for this analysis. Of these, 57 pts were treated with R-HCVAD (50) or ASCT (7) in the first-line setting. 154 PET-CT scans were reviewed. Overall treatment response rate (IWG) was 93% (76% CR + 17%PR). With median follow-up of 23 months (disease progression) and 27 months (overall survival), 3 year PFS and OS estimates were 70% (CI 53–82%) and 82% (CI 65–91%) respectively. Median baseline characteristics: WBC 7.4, ECOG PS 1, LDH/ULN .82, Ki-67 (MIB-1) 28% (range 10–90%), MIPI 3.5 (31% intermediate risk, 19% high risk). 20% and 30% of pts were blastoid variant and leukemic phase at diagnosis respectively. Pre-treatment PET-CTs were FDG-avid in 92% of MCL patients with a median SUV max of 7.8 (range 2.4–36.7) at a suspected site of disease. Pre-treatment PET-CT SUV max was positively associated with high Ki-67 (variance-weighted least-squares regression, p=.01). PET-2 and PET-3 were positive in 34% and 18% of patients respectively. Kaplan Meier and Cox regression survival analyses were used to test the association between PET-CT and survival. Interim PET-CT status was not associated with PFS (HR 1.1, CI .4-3.6, p=.8) or OS (HR .8, CI .15-4.6, p=.8). Post treatment PET-CT status was statistically significantly associated with PFS (HR 5.4, CI 2.0–14.5, p=.001, Harrell's C =.70, Figure) and trended towards significant for OS (HR 3.2, CI .8-11.9, p=.1). Post treatment PET-CT status remained an independent predictor of PFS in multivariate analysis which included MIPI score, blastoid variant and Ki-67. Conclusion:Our cohort is the first large series of MCL patients treated essentially with R-HCVAD examining the correlation between PET-CT and outcome in the front-line setting. A positive PET-CT following the completion of therapy identifies patients with an inferior PFS and a trend towards inferior OS. These data do not support the prognostic utility of PET-CT in pre-treatment (no upstaging) and interim treatment settings. This information should be incorporated into the design of future prospective clinical trials. We are currently examining the relationship of novel computer-assisted quantitative FDG-PET/CT measures of total tumor volume and total tumor metabolic burden with clinical outcome in patients with mantle cell lymphoma. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Improvement of Early 18F-FDG PET Interpretation in Diffuse Large B-Cell Lymphoma: Importance of the Reference Background

This study investigated whether the reference background above which a residual mass is considered positive in the International Harmonization Project criteria should be modified for early (18)F-FDG PET evaluation. In 92 patients with newly diagnosed diffuse large B-cell lymphoma, the maximal standardized uptake value (SUVmax) was measured on post-cycle 2 PET in the most intense residual mass (or, in the case of negative PET findings, in the area of most intense tumor uptake before therapy), in the mediastinal blood pool (MBP) and the liver, as potential reference background tissues. With MBP as a reference (SUVmax, 2.0 ± 0.6), PET was unable to distinguish early responders from nonresponders. In contrast, with liver as a reference (SUVmax, 2.5 ± 0.7), 2-y progression-free survival was significantly different between patients with PET-negative findings (81.8% [95% confidence interval, 71%-93%]) and patients with PET-positive findings (51.8% [95% confidence interval, 35%-69%], P = 0.003). When assessing early response, particularly in risk-adapted therapeutic trials, it seems preferable to refer to a background tissue (liver) with a higher level of uptake than that of current international criteria (MBP) which were designed for end-of-treatment evaluation.

EARLY [18F]FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY–BASED RESPONSE EVALUATION AFTER TREATMENT WITH GEMCITABINE AND VINORELBINE FOR REFRACTORY HODGKIN DISEASE: A CHILDREN’S ONCOLOGY GROUP REPORT

The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies.

Accounting and Business Ethics: An Introduction

Despite the enormous impact of various accounting scandals on the accounting profession, the general malaise amongst the profession more broadly, and the significant legislative and institutional reforms that have taken place as a result, there are still surprisingly few textbooks on accounting ethics. This concise introductory text takes a broad view of ethics and accounting, taking into account contemporary social trends, such as globalization and terrorism. Rather than delineating codes of professional conduct, this text pushes the reader towards an understanding of the nature of ethical dilemmas and the factors that influence the ways in which accountants frame ethical questions. The book is divided into two parts. The first part focuses on developing thinking about the different kinds of ethical questions that could be posed in relation to accounting. The second part focuses more explicitly on accounting practice, exploring the ethical function of accounting in relation to the market economy, ethics in relation to the accounting profession, and the ethics of the international accounting harmonization project. Accounting and Business Ethics is a compact introduction aimed at both students and practitioners who want to understand more about the ethics of accounting.

Interim PET in lymphoma: a step towards standardization

In this issue, Barrington et al. propose well-defined criteriafor interim PET/CT reporting in lymphoma [1]. Thesecriteria, based on a five-point scale, introduce two mainconcepts which are highly relevant for interim PETanalysis: (1) the intensity of the residual uptake frequentlyobserved at interim is graded relative to various levels ofreference background (RB)—mediastinal blood pool(MBP) and liver—and (2) this grading process is indepen-dent of the size of the residual tumour. Furthermore, theauthors reported that this five-point scale assessed on asample of 50 patients with advanced stage Hodgkin’slymphoma (HL) by 4 pairs of experts from 4 Europeancentres: (1) seems a reproducible tool for guiding thera-peutic strategy after 2 cycles of ABVD (Adriamycin,bleomycin, vinblastine, dacarbazine) when liver is chosenas an RB and (2) is robust enough to be used in multicentretrials for interim PET reporting.The authors have decided to use this scale in theResponse Adapted Treatment in Hodgkin Lymphoma(RATHL) trial, an interim PET-driven therapeutic strategyin patients with advanced stage HL. Although manytrials are ongoing worldwide in HL and non-Hodgkin’slymphoma (NHL) to test whether the results of an interimPET performed after one to four cycles of chemotherapycan tailor a response-adapted therapy, standardized interimPET criteria are still missing. Interim PET requires indeedspecific criteria which should be different from thosedefined for end treatment by the International Harmoniza-tion Project (IHP) in Lymphoma [2]. In the context of drugdevelopment and survival improvement observed inlymphoma, the rationale of interim PET is to define ana posteriori prognostic index reflecting tumour chemo-sensitivity during first-line therapy, allowing earlychanges of therapy (escalation or de-escalation) adaptedto specific situations. In many trials the strategy can bemodified according to the results of two interim PETexams performed at different times during inductiontreatment. As a matter of fact, depending on thecharacteristics of tumour growth and histological typethe evolution of PET under treatment is different. Indiffuse large B-cell lymphoma (DLBCL) neoplastic cellsconstitute more than 90% of the total cell population.The metabolic activity during therapy decreases in acontinuous mode, with cell killing. Interim PET after oneor two cycles of chemotherapy evaluates the response ofthe cells with the highest mitotic index, thereby providingan early evaluation of chemosensitivity and identifyingresponders and non-responders [3, 4]. On the other hand,after three or four cycles of therapy, FDG uptake is moredependent on the tumour regrowth [5]. In HL, the Reed-Sternberg (RS) cells account for less than 1% of the tumour.Bystander, lymphomononuclear cells work, throughcytokines, as an amplifier of the PET detection power. Thesecells are switched off very early (one to two cycles) bychemotherapy [6]. Therefore, the amount of residual activityat interim varies with the kinetics of tumoral destruction, thehistology of lymphoma, the tumoral microenvironment, thetreatment and the time point (two cycles or more) at whichPET is performed. These variations are better described by aquantitative analysis by reference to the baseline PET thanby using a visual dichotomous analysis (positive or negative)which results in a loss of information [3, 5]. In this regard thefive-point scale proposed by Barrington et al. is goingtowards the right direction by giving the possibility to grade

Utility of Positron Emission Tomography Imaging in Lymphoma: A Clinician's Point of View

Positron emission tomography (PET) using fluorine-18 (FDG) is increasingly used in the staging of lymphoma. Results of the use of PET during and after completion of therapy for staging of Hodgkin’s lymphoma and aggressive non-Hodgkin’s lymphoma demonstrate a highly predictive value for outcome. Based on recommendations of the International Harmonization Project, FDG-PET has been incorporated into the revised response criteria of lymphoma. There is currently no evidence to support the use of FDG-PET in indolent lymphoma, nor for its routine use during follow-up. Evidence also lacks on the impact of FDG-PET on treatment outcome. Clearly, well designed clinical trials are warranted to determine the subsets of patients that will benefit from this modality.

Does a negative post-therapy PET obviate the need for any further follow-up imaging in patients with nonbulky early-stage Hodgkin's lymphoma (HL)?

8058 Background: Recent reports suggest that medical imaging, besides potentially harmful, could turn out neither cost- effective, nor beneficial. We investigated whether this can be justified in the post-treatment follow-up of patients with nonbulky early-stage HL (nbHL) Methods: We identified all nbHL patients who underwent post-tx PET/CT from 11/04-1/09 at Az. Ospedaliera S. Croce e Carle in Cuneo, Italy or from 7/03-8/05 at the University of Iowa, and met the following criteria: received ≥ 4-8 cycles of chemotx alone or 3-6 cycles of chemotx followed by involved-field radiation therapy (IFRT); had PET/CT performed within 3-12 wks post-tx and adequate clinical, laboratory, and radiological follow-up for ≥ 1 y post-tx or until evidence of treatment failure. PET/CT scans were interpreted by nuclear medicine experts using the International Harmonization Project criteria. Results: Forty patients met the entry criteria for the study: all stage II; 23 received 4-6 cycles of ABVD alone, sixteen 3-6 cycles of ABVD followed by IFRT, 1 patient received Stanford V with RT. Thirty-seven patients (93%) had a negative post-tx PET, 3 (7%) had a positive scan. Median overall F/U was 3.1 y (range; 0.6-5.6) and 3.1 y in patients without progression. Two of the three patients with positive PET scans had persistent disease or progressed at 0.6 and 0.7 y while the third remains with no evidence of disease at 4.7 y post-tx. None of the 37 pts with negative PET progressed or relapsed. Conclusions: Incidence of relapse in nbHL patients with a negative posttherapy PET is extremely low, justifying eliminating any further follow-up imaging in these patients unless there is clinical/biochemical suspicion of recurrence. This conclusion is further supported by previous observations that > 80% of any eventual relapses are discovered by the patient and/or physician without imaging. No significant financial relationships to disclose.