Interim PET Results Research Articles

To Perform, or Not to Perform Interim PET: Questioning the Impact of Midtherapy Evaluation During PRRT in GEP-NET Patients.

This study aimed to analyze the impact of interim evaluation on the continuation of 177Lu-based peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to survey its usage across German university hospitals. In 119 GEP-NET patients who underwent PRRT, we retrospectively assessed the results and therapeutic impact of restaging performed after 2 cycles using MRI/CT/somatostatin receptor imaging. Therapeutic decisions based on interim PET results were made in multidisciplinary tumor board meetings. Additionally, an online survey was conducted among 37 German university hospitals regarding their interim evaluation practices, focusing on the change in management. Of 119 patients, 83 completed 4 PRRT cycles; 36 stopped after 2: 27 showed PD, 3 had PR leading to surgery, 5 experienced toxicity, and 1 died. Those completing 4 cycles showed a median PFS of 38.0 months (95% confidence interval, 32.2-43.8). Seventeen of 37 surveyed hospitals routinely used interim evaluation. In a survey among 37 German university hospitals, 62% reported offering PRRT for GEP-NET patients, with 74% of these performing a routinely interim evaluation after 2 cycles of PRRT, primarily using PET/CT imaging techniques. Interim PET after 2 PRRT cycles helps to identify early progression in GEP-NET patients. Standardizing interim evaluation practices could enhance the comparability of clinical outcomes and optimize patient management.

Cost-Effectiveness of Shortening Treatment Duration Based on Interim PET Outcome in Patients With Diffuse Large B-cell Lymphoma

BackgroundGuideline recommendations for diffuse large-B-cell lymphoma (DLBCL) treatment are shifting from long to short treatment duration, although it is still unclear whether shortening treatment duration does not cause any harm. As interim PET (I-PET) has high negative predictive value for progression, we evaluated the cost-effectiveness of shortening treatment duration dependent on I-PET result. Materials and MethodsWe developed a Markov cohort model using the PET Re-Analysis (PETRA) database to evaluate a long treatment duration (LTD) strategy, ie 8x R-CHOP or 6x R-CHOP plus 2 R, and a short treatment duration (STD) strategy, ie 6x R-CHOP. Strategies were evaluated separately in I-PET2 positive and I-PET2 negative patients. Outcomes included total costs and quality-adjusted life-years (QALYs) per patient (pp) from a societal perspective. Net monetary benefit (NMB) per strategy was calculated using a willingness-to-pay threshold of €50,000/QALY. Robustness of model predictions was assessed in sensitivity analyses. ResultsIn I-PET2 positive patients, shortening treatment duration led to 50.4 additional deaths per 1000 patients. The STD strategy was less effective (-0.161 [95%CI: -0.343;0.028] QALYs pp) and less costly (-€2768 [95%CI: -€8420;€1105] pp). Shortening treatment duration was not cost-effective (incremental NMB -€5281). In I-PET2 negative patients, shortening treatment duration led to 5.0 additional deaths per 1000 patients and a minor difference in effectiveness (-0.007 [95%CI: -0.136;0.140] QALY pp). The STD strategy was less costly (-€5807 [95%CI: -€10,724;-€2685] pp) and led to an incremental NMB of €5449, indicating that it is cost-effective to shorten treatment duration. Robustness of these findings was underpinned by deterministic and probabilistic sensitivity analyses. ConclusionTreatment duration should not be shortened in I-PET2 positive patients whereas it is cost-effective to shorten treatment duration in I-PET2 negative patients.

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies.

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies.

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies

The combined role of biomarkers and interim PET scan in prediction of treatment outcome in classical Hodgkin's lymphoma: a retrospective, European, multicentre cohort study

Early-interim fluorodeoxyglucose (FDG)-PET scan after two ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy courses (PET-2) represents the most effective predictor of treatment outcome in classical Hodgkin's lymphoma. We aimed to assess the predictive value of PET-2 combined with tissue biomarkers in neoplastic and microenvironmental cells for this disease. We enrolled 208 patients with classical Hodgkin's lymphoma and treated with ABVD (training set), from Jan 1, 2002, to Dec 31, 2009, and validated the results in a fully matched independent cohort of 102 patients with classical Hodgkin's lymphoma (validation set), enrolled from Jan 1, 2008, to Dec 31, 2012. The inclusion criteria for both the training and validation sets were: the availability of a representative formalin-fixed, paraffin-embedded tissue sample collected at diagnosis; treatment with ABVD with or without radiotherapy; baseline staging and interim restaging after two ABVD courses with FDG-PET; no treatment change based solely on interim PET result; and HIV-negative status. We used Cox multivariate analysis classification and regression tree (CART) to compare the predictive values of these markers with that of PET-2 and to assess the biomarkers' ability to correctly classify patients whose outcome was incorrectly predicted by PET-2. In multivariate analysis, PET-2 was the only factor able to predict both progression-free survival (hazard ratio [HR] 33·3 [95% CI 13·6-83·3]; p<0·0001) and overall survival (HR 31·3 [95% CI 3·7-58·9]; p=0·002). In the training set, no factor had a stronger adverse predictive value than a positive PET-2 scan and none was able to correctly reclassify PET-2 positive patients. In PET-2 negative patients, expression of CD68 (≥25%) and PD1 (diffuse or rosetting pattern) in microenvironmental cells, and STAT1 negativity in Hodgkin Reed Sternberg cells identified a subset of PET-2 negative patients with a 3 year progression-free survival significantly lower than that of the remaining PET-2 negative population (21 [64%] of 33 [95% CI 45·2-79·0] vs 130 [95%] of 137 [95% CI 89·4-97·7]; p<0·0001). These findings were reproduced in the validation set. The CART algorithm correctly predicted the response to treatment in more than a half of patients who had a relapse or disease progression despite a negative PET-2 scan, thus increasing the negative predictive value of PET-2. In keeping with preliminary results from interim PET response adapted clinical trials of patients with advanced Hodgkin's lymphoma, there might be a non-negligible proportion of treatment failures in the interim PET negative group treated with standard ABVD. Italian Association for Cancer Research, Bologna Association against leukaemia, lymphoma and myeloma, and Bologna University.

Prognostic Value of Interim and End of Treatment FDG-PET/CT Scan Results in Adult Patients with Burkitt Lymphoma - a Retrospective Analysis of a Single Center Cohort

Introduction: End of treatment FDG-PET/CT activity is a powerful predictor of survival outcome in patients with Hodgkin, Diffuse large B cell and Follicular lymphomas. The predictive value of interim PET/CT scan on survival in Hodgkin lymphoma is also well established. To date, there are limited data regarding the prognostic significance of interim and end of treatment FDG-PET/scan results in adult patients with Burkitt lymphoma (BL), mainly due to the rarity of this entity. In this single-center retrospective study we analyzed the survival outcomes of patients with BL according to the findings on interim and end of treatment FDG-PET/CT scans using the Deauville criteria.Methods: We thoroughly reviewed the clinical records of all BL patients who were treated in our medical center between 2005-2014. Thirty three patients and 104 scans were included in our final analysis. Interim PET/CT scan was performed before starting the 3rd cycle of the therapy. PET/CT scans were scored as positive or negative based on the five-point scale: scores 1-3 represented complete metabolic response (CMR) and scores 4-5 defined persistent or progressive disease. Response and survival outcomes were defined according to the Lugano Classification. Survival was calculated with the Kaplan-Meier method and survival comparison was analyzed with the Log-Rank test.Results: Twenty four (73 %) were males and median age was 48 years (22-78). Two patients were HIV positive. Twenty four patients (73%) had stage 3 or 4 disease and 25 patients (76%) had high-intermediate or high risk disease according to the International Prognostic Index. All patients received intensive regimens, and the majority of them (78%) were treated according to the GMALL-B-ALL/NHL2002 protocol. Rituximab was part of treatment in 28 (85%) patients. After a median follow-up of 1.92 years (yrs) (0.08-9.58), 7 patients (21%) have died: six due to advanced BL and one from treatment related toxicity. The overall (OS) and progression-free survival (PFS) at 3-yrs for all patients were 76% and 70%, respectively. Importantly, OS was predicted by the results of end of treatment PET/CT scans: patients in CMR (n=21) had OS of 90% while those with positive PET/CT (n=5) had OS of 30% at 3 years (Figure 1, p=0.001). Early-interim PET/CT results did not predict either PFS or OS at 3 years (OS - 85% for patients in CMR and 60% for patients with positive PET, p=0.27).Conclusions: The current retrospective study indicates that adult patients with BL, who receive rituximab-based intensive regimens, such as the GMALL-B-ALL/NHL2002 protocol, have a favorable outcome. End of treatment PET activity strongly predicted survival outcomes while interim PET result did not correlate with prognosis. Based on our data, it appears that changing treatment in adult patients with BL only on the basis of interim PET/CT results is not advised, unless there is clear evidence of progression.*Authors EP, MK & TD equally contributed to this study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PET-Based Textural Analysis Assessment in Early Stage Hodgkin Lymphoma Treated with Standard Combined Approach

BACKGROUNDInterim 18F-fluorodeoxyglucose positron tomography (PET) has been shown to be a prognostic factor for clinical outcome in Hodgkin lymphoma (HL). Predicting an early cancer's response to chemotherapy could enhance clinical care management by enabling the personalization of treatment plans based on predicted outcome. Tumour texture can be measured from medical images that provide a non-invasive method of capturing intratumoral heterogeneity and hence could potentially allow a prior assessment of a patient's predicted response to treatment.PURPOSEThe aim of the study was to assess the applicability of the pre-treatment PET-based textural analysis (TA) in a cohort of early stage HL and its correlation with early response to chemotherapy.METHODSWe reviewed medical records of patients with early stage HL diagnosed between January 2012 and December 2014 treated with standard combined modality therapy. All PET scans were reviewed by a local nuclear medicine physician, blinded for the clinical outcome and interim PET (iPET) results. TA was applied to pre-treatment PET images in order to extract features which can be used as prognostic factors for early treatment response. TA features provide unique information about the spatial variation of pixels in the segmented Volume of Interests (VOIs) where it is applied thus they are able to quantitatively score tumor heterogeneity. In order to do this, two different strategies were employed. First was to segment pathological lymph nodes with a 40% of SUVmax isocontour algorithm. Each lymphnode was analysed with TA as a "stand-alone patient" in order to increase the number of observations. Second strategy was to extract two cubes of 3 and 4 cm3 of volume from the highest metabolically active mediastinic region. Seventy-four textural features were calculated mathematically and then analyzed with statistical non parametric test (Kruskall Wallis test). Features which showed prognostic power (or patient stratification ability) were employed to build Receiver Operating Curve (ROC) in order to score their sensibility and specificity.RESULTSTwenty-four patients were selected. After iPET revision, 17 patients were considered disease free after 2 cycles of ABVD whereas the remaining 7 patients had a positive iPET. Considering each lymph node as a "stand-alone patient" we were able to analyse 84 cases.The Kruskall Wallis test showed that 5 out of 74 TA features could separate iPET responders and non-responders patients with statistical significance (p<0.01). Among these 5 features (40% SUVmax segmentation algorithm applied on captant lymph nodes), "coarseness feature" (a feature that scores the granularity of lymph node activity) is able to provide a good discrimination (p<0.005) between iPET responders and non-responders, with an efficiency of 73% (77% sensitivity, 70% specificity). This means that lymph nodes which appear coarser in pre-treatment PET images have a higher probability of being positive at iPET. Results obtained employing the second technique showed that 4 features are able to predict iPET response with statistical significance (p<0.02) but with an even better discrimination efficiency up to 85% employing "uniformity feature" as prognostic factor as can be seen in Fig. 1 and Fig. 2.CONCLUSIONTextural biomarkers as an intratumoral heterogeneity quantification tool hold great promise for the early prediction of tumor outcomes. In this work, we demonstrated the applicability of the PET-based TA in a cohort of cases with early HL. This method requires further validation in a larger prospective study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PET response-adapted clinical trials in Hodgkin lymphoma: a comprehensive review

Hodgkin lymphoma (HL) is a highly curable disease, as most HL patients become long-term survivors, with 10-years cure and survival rates after first-line treatment exceeding 80 and 90 %, respectively. Despite these rewarding results, 10–15 % of early stage and 20–25 % of advanced stage patients became chemo-refractory to first-line treatment, and nearly half of them ultimately succumb to their disease. On the other hand, a small but significant fraction of long-term survivors, especially those treated with combined chemoradiation, experience treatment related morbidity and mortality with cardiovascular events and secondary neoplasms arising 5–20 years after the end of therapy. Therefore, an unfulfilled need still exists for a risk-adapted strategy, with a very effective treatment in high-risk patients and a low toxicity regimen in the vast majority of patients who are indeed chemo sensitive. Interim PET scan, performed after few cycles of chemotherapy proved the main predictor of treatment outcome in ABVD-treated patients and superseded the predictive role of traditional prognostic markers. Moreover, simple and reproducible rules for interim PET interpretation agreed among experts have been validated in HL, and are now available for the clinical practice. A number of phase II trials yielded the prof of concept that adapting treatment to interim PET result could ultimately increase long-term disease control in the entire patient population, compared to that obtained with the standard chemotherapy approach. In the present article the results of these pioneer single-centre small trials, as well as the preliminary results of large international prospective trials will be reviewed.

Prognostic Role of the CD68+ Cell Count and Early Response Evaluation with Interim-PET and Levels of Plasma Thymus and Activation-Regulated Chemokine (TARC) in ABVD-Treated Classical Hodgkin Lymphoma

▪Prognostication in classical Hodgkin lymphoma (cHL) has mainly explored three areas of interest beyond the use of clinical risk factors in recent years: I. Early response evaluation with positron emission tomography scan (“interim PET”) after 2 cycles of treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has become the most interesting functional imaging technique to accurately predict treatment response in cHL. II. An increased number of tumor-infiltrating macrophages stained with the CD68 antigen in the microenvironment of cHL has been shown to be a simple tissue biomarker with an adverse impact on outcome. III. Among circulating biomarkers, early changes in plasma levels of the chemokine TARC during therapy have been proposed as alternative biomarker for response evaluation.The aim of our study was to evaluate plasma levels of TARC at diagnosis and at interim PET in combination with the tissue biomarker CD68 and interim PET as predictors of outcome in cHL. We included 84 patients diagnosed with cHL (45 limited stage, 39 advanced stage) between 2007 and 2013 who were treated with ABVD in our department. Median age was 34 years (range 15-73), 43 patients were males and 41 females. PET-CT scan was performed at baseline and after two courses of chemotherapy. Interim PET results were assessed using the Deauville five-point scale. Treatment changed according to the PET result in 2 patients only. Plasma TARC levels were measured using ELISA (Human CCL-17/TARC DuoSet, R&D Systems Inc), and CD68+ cells were stained using the PGM1 antibody.When compared to normal individuals? (n=63), plasma TARC levels were elevated above the normal range (upper limit 162 U/ml) at diagnosis in 89% (73/82) patients with cHL. Significantly higher TARC levels were observed in patients with advanced stage disease (p=0.05) and patients with bulky disease (p<0.001). There was no significant association to the CD68+ cell count in the tumor tissue (>5% vs <5%, p=0.09). After 2 cycles of ABVD, interim PET according to Deauville criteria was negative (score 0-3) in 67 (85%) patients and positive (score 4-5) in 12 patients (15%). At interim PET, TARC levels were elevated (>162 U/ml) in 18% of patients and were significantly associated with a positive PET result (p=0.007). Progression-free survival (PFS) at a median observation of 28 months was 76% (95% CI, 65-84%). Strong predictors for PFS were a negative interim PET (86% vs 25% , p<0.0001) and CD68+ cell count <5% (88% vs 66%, p<0.03). Limited stage of disease (p=0.005) and age < 45 years (p<0.05) were favorable prognostic factors. TARC levels (with different cut-off levels and as continuous variable) both at diagnosis and at interim evaluation, were not associated to prognosis. The multivariate analysis including interim PET, CD68 count , stage and age, showed that only a positive interim PET and CD68+ cell count >5% remained independent predictive parameters for PFS (Hazard ratio 11.3, 95% C.I, 3.3-38.4, p<0.001; and hazard ratio 5.8, 95% C.I. 1.4-25, p<0.02, respectively).In conclusion, baseline TARC levels are elevated in the vast majority of patients with classical HL in relation to tumor burden, and turn to normal in most patients after 2 courses of ABVD. Persistent elevated levels of TARC associate with a positive interim PET, but cannot substitute for it as outcome predictor. Interim PET and CD68+ cell counts in the microenvironment maintain their prognostic significance both in univariate and multivariate analysis. DisclosuresNo relevant conflicts of interest to declare.

Interim18F-FDG PET in Hodgkin Lymphoma: Would PET-Adapted Clinical Trials Lead to a Paradigm Shift?

Hodgkin lymphoma (HL) is a curable disease with currently available chemotherapy regimens. Major late morbidities can potentially be avoided in most limited-stage HL patients if the treatment can be adapted to the patient's early response profile. The therapy efficacy can also be increased early during therapy in nonresponding HL patients with the addition of involved-field radiation therapy or a switch to an escalated therapy protocol, particularly in advanced-stage or unfavorable-risk patients. (18)F-FDG PET is a well-established surrogate for tumor chemosensitivity early during therapy. The ongoing PET-adaptive clinical trials are testing the hypothesis that a decision can reliably be made on escalating or deescalating therapy based on interim PET results. Discussed in this review is the integral role of interim (18)F-FDG PET in HL, challenges, critical issues to improve its accuracy, and the observations from completed interim PET studies and ongoing PET-adaptive clinical trials.

Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials?

AbstractDespite the rewarding results achieved in the treatment of Hodgkin lymphoma (HL), concerns have been raised regarding the long-term complications induced by therapy. Hence, the current challenge is to develop a new therapeutic strategy maintaining excellent patient outcome while reducing potentially life-threatening late adverse effects. Therefore, it would be beneficial to identify chemoresistant or refractory patients early during therapy for appropriate and timely escalation of treatment. Recently, compelling data have emerged on the prognostic role of interim [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) performed early during the course of treatment to predict ultimate outcome, even proving superior to conventional prognostic factors. Several ongoing prospective trials are exploring the feasibility of treatment de-escalation strategies in patients with a negative interim PET, as well as therapy escalation in advanced-stage HL patients who have a positive interim PET result. In this article, the published reports on the contribution of interim PET to the design of ongoing response-adapted clinical trials are reviewed. Moreover, some of the unresolved issues revolving around the suboptimal positive predictive value of interim PET are addressed with an emphasis on the interpretation criteria. A final remark on the appropriate use of interim PET is also provided.

Prognostic Value of Interim PET/CT in Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL). Experience of the Spanish Geltamo Group

AbstractAbstract 5076 Background:Interim FDG-PET appears to be useful to guide risk stratification of patients with DLBCL, but remains controversial because the absence of consensus criteria for assessment. The reduction of maximum Standardized Uptake Value (SUVmax) between baseline and interim PET improves the accuracy and reproductibility of this method (Casasnovas, Blood 2011). Patients and Methods:A prospective non randomized phase II trial (EudraCT:2006-005254-68) was undertaken in young patients (pts) newly diagnosed of poor risk DLBCL. Therapy was changed after 3 cycles of R- MegaCHOP based on PET (using local assesment and visual scale); pts with positive PET received early salvage therapy. Primary end points were Progression free survival (PFS) and Overalll survival (OS). Retrospectively, central review was done by three experts using visual assessment (Deauville criteria) and semiquantitative asessment. Baseline and interim SUVmax, and ΔSUVmax were evaluated (cutt off ΔSUVmax: 66%). Significance of PET parameters in OS was analyzed. Results:71 pts were enrolled and central review was possible in 50 pts, from which 80% have complete follow up (mean 37, 6 months, 3. 4–56. 4). OS was significantly influenced by interim PET result, using visual (p=0. 046) but mainly by semiquantitative analysis (p=0. 0008). ΔSUVmax had impact on the overall survival (p=0. 007) whereas basal SUVmax did not. Conclusions:Our preliminary results show that outcome of DLBCL pts with a positive interim PET is worse despite change of therapy. Semiquantitative PET evaluation seems to be necessary, being ΔSUVmax a good prognostic parameter. Disclosures:No relevant conflicts of interest to declare.

Metabolic Tumor Volume Is an Independent Prognosis Factor Predicting patient's Outcome in Hodgkin Lymphoma

AbstractAbstract 3631Positron emission tomography with [18F]fluorodeoxyglucose (PET) performed after two cycles of chemotherapy allows to predict treatment outcome in Hodgkin lymphoma (HL) with a pretty good accuracy specifically when the SUVmax reduction (DSUVmax) of the most hypermetabolic lesion is used to interpret interim PET. However, about 15% of false negative and 30% of false positive interim PET results are observed. To investigate the prognosis impact of the metabolic tumor volume at baseline (MTV0) we compared the respective clinical usefulness and prognosis value of the MTV0 and the SUVmax reduction between baseline PET (PET0) and interim PET (PET2) performed after 2 cycles of chemotherapy (DSUVmaxPET0–2) in a retrospective single centre study.From January 2007 to January 2010, 59 consecutive patients with a first diagnosis of HL were treated in our institution. All patients received 4 to 8 cycles of chemotherapy including ABVD in 50 cases (85%) and BEACOPP in 9 cases. Radiotherapy was performed in 14 responding patients with localized disease. PET was done at baseline (PET0) and after 2cycles of chemotherapy (PET2) and therapeutic strategy was not modified according to PET2 result. All PET scans were reviewed by SK, ABR and IDC. MTV0 was measured with a semi-automatic method using various volume shapes and systematic 41% SUVmax thresholding. Based on a receiver operating characteristics approach patients with a MTV0 >225 cc were considered to have a hypermetabolic bulky disease. Interim PET were interpreted using DSUVmaxPET0–2 and patients with a DSUVmaxPET0–2 >71% were considered as good responders after 2 cycles. Progression-free survival (PFS) and freedom from treatment failure (FFTF) were analyzed according to MTV0 and DSUVmaxPET0–2.Median follow-up was 39 months (range: 6–62).Median MTV0 was 120 cc (range: 10 – 1610) and 17 patients (29%) had a MTV0 >225 cc. Patients with a MTV0 >225 cc had more frequently a bulky tumor>10 cm (41% vs 5%; p = 0.0021). MTV0 (≤ 225 vs > 225) was predictive of 3-year PFS (85% vs 42%; p = 0.001) and FFTF (88% vs 45%; p = 0.0015). Bulky tumor was also predictive of 3-year PFS (44% vs 78%, p <0.04), but of border line significance for 3-year FFTF (80% vs 53%, p = 0.09). In multivariate analysis, using the international prognosis score, DSUVmaxPET0–2, MTV0 and bulky tumor as covariates, only DSUVmaxPET0–2 and MTV0 remained independent predictors for PFS (p= 0.0005; RR=6.4, and p<0.007; RR= 4.2, for DSUVmaxPET0–2 and MTV0 respectively) and FFTF (p= 0.0002; RR= 8.2,and p= 0.01; RR= 4.4, for DSUVmaxPET0–2 and MTV0 respectively). Then, 3 prognosis groups could be identified (Figure 1): patients with either DSUVmaxPET0–2>71 and MTV0≤225 (n = 37; 63%), or DSUVmaxPET0–2<71 or MTV0>225 (n = 17; 29%), or DSUVmaxPET0–2<71 and MTV0>225 (n = 5; 8%), had a 92%, 48%, and 20% 3-year PFS (p<0.0001) and a 94%, 54% and 20% 3-year FFTF (p<0.0001) respectively.MTV0 is more relevant that tumor bulk to predict outcome of patients with Hodgkin lymphoma, and adds significant prognosis insights to interim PET response assessment. The combination of MTV0 with DSUVmaxPET0–2 allows identifying 3 subsets of HL patients with significantly different outcomes that may help clinicians to guide therapeutic strategy. [Display omitted] Solid line: patients with DSUVmaxPET0–2 >71 and MTV0 ≤225.Dashed line: patients with DSUVmaxPET0–2 <71 or MTV0 >225.Dotted line: patients with DSUVmaxPET0–2 <71 and MTV0 >225. Disclosures:No relevant conflicts of interest to declare.

Interim fluoro-2-deoxy-D-glucose–PET predicts response and progression-free survival in patients with Hodgkin lymphoma and HIV infection

Interim PET scans in HIV-negative patients with Hodgkin lymphoma has emerged as one of the most important prognostic tools. However, equivalent studies in HIV-positive patients are yet to be performed. We evaluated the prognostic value of interim [18F]-fluoro-2-deoxy-D-glucose-PET (18F-FDG PET) after two or three cycles of chemotherapy using adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) with concomitant HAART in HIV-positive patients with Hodgkin lymphoma. Patients with advanced HIV-Hodgkin lymphoma (HIV-HL) from six UK centres were included. Interim PET scans after two or three cycles of ABVD (PET-2 or PET-3) were carried out. Prognostic analysis correlated the 2-year progression-free survival (PFS) rate with the interim PET result. Twenty-three evaluable patients were assessed, 21 achieved a negative interim PET and 22 achieved complete remission by computerized tomography scan criteria after ABVD therapy. After a median follow-up of 27 months (range 12-50), disease progression was seen in one patient. Treatment failure was seen in one of the two interim PET-positive patients and none of the interim PET-negative patients. The 2-year PFS for interim PET-positive patients was 50%, and 100% for interim PET-negative patients (P = 0.0012). A negative interim 18F-FDG PET result is highly predictive of treatment success in HIV-HL patients.

A Prognostic Nomogram for Diffuse Large B Cell Lymphoma Incorporating the International Prognostic Index with Interim-PET Findings,

Abstract 3664 Background:Positron Emission Tomography scans performed during chemotherapy (Interim-PET) have been used prognostically in patients with Diffuse Large B-cell Lymphoma (DLBCL) and as a tool in response-adapted therapy trials. However, evidence on the predictive role of interim-PET in DLBCL has been limited by study heterogeneity in lymphoma subtypes and treatment regimens. Although earlier studies reported positive interim-PET predicted poorer outcome, a systematic review (Terasawa et al. J Clin Oncol 2009; 27(11):1906–14) could not draw reliable conclusions due to heterogeneity. Recent studies, which maintained a homogeneous patient group with regards to lymphoma subtype (DLBCL) and treatment (Rituximab-CHOP), showed conflicting results (Vitolo et al, Blood 2010; 116: Abs. 2819. Yang et al, Blood 2010; 116: 1799. Gonzalez-Barca et al Blood 2010; 116: Abs. 2793.) Aim:To evaluate the prognostic value of interim-PET in DLBCL patients receiving R-CHOP, without the confounding effect of therapy change based on interim-PET result. We seek to improve our prognostic ability by combining the International Prognostic Index (IPI) with Interim-PET results. Methods:We reviewed retrospectively consecutive DLBCL patients treated with R-CHOP as frontline therapy from 2005 to 2010 at a single institution. Interim-PET images were re-examined by a nuclear medicine physician blinded to the IPI and clinical outcomes. The PET results were classified as Negative or Positive, based on qualitative assessment of the relative intensity of FDG uptake of the area of disease compared to the adjacent mediastinal blood pool or aorta/IVC. Interim-PET was categorised as positive if the uptake was more than mildly above the blood pool intensity.One hundred patients commenced R-CHOP (14 or 21) therapy for DLBCL; 24 patients did not receive interim-PET for logistics reasons and were excluded. Progression free survival (PFS) and overall survival (OS) were analysed by the Cox proportional hazards model and prognostic accuracy was assessed using Harrell's C statistics. Results:In 76 patients analysed, the median age was 61 years (range 16–87); 59% were males. The IPI distribution was: IPI 0 (n=10), 1 (19), 2 (21), 3 (13), 4 (12), 5 (1). The median time of the interim-PET was after cycle 3.Eleven patients (14%) were positive and 65 patients (86%) were negative at Interim-PET. With a median follow-up of 32.5 months, 2-year OS and 2-year PFS (figures 1 and 2) were 70.8% and 60.0% respectively in the PET-negative group, 36.4% and 36.4% for the PET-positive group (log-rank p-value 0.003 for OS, 0.011 for PFS). [Display omitted] [Display omitted] Correlation analysis showed that the IPI and Interim-PET were minimally associated (rho=0.0873) and were both independent prognostic factors for survival. Cox regression analysis showed that interim PET and IPI were both significant indicators of PFS (p < 0.001 and p=0.002 respectively).The PET result makes a significant contribution to prognostication if IPI is greater than 2 (p<0.0001) and we found the contribution to vary by IPI when the score was greater than 2 (data not shown). In isolation, the prognostic accuracy of a negative PET result is poor (C = 0.63) as it is for IPI (C = 0.75), but when the two indicators are combined the predictive accuracy is improved (C = 0.81). A nomogram utilising the IPI and interim-PET results in the prediction of the 24 month relapse-free survival was created (Figure 3). [Display omitted] Conclusion:In our hands, IPI and PET provide independent prognostic information; we found interim PET to have a negative predictive value that varies according to the IPI at diagnosis. By combining the two, a more powerful predictive model may be created as a nomogram. This should be readily testable in larger patient populations where PET data is available, and then ideally prospectively in randomised clinical trials.Example of using the Sir Charles Gairdner Hospital Nomogram: a patient with an IPI of 2 will receive a score of 33; if their interim-PET result is positive, this will produce a score of 70, resulting in a total score of 103. On the lower 2 panels, a total of 103 points is estimated to give rise to a 40% probability of Relapse-free survival at 24 months. Disclosures:No relevant conflicts of interest to declare.

Prognostication and Risk-Adapted Therapy of Hodgkin's Lymphoma Using Positron Emission Tomography

The use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for response assessment in lymphoma is now widespread. Prognostic information obtained from PET performed after two to three cycles of chemotherapy may guide more individualized, risk-adapted therapeutic strategies. Progress in the risk stratification of Hodgkin's lymphoma through midtreatment PET is reviewed, with a focus on management implications in newly diagnosed and relapsed disease. How to tailor treatment on the basis of the interim PET result is not yet defined but is the subject of ongoing trials.

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.

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.

Interim and End-of-Treatment 18F-FDG-PET Evaluation of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 6 Cycles of Dose-Dense R-CHOP-14 Immunochemotherapy Plus Pegfilgrastim for First-Line Treatment: An Open-Label Clinical Trial in Spain.

Abstract 3692Poster Board III-628 BackgroundDLBCL is the most frequent aggressive non Hodgkin's lymphoma in adults. The International Prognostic Index (IPI) is currently the most used tool to identify different risk patients. The role of an interim PET to early identify patients with bad response to chemotherapy is controversial. However end of therapy PET correlates strongly with progression free survival. AimsThe aim of this analysis is to evaluate the results of an interim PET (after 2 chemotherapy cycles) and PET at the end of treatment (6 chemotherapy cycles of dose-dense R-CHOP) in patients with DLBCL. MethodsThis is a prospective clinical trial for patients with DLBCL older than 65 with IPI 0-5 or younger than 65 with IPI 0-2. Treatment consists of 6 cycles of R-CHOP administered every 14 days followed by pegfilgrastim (6 mg per cycle) on day 2. 63 patients, who completed all 6 cycles of chemotherapy and have had both PET evaluations after 2 cycles of R-CHOP and at the end of treatment, have been selected for this sub-analysis. All evaluations were made by combined PET/ CT, except for 14 patients who were evaluated by PET alone. PET was determined to be positive or negative based on the radiology reports. Interim PET results did not change the planned treatment. Results109 patients were analyzed for response. 17 patients (15.5%) did not finish 6 cycles of treatment: 2 due to serious adverse events, 3 due to progression disease / stabilization, 5 due to investigators decision and 7 due to death. Over 92 patients who completed 6 cycles of treatment, 63 patients who had both a PET evaluation after 2 cycles of treatment and at the end of treatment, were included in this analysis. Median age was 60 years old (range 18.2-78.9), 30 (47.6%) were older than 65, 32 (51%) were male. Fifty-four (85.7%) had ECOG 0-1. Characteristics of the disease at diagnosis were as follows: stage III-IV: 39 (61.9%), bulky disease: 15 (23.8%), > 2 extra-nodal sites involvement: 4 (6.4%), B symptoms: 15 (23.8%), elevated LDH: 31 (49.2%), elevated beta-2-microglobulin: 20/57 (35.1%), IPI 3-5: 19 (30.2%). Thirty-one (49.2%) patients achieved a negative PET evaluation after 2 R-CHOP cycles and 53 (84.1%) at the end of treatment. Twenty-nine (93.6%) patients with an interim negative PET remained negative at the end of therapy. Among the 32 patients with a positive PET after 2 cycles of therapy, 24 (75%) turned negative at the end of therapy. Patients with bulky disease had a positive interim PET more frequently (66.7% vs 45.8%), but most of them turned negative at the end of treatment (positive PET 6.7%). ConclusionsAn early positive PET is not predictive of a persistent positivity at the end of treatment. In fact, patients with bulky disease more frequently have an early positive PET, but most of them turn negative after 6 cycles of R-CHOP14. On the other hand, an early negative PET is highly predictive of a negative end-of-treatment PET. In conclusion, our data do not support an early intensification of patients with DLBCL with a positive interim PET, although a longer follow-up is necessary to confirm these results. Disclosures:No relevant conflicts of interest to declare.

Positron Emission Tomography Guided Therapy of Aggressive Non-Hodgkin's Lymphomas (PETAL trial): Correlation between Clinical Variables and PET Parameters.

Abstract 2695Poster Board II-671 Introduction:Positron emission tomography (PET) performed after a few cycles of chemotherapy (interim-PET) in aggressive lymphomas correlates with long-term outcome: While the majority of patients with a negative interim-PET scan enjoy long-lasting remissions, patients with persistent pathological glucose uptake almost invariably relapse. The multicenter PETAL trial was initiated in Germany in 2008 to resolve the question whether a change in treatment protocol may improve the outcome of patients with a positive interim-PET scan (ClinicalTrials.gov Identifier: NCT00554164). Patients and Methods:The PETAL trial is open for patients with newly diagnosed aggressive B cell or T cell non-Hodgkin's lymphomas between 18 and 80 years of age with a performance status of 0 to 3 according to the Eastern Cooperative Oncology Group scale and a positive PET scan before starting any lymphoma-directed therapy. Interim-PET is done after 2 cycles of the CHOP protocol (cyclophosphamide, doxorubicine, vincristine, prednisone; plus rituximab (R) in CD20-positive lymphomas) administered at a 14-day interval. Precautions were taken to minimize the risk of false-positive interim-PET results. First, the interval between the second (R-)CHOP cycle and the interim-PET scan is three weeks. Second, hematopoietic growth factors accelerating blood cell recovery are not allowed after the second cycle of chemotherapy. Third, quantitative standard uptake value (SUV)-based assessment rather than exclusive visual interpretation is used for interim-PET evaluation as described by Lin et al (J Nucl Med 48: 1626, 2007). Results:So far, a total of 266 patients have been recruited into the trial. A negative pre-treatment scan was observed in 18 patients, the majority of whom had complete lymphoma resection. 196 patients have reached interim-PET scanning, 168 with diffuse large B cell lymphoma (86%), 11 with grade 3a/b follicular lymphoma (6%), and 17 with peripheral T cell lymphoma (8%). Median SUVmax at staging did not differ across these three lymphoma subgroups. However, the SUVmax reduction at interim-PET was significantly lower in T-cell lymphomas as compared to B-cell lymphomas. Six patients (3%) with a low SUV at staging (<10) were rated as non-responders by quantitative, but as responders by visual assessment. Maximum SUV at staging and SUV reduction after two cycles of (R-)CHOP were independent of the International Prognostic Index (IPI). In contrast to lymphoma patients with baseline SUV values below 30, patients with higher SUV values almost invariably met the predefined criteria for therapy response (p = 0,033, Fisher's exact test). With a median follow up of less than six months, lymphoma relapses across all IPI risk groups have occurred more frequently in patients with a positive interim-PET scan than in patients with a negative scan. Neither absolute baseline SUVmax levels nor magnitude of SUVmax reduction at interim-PET were predictive of relapse. Conclusion:A combined strategy of SUV-based quantitative and visual qualitative interim-PET assessment is feasible in a multicenter randomized trial designed to guide treatment in lymphoma patients. In this largest series of interim-PET scanning in aggressive lymphoma reported so far, interim-PET response and the IPI risk score proved to be independent. With an as yet short follow-up period relapses were unevenly distributed between PET responders and non-responders. The PETAL trial will help define criteria for interim-PET scanning and response prediction. Recruitment into the trial continues. Disclosures:Hüttmann:Roche: Research Funding; Amgen: Research Funding. Duehrsen:Amgen: Research Funding; Roche: Research Funding.