ALBERT

Description: Standardized response criteria are essential for interpretation of clinical data, comparisons among clinical trials, development of new therapies, and approval of agents by regulatory agencies. In 1999, an International Working Group (IWG) developed recommendations for response assessment for non-Hodgkin’s lymphomas (NHL) that were adopted internationally by study groups and regulatory agencies and, subsequently, by clinical trials groups for Hodgkin lymphoma (HL) as well (Cheson et al, J Clin Oncol, 17:1244, 1999). Since their publication, several observations compelled a reassessment and, ultimately, revision of those guidelines, e.g., the availability of FDG-PET scans, new insights into lymphoma pathology and biology, the failure of the IWG guidelines to include HL and extranodal NHL, and features of the original guidelines that were found to be unclear as they were implemented into clinical trials. Most notable of these was the interpretation of the response category of Complete Remission unconfirmed (CRu). In the context of the IHP, a group of international lymphoma investigators with expertise in medical hematology/oncology, radiation oncology, nuclear medicine and imaging, pathology, biostatistics, and pediatrics were convened to revise the IWG guidelines. Committees focused on Response Criteria, Pathology/Biology, Endpoints, and Clinical Features, and discussions were initiated to undertake a major revision of the IWG guidelines. The important modifications that will be presented included, but were not limited to, integration of PET according to recent data (Juweid et al, J Clin Oncol, 23:4652, 2005), to facilitate the distinction between persistent tumor and scar/fibrosis, virtually eliminate the designation of CRu, and improve prediction of outcome. Guidelines were provided for the specific indications where this test can be currently recommended. Other proposals involved the role of flow cytometry and assessment of minimal residual disease. Response criteria for extranodal sites were also incorporated. Adoption of these revised guidelines by study groups will further improve the conduct and interpretation of clinical trials leading to more effective therapies for patients with lymphomas.

Description: Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET+ interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: κ statistic = 0.445 using ECOG criteria, and κ statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924.

Description: Abstract 5107 Purpose: TS is critical for the de novo synthesis of thymidine needed for tumor cell proliferation and DNA damage repair, whereas thymidine kinase 1 (TK1) is key to the salvage pathway providing thymidine recovered from plasma. While TK1 expression has been previously shown to correlate with proliferation in DLBCL, little is known about TS levels in these neoplasms. We hypothesized that, similarly to TK1, TS expression levels associate with increased proliferation and thus may represent a novel therapeutic target in large cell lymphoma. Methods: To address this hypothesis, we determined the expression of TS in lymph node biopsies from 43 DLBCL patients sequentially enrolled in the study with no pre-selection criteria other than the primary histological diagnosis of lymphoma, and then compared it to TK1 expression. In addition, Ki-67 (MIB1) was included as an established marker of cell proliferation. Pearson correlation along with the correlation coefficient and two-tailed P values were calculated to measure the extent of covariation. Results: TS expression and both MIB1 and TK1 were significantly correlated with correlation coefficients of 0.43 and 0.65, respectively (95% CI 0.13 to 0.65 and 0.44 to 0.8; P values = 0.006 and

Description: Background: Positive interim PET scans have been associated with inferior outcomes in DLBCL treated with chemotherapy, alone or with rituximab. In the ECOG 3404 study for bulky and advanced DLBCL, PET scans at baseline and after 3 R-CHOP are centrally reviewed by a single reader; those with positive scans cross-over to R-ICE after 4 R-CHOP, whereas those with negative scans continue on R-CHOP. The primary endpoint of E3404 is progression-free survival. To determine the reproducibility of interim PET scan interpretation, we convened an expert panel. Methods: Three external nuclear medicine physicians visually scored baseline and interim PET scans independently and blinded to other clinical information or outcome. ECOG study criteria were binary (0,1) based on residual disease in initially involved sites with uptake greater than the liver. London criteria were on a scale of 0–5, where 4–5 was positive, based on increased uptake relative to the liver. Overall scores and agreement among experts were evaluated for both criteria, with application of the kappa statistic to correct for chance. Results: Using the ECOG criteria, external reviewers were in complete agreement in 68% of 38 interim scans and completely agreed with the central review in the same 68% cases. Agreement among the experts was 71% employing the London criteria in these cases. The range of PET+ interim scans by reviewer was 16.8% to 34.2% (p=NS) by both ECOG and London criteria. The kappa statistic for overall pairwise correlation between readers was 0.445 (0.396–0.533) using ECOG and 0.502 (0.396–0.630) using London criteria – indicating moderate consistency. Areas of disagreement often, but not exclusively, related to bone disease, the shape and focality of residual uptake, splenic disease, and rare scans without CT-fusion. Conclusions: These data show that visual criteria, either ECOG or London in this series, for interim PET results are moderately reproducible among individual nuclear medicine experts. Our finding of variability among experts indicates the need for caution in interpreting interim PET results in studies and in practice. Review of all E3404 cases is planned after accrual is completed (projected 12/08). Other ongoing studies evaluating interim PET after 1–3 cycles of therapy, the application of quantitative criteria, and consensus panels may provide further valuable information.

Description: To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and gemcitabine 800 mg/m2 (1000 mg/m2 in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00086801.

Description: Abstract 3236 Poster Board III-173 We have observed that the uptake of the thymidine analog 18F-fluorothymidine (FLT) is highly disproportional to cellular proliferation in untreated low-grade follicular lymphoma (FL). Since the uptake of thymidine/thymidine analogs is also increased with enhanced DNA repair synthesis, we investigated whether the “excess” uptake of FLT in FL may be related to DNA repair. We stained tumor samples from 20 patients each with grade 1 FL and DLBCL for Ki-67, a marker of cell proliferation and DNA replication but not DNA repair and 2 DNA replication and repair biomarkers: proliferating cell nuclear antigen (PCNA) and replication protein A (RPA). Median %Ki-67-positive cells (Ki-67 index) was 10% (range; 5-20%) in FL compared to 80% (range 60-90%) in DLBCL (P 70% of FLT uptake in FLs with a Ki-67 index of ≤10% was due to DNA repair. In contrast, contribution of DNA repair to overall FLT uptake in DLBCL with a Ki-67 index of ≥ 80% was

Description: Background: CT imaging has routinely been used for assessing therapy response in most malignancies including Non-Hodgkins Lymphoma (NHL). The presence of residual tumor is generally categorized using the International Workshop Criteria from CT imaging and bone marrow biopsies for assessing response after treatment. CT imaging has limitations in assessment of response to therapy in NHL with false positive results due to residual masses having viable tumor cells in less than 20% and the remainder being fibrosis or necrosis. In addition false negative CT results are seen due to viable tumor cells in nodes measuring less than 1.5 cm in size. F-18 FDG PET scans provide metabolic imaging of viable tumor cells due to uptake and retention of F-18 fluorodeoxyglucose preferentially in malignant cells. Method: Forty-eight patients with aggressive NHL having completed anthracycline-based chemotherapy had the post therapy FDG PET scans and CT scans reviewed by experienced readers blinded from the comparison scan and from the clinical history. PET scans were read as positive or negative for abnormal FDG consistent with residual viable tumor and the CT was read as positive or negative for nodes greater than 1.5 cm in diameter. Records were reviewed for tumor histology and evidence of tumor relapse with a median follow-up of 35 months. Results: The FDG PET and CT imaging prediction of PFS at 2 years had positive predictive values of 67% and 38%, negative predictive values of 88% and 78%, and accuracy of 81% and 50% respectively. The sensitivity and specificity of the FDG PET scan was 71% and 82% for predicting disease progression within 2 years from beginning treatment. Conclusion: FDG PET imaging was compared with CT imaging done after completing initial chemotherapy for aggressive NHL and demonstrated superior prediction of tumor response status at 2 years. These results indicate that FDG PET imaging should be combined with bone marrow biopsy for restaging aggressive NHL after completion of chemotherapy. The use of FDG PET is more accurate and should replace response assessment by CT imaging in most pateints with aggressive NHL following treatment.

Description: Abstract 1556 Poster Board I-579 Background IHP-based interpretation of PET/CT post-tx of lymphoma is now widely used but there is little data regarding its reproducibility and accuracy. We determined interobserver variability using IHP criteria and compared its accuracy with semiquantitative approaches using the residual mass (RM) absolute standardized uptake value (SUVmax) alone and the ratio of the RM SUVmax to mediastinal blood pool (MBP) SUVmean. Methods Three expert nuclear medicine physicians blinded to patient (pt) outcome independently visually interpreted post-tx PET/CT scans based on the IHP-criteria. RMs were scored on a scale of 0-4, where 3-4 was positive for RMs ≥ 2 cm whereas 1-4 was positive for RMs 〈 2 cm; scans without RMs were similarly scored, depending on whether there were PET positive or negative. RM SUVmax, MBP SUVmean and the RM SUVmax to MBP SUVmean ratio were determined. Since outcome data were available on all 50 pts (median follow-up of pts without progression = 49 months), the positive predictive value (PPV), negative predictive value (NPV) and accuracy for prediction of residual disease/progression were compared between the IHP-criteria and the semiquantitative approaches. Results A total of 50 post-tx scans in 50 pts with aggressive NHL (n=24) and HL (n=26) were interpreted by the 3 readers. On a patient-by-patient basis, the 3 readers were in complete agreement with respect to final scan interpretation (i.e., pos/neg) 90% of the time using the IHP-criteria. Percentage of PET+ scans ranged from 20%-30% and PET+ RMs from 45%-55% for the 3 readers. On a per-patient basis, visual criteria resulted in PPVs of 47%-70%; NPVs of 86%-88% and accuracies of 74%-84% for the 3 readers. In contrast, cut-off RM SUVmax of 2.5 or cut-off RM SUVmax to MBP SUVmean ratio of 1.75 resulted in PPV, NPV and accuracy of 75%, 86% and 84% with areas under the receiver operating characteristic (ROC) curve of 0.765 and 0.787, respectively. Conclusions Visual IHP-criteria provide fairly reproducible interpretations among nuclear medicine experts with fair to moderate diagnostic/prognostic accuracy. Compared with the IHP criteria, the semiquantitative approaches provide, at least for some readers, substantial improvement in PPV and overall accuracy. These approaches should, therefore be considered for a more consistent scan interpretations after standardization of the timing of imaging after FDG injection. Disclosures No relevant conflicts of interest to declare.

Description: 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) is a noninvasive, 3-dimensional imaging modality that has become widely used in the management of patients with malignant lymphomas. This technology has been demonstrated to be more sensitive and specific than either 67gallium scintigraphy or computerized tomography, providing a more accurate distinction between scar or fibrosis and active tumor. PET scans have been evaluated in pretreatment staging, restaging, monitoring during therapy, posttherapy surveillance, assessment of transformation, and, more recently, as a surrogate marker in new drug development. Data to support these various roles require prospective validation. Moreover, caution must be exercised in the interpretation of PET scans because of technical limitations, variability of FDG avidity among the different lymphoma histologic subtypes, and in the large number of etiologies of false-negative and false-positive results. Recent attempts to standardize PET in clinical trials and incorporation of this technology into uniformly adopted response criteria will hopefully lead to improved outcome for patients with lymphoma.