Early PET Research Articles

Role of early PET in the management of diffuse large B-cell lymphoma

This article reviews the role of interim fluorine-18-fluorodeoxyglucose (FDG)-PET in the management of aggressive non-Hodgkin lymphoma. In the diagnosis of diffuse large B-cell lymphoma, FDG-PET has proved to be a highly sensitive imaging modality. The specificity of 18FDG-PET is improved with the addition of computed tomography (CT) and combined PET/CT is now considered a standard staging procedure for aggressive lymphoma. In addition, residual FDG positivity at the end of therapy is strongly predictive for inferior survival and has been incorporated into revised response criteria for aggressive lymphoma. With the established prognostic value of PET/CT both before and after therapy, interest has now turned to whether interim FDG-PET could be an early indicator of tumor sensitivity. Current clinical trials are now focused on clarifying the role of PET/CT in the early distinction between good and poor responders to standard immunochemotherapy. The interest in such early patient selection assumes that a rapid metabolic response to standard immunochemotherapy predicts a better therapeutic response and survival, and that nonresponders may benefit from an early change in therapy. Preliminary data suggested that interim PET could identify the early presence of such residual disease. However, recent publications are hindered by important variances in patient populations and treatment protocols, the timing and methodology of scans, the reporting criteria used to assess response, and the reproducibility of reporting in accordance with these criteria. Questions remain on the utility of FDG-PET in this indication.

SU‐GG‐J‐151: Intra‐Patient Response Heterogeneity Using FLT PET during Chemotherapy in Canine Subjects with Lymphoma

Purpose: PET is routinely used for treatment response assessment in lymphoma after the completion of therapy. However, characterization of lymph node response heterogeneity during therapy could result in treatment modification to improve outcome. We used PET during chemotherapy to assess intra‐patient response heterogeneity in canine subjects with lymphoma. Method and Materials: Nine dogs with lymphoma were treated with GS‐9219, a novel antineoplastic agent preferentially targeting proliferative lymphoid cells. Using the cellular proliferation marker [18F]FLT, whole‐body PET/CT scans were acquired pre‐treatment and after 1, 3, and 5 chemotherapy cycles. Lymph nodes (∼16/dog) were segmented on CT images and these contours were applied to PET images to extract mean and maximum SUV for each node. Lymph node response was defined as relative change in SUV. For each dog, nodal responses and baseline values were normalized to their respective means. Heterogeneity was measured using the coefficient of variation (CV) and range of nodal responses and baseline values. Results: Intra‐patient heterogeneity of lymph node baseline values and responses were substantial. Within each dog, the average variation of mean SUV baseline values (CV: 30%) was slightly less than that of response (CV: 40%). Similar heterogeneities were measured using maximum SUV. There was no significant correlation between heterogeneities of baseline uptake and response (p=0.3). Individual dogs responded differently to treatment as some responses were very heterogeneous (most heterogeneous, CV: 115%) while others were quite uniform (least heterogeneous, CV: 5%). Response heterogeneity increased throughout therapy with CV of 35% after 1 chemotherapy cycle, 55% after 3 cycles, and 60% after 5 cycles. Heterogeneity trends measured using CV and ranges were consistent. Conclusions: During chemotherapy, there was substantial intra‐patient response heterogeneity (∼40%) in dogs with lymphoma. Early PET assessment of nodal response heterogeneity may identify poorly responding lymph nodes, permit early intervention, and improve outcomes in lymphoma patients.

Early PET analysis to identify responders to erlotinib treatment of advanced NSCLC.

e18092 Background: EGFR mutations predict response to erlotinib treatment in advanced NSCLC. However, identification of EGFR mutations is not always possible due to lack of adequate tissue. We therefore investigated whether early PET might be a suitable tool to identify EGFR mutation positive responders. Methods: Six patients with NSCLC stage IIIB/IV showing partial remission according to RECIST criteria to first-line erlotinib treatment were analyzed and compared to 31 patients without response to first-line treatment with erlotinib. All patients were examined by [18F] FLT-PET and [18F] FDG-PET at baseline and after 1 week of treatment with erlotinib. The change in the sum of the maximum standard uptake value (sSUVmax) was calculated. Mutational status in each patient was analyzed by conventional Sanger sequencing. In case of negative results parallel sequencing using 454 technology was performed (EudraCT number 2005-005393-73; NCT00568841). Results: The median PFS for the 6 responding patients was 412 days. The mean reduction in the sSUV max was 37% (16-61) for [18F] FDG and 33% (0-55) for [18F] FLT after 1 week of treatment. Sanger sequencing of tissue available for molecular analyses revealed a sensitizing EGFR mutation in 3 of these 6 patients. Using the highly sensitve 454 technology an EGFR mutation could be demonstrated in 1 further patient. In the remaining two patients there was no diagnostic material allowing further molecular analyses. By comparison, the mean change in sSUVmax in patients not responding to erlotinib (n=31) was + 3% for [18F] FLT and -3% for [18F] FDG (p<0.005, T test). In the ROC analysis the AUC was calculated with 0.88 (0.73-1.00, p=0.004) for detection of response. Conclusions: Early [18F] FLT-PET and [18F] FDG-PET might be a suitable tool to detect patients with sensitizing EGFR mutations when treated with erlotinib. This might circumvent EGFR mutational analyses in patients with insufficient diagnostic material and enable early prediction of clinical response. Pat ID Histology Sanger 454 Change in sSUVmax LT-PET Change in sSUVmax FDPET 01-08 Adeno 0 del exon 19 -30 -44 01-18 Adeno del exon 19 N/A -44 -16 01-27 Adeno 0 N/A -55 -61 01-31 Adeno 0 N/A -39 -45 01-28 Adeno del exon 19 N/A 0 -38 01-25 Adeno L858R N/A -30 -22 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche

Correlation of FDG-PET results after one cycle and after two cycles of chemotherapy in Hodgkin lymphoma.

8061 Background: FDG-PET after two cycles of chemotherapy is highly predictive of treatment response and progression-free survival in Hodgkin lymphoma (HL). Early interim PET after two therapy cycles is used to direct early PET-response adapted therapy in numerous clinical trials. However, due to the risk of early chemoresistance, a treatment escalation should be considered as early as possible to non-responding patients. The purpose of this trial is to study the correlation of PET results after one cycle and after two cycles of chemotherapy, and to investigate if the high predictive value of PET after two cycles is obtainable already after one cycle of chemotherapy. Methods: Two institutions take part in this trial. In Copenhagen, all enrolled HL patients had PET scans at baseline, after one cycle and after two cycles of chemotherapy (29 patients). In New York, all patients are scanned at baseline and after one cycle of chemotherapy, while only patients who are PET-positive after one cycle have a repeat PET after two cycles (7 patients). 34 patients were treated with ABVD and two patients with BEACOPPesc. Results: From a total of 36 patients, 22 were PET-negative after both one and two cycles. 11 patients were PET-positive after both one and two cycles. Three patients were PET-positive after one cycle and became PET-negative after two cycles. No PET-negative patient after one cycle turned PET-positive after the second cycle of therapy. The median follow-up time is short and does not yet allow for a survival analysis. Conclusions: There is a very high correlation between the results of FDG-PET after one cycle and after two cycles of chemotherapy for HL. These results show that the negative predictive value of PET is at least as high after one cycle as after two cycles of chemotherapy. A few patients who still have pathological FDG uptake after one cycle turn PET-negative after two cycles. A higher risk of false positive results after one cycle than after two cycles or alternatively a better positive predictive value after one cycle is yet to be determined with longer follow-up data. Patients with unsatisfactory PET-response to ABVD could benefit from having an escalation of therapy already after the first cycle of chemotherapy. No significant financial relationships to disclose.

PET/CT with 18F-FLT: Does It Improve the Therapeutic Management of Metastatic Germ Cell Tumors?

Because (18)F-FDG PET alone has only limited value in metastatic germ cell tumors (GCTs), we investigated the addition of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to (18)F-FDG for early response monitoring and prediction of the histology of residual tumor masses in patients with metastatic GCT. Eleven patients with metastatic GCT were examined with both (18)F-FDG PET/CT and (18)F-FLT PET/CT before chemotherapy, after the first cycle of chemotherapy (early response), and 3 wk after completion of chemotherapy. In 1 patient with negative (18)F-FLT PET/CT results before chemotherapy, no further (18)F-FLT scanning was performed. PET images were analyzed visually and, using standardized uptake values (SUVs), semiquantitatively. The results were compared with the findings of CT and tumor marker levels and validated by histopathologic examination of resected residual masses, including Ki-67 immunostaining (7 patients), or by clinicoradiologic follow-up for at least 6 mo (4 patients). A responder was defined as a patient showing the presence of necrosis, a complete remission, or a marker-negative partial remission within a minimum progression-free interval of 6 mo. Early treatment response was judged according to the criteria of the European Organization for Research and Treatment of Cancer. Before chemotherapy, reference lesions showed increased (18)F-FDG uptake (mean SUV, 8.8; range, 2.9-15.0) in all patients and moderate (18)F-FLT uptake (mean SUV, 3.7; range, 1.7-9.7) in 10 of 11 patients. After 1 cycle of chemotherapy, mean SUV decreased in responders and nonresponders by 64% and 60%, respectively, for (18)F-FDG (P = 0.8) and by 58% and 48%, respectively, for (18)F-FLT (P = 0.5). After the end of chemotherapy, mean SUV decreased in responders and nonresponders by 85% and 73%, respectively, for (18)F-FDG (P = 0.1) and by 68% and 65%, respectively, for (18)F-FLT (P = 0.8). The results of early and final PET were inconsistent in 6 of 11 patients for (18)F-FDG and in 4 of 10 patients for (18)F-FLT. Both patients with teratoma had false-negative results on both (18)F-FDG and (18)F-FLT. The sensitivity, specificity, positive predictive value, and negative predictive value for detection of viable tumor after 1 cycle of chemotherapy were 60%, 33%, 43%, and 50%, respectively, for (18)F-FDG and 60%, 80%, 75%, and 67%, respectively, for (18)F-FLT PET/CT. The respective values after the end of chemotherapy were 20%, 100%, 100%, and 60% for (18)F-FDG and 0%, 100%, 0%, and 50% for (18)F-FLT PET/CT. PET-negative residual masses after chemotherapy of metastatic GCT still require resection, since the low negative predictive value of (18)F-FDG PET for viable tumor cannot be improved by application of (18)F-FLT.

Total Choline at 1H-MRS and [18F]-Fluoromethylcholine Uptake at PET

The use of in vivo imaging techniques for assessing choline metabolism to detect cancer is supported by studies showing increased choline kinase and transporter gene expression, transmembrane choline transport, and tissue choline metabolite concentration in a number of malignancies [1, 2]. Early clinical studies employing techniques for in vivo imaging of choline metabolism looked promising, with early PET studies demonstrating increased choline tracer uptake in a variety of tumors, and independently, studies employing proton magnetic resonance spectroscopy (1H-MRS) demonstrating increased tissue levels of choline metabolites in several malignancies [2–5]. However, the use of these two very different in vivo methods to study choline metabolism have raised questions as to how their measurements interrelate; and there have been instances where choline tracer uptake on PET fails to correlate well with the tissue measurements of choline provided by 1H-MRS [6]. To address these questions, Rommel et al., in their study titled “Rodent Rhabdomyosarcoma: Comparison Between Total Choline Concentration at 1H-MRS and [F]-fluoromethylcholine (FCH) Uptake at PET Using Accurate Methods for Collecting Data”, employed methods for achieving highly accurate spatial correspondence between small-animal PET and MRI to study the relationship between FCH uptake and spectroscopic measurement of tissue choline metabolites in a rhabdomyosarcoma animal model. Their study did not confirm a quantitative relationship between tumor FCH uptake and measures of choline concentration obtained with 1H-MRS in their experimental model. The authors offered several biological hypotheses to explain the lack of correlation between FCH uptake and choline metabolite concentration: one involving the presence of a negative feed-back mechanism of elevated levels of intracellular choline compounds on FCH uptake; another involving the rapid transport and incorporation of choline into membrane phosphatidylcholine (which is not detectable by 1H-MRS) to explain increases in FCH uptake without corresponding increases in total choline metabolite concentration on 1H-MRS. In addition to these biological hypotheses, the limited ability of in vivo 1H-MRS to discriminate specific choline metabolites may also be worth considering as a potential explanation for their observations. Specifically, the “choline peak” at 3.2 ppm that is often used for in vivo 1H-MRS studies is known to actually reflect a number of important choline metabolites [7]. Ex vivo and in vitro NMR can readily differentiate several of these metabolites bearing the choline moiety. They include free choline, phosphocholine (PC; at 3.23 ppm), and glycerophosphocholine (GPC; at 3.24 ppm) [8, 9]. However, due to their spectral proximity it has proven difficult to resolve these compounds in vivo [2]. PC is a predominant biosynthetic product whose concentrations in malignancy can increase as a result of choline kinase upregulation [1]. GPC, on the other hand, is primarily a product of phospholipase activation [10, 11]. In the study by Rommel et al., the inability to separate the spectral contributions of these biochemically distinct compounds should raise the question of whether FCH uptake is actually being compared to the net result of several anabolic and catabolic processes in the CDP-choline pathway. Such a situation could potentially explain the lack of correlation observed between total choline concentration and FCH uptake. Work by DeGrado et al. has suggested FCH to be a marker of biosynthetic PC metabolism with specificity for the transmembrane choline transporter and choline kinase [12, 13]. Consequently, the tissue concentration of PC, rather than total choline, may correlate best with FCH uptake. The relationship between PC and GPC metabolism under some tumor conditions has been studied. For example, activation of phospholipase can decrease PC and increase GPC levels in breast and prostate cancer cells, potentially leading to a less aggressive phenotype [11, 14]. Exposure to chemotherapeutic agents can also decrease tissue levels of PC while increasing the levels of GPC [15, 16]. These results suggest the possibility of assessing tumor therapeutic response through specific measurement of PC or GPC metabolism.We look forward to future studies comparing FCH PET to other methods for measuring PC metabolism in vivo.

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Early sequential PET scanning and use of modified RECIST criteria in the evaluation of malignant pleural mesothelioma (MPM)

Early sequential PET scanning and use of modified RECIST criteria in the evaluation of malignant pleural mesothelioma (MPM)

Predictive role of Early Interim FDG-PET in Hodgkin Lymphoma.

Abstract 1659Poster Board I-685 BackgroundHodgkin lymphoma (HL) is a curable malignancy with a long-term survival of around 80%. FDG-PET is a noninvasive imaging modality widely used in lymphoma patients. Early PET assessment of response to therapy is a routine part of management in HL patients, and an independent, strong predictor of progression-free survival. Patients and Methods178 patients, with a diagnosis of HL, underwent to an early PET evaluation during their course of chemotherapy and were considered eligible for the study. 85 patients (48%) were male and 93 (52%) female; the median age at diagnosis was 33 (13-78) years. 6 patients (3%) had stage I disease; 106 patients (60%) stage II; 34 (19%) stage III and 32 (18%) stage IV (bone marrow involvement in 5 cases).B-symptoms were detected in 81 patients (46%). A mediastinal bulk was detected in 54 cases (30%). The majority of patients (173, 97%) underwent to ABVD as first line therapy; 5 received BEACOPP chemotherapy (3%). Early PET evaluation was performed after the second course of therapy. Results were classified into complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) according to International Workshop standardized response criteria. PET scan was performed again at the end of the first-line treatment. 44 patients have been addressed to a second-line therapy, in presence of PR, PD or relapsing disease; in particular, 39 patients received an autologous stem-cells transplantation (ASCT), and 3 an allogeneic bone marrow transplantation (ABMT). ResultsAt a median follow up of 41,85 (5,23-141,77) months, 152 patients are alive and in CR; 7 in PR; 3 alive with SD and 7 present a PD. 9 patients have died. 150 patients presented with a negative PET after 2 cycles, and 28 with a positive one (26 in PR, 1 with SD and 1 with PD). More specifically, of the 178 initial patients, 150 (84%) had a negative early PET and 28 (16%) a positive early PET. Of those with a negative PET, 135 (90%) experienced a continuous CR, while among those with a positive early PET, none obtained at least a stable CR. Of this unfavourable group of patients, 9 (32%) reached, and still maintain, a CR after ASCT. ConclusionsOur experience indeed confirms the highly predictive value of a negative early PET during the therapy for HL. Moreover we may suggest the potential role of ASCT in inducing a CR in around one-third of those unfavorable patients with a positive early interim PET. DisclosuresNo relevant conflicts of interest to declare.

Early 18fluorodeoxyglucose PET Scan as a Prognostic Tool in Diffuse Large B-Cell Lymphoma Patients Treated with An Anthracycline-Based Chemotherapy Plus Rituximab.

Abstract 98 Background:18Fluorodeoxyglucose PET has been quickly integrated to the diagnostic and therapeutic armamentarium in diffuse large-B cell lymphoma (DLBCL). Moreover, early PET appears a promising prognostic tool for tailoring treatment strategies. We evaluated the predictive value of early PET in a large prospective cohort of patients treated with immunochemotherapy. Patients and methods:112 previously untreated patients from three institutions were treated between January 2000 and October 2008 for DLBCL using an anthracycline-based regimen plus Rituximab. Chemotherapy was either an R-CHOP21 regimen (n=57) or a dose-dense regimen (R-ACVBP, n=31 or R-CHOP14, n= 24). PET was performed at diagnosis and after two cycles of treatment. Early PET results were interpreted visually as positive (PET2p) or negative (PET2n), as previously described1, but did not modify the scheduled therapy. Results:Median age at diagnosis was 59 years (range 20–79 years) and 67% of patients were males, 44% were over 60 years, 81% presented with an advanced Ann Arbor stage (III–IV), 29% had a poor performance status (ECOG 2-4), 36% had more than one extra-nodal site involved and LDH were elevated in 68%. The repartition on the basis of the International Prognosis Index was the following: low=5%, low-intermediate =35%, intermediate-high=37% and high risk=23%. After two cycles, 70 patients (63%) were PET2n and 42 (38%) were PET2p (38 patients in partial response and 4 with stable disease). Median follow-up was 38 months for living patients. Ten of 70 (14%) PET2n patients showed progression versus 22 of 42 (52%) PET2p patients. The estimated 5-year progression free survival (PFS) was 81% for PET2n and 47% for PET2p patients (log rank test, p<0.0001). Prognostic value of early PET was significant in terms of PFS whether patients were treated with R-CHOP21 (p=0.0006) or with dose-dense regimens (p=0.0056). Nine of 70 (13%) PET2n and 15 of 42 (36%) PET2p patients died. The estimated 5-year overall survival (OS) was 88% for PET2n and 62% for PET2p patients (log rank test, p<0.0034). Prognostic value of early PET was significant in terms of OS for patients treated with R-CHOP21 (p=0. 0225) but not for those treated with dose-dense regimens (p=0.133). Conclusion:Early PET after 2 cycles of treatment is a powerful tool to predict outcome in DLBCL patients treated with Rituximab combined with an anthracycline-based chemotherapy. It brings promising opportunities in the designing of new treatment strategies for DLBCL.Reference : 1 Haioun et al. Blood 2005; 106(4):1376–81. Disclosures:No relevant conflicts of interest to declare.

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.

The International Prognostic Factor Project Score (IPS) in Advanced Stage Hodgkin Lymphoma Has Limited Utility in Patients Treated in the Modern Era.

Abstract 1554Poster Board I-577 IntroductionThe International Prognostic Factor Project Score (IPS) is the most widely utilized risk stratification index for Hodgkin lymphoma (HL) (Hasenclever, N Engl J Med, 1998). Based on patients treated before 1992, it incorporates 7 adverse risk features (male gender, age ≥45 y, stage IV, hemoglobin <105 g/L, WBC ≥15 × 109/L, lymphocyte count <0.6 × 109/L or <8% of differential, albumin <40 g/L) and predicts for a 5-year freedom-from progression (FFP) ranging from 42-84%.The IPS has not been validated in a more recently treated population, where more accurate pathologic diagnosis, routine use of growth factors and enhanced supportive care may have improved outcomes compared with historic results. MethodsThis retrospective population-based analysis used the British Columbia Cancer Agency Lymphoid Cancer Database to identify all patients ages 15-65 y diagnosed from January 1st,1990 to June 30th, 2008 with advanced stage HL (stage III/IV, or stage I/II with B symptoms or bulky disease ≥10 cm), who were treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or an ABVD-equivalent regimen and had complete information including all IPS variables. Primary endpoint was FFP, defined as the interval from diagnosis to first progression or relapse or death due to treatment toxicity; deaths from unrelated causes were censored. Results579 patients were identified. Median age was 29 y (range 15-65); 11 (2%) stage I, 239 (41%) stage II, 202 (35%) stage III and 127 (22%) stage IV; 245 (42.3%) had bulky disease; and 359 (62%) had B symptoms. Histologies included: 455 (79%) nodular sclerosing, 35 (6%) mixed cellularity, 7 (1%) lymphocyte-rich, 11 (2%) lymphocyte depleted, 13 (2%) nodular lymphocyte predominant, 58 (10%) HL NOS. 161 (28%) patients received IFRT with primary treatment. Adverse prognostic factors were present as follows: 119 (21%) age≥45, 375 (65%) albumin <40 g/L, 88 (15%) WBC ≥15 × 109/L, 116 (20%) hemoglobin <105 g/L, 57 (10%) lymphocyte count <0.6 × 109/L or <8%, 302 (52%) male, 127(22%) stage IV. Only 37 (6.4%) patients had a prognostic score ≥5. With a median follow-up of 73 months (range, 1-222), 512 (88.4%) patients were alive and 67 (11.6%) had died (39 with HL, 7 due to toxicity and 21 from unrelated causes). Five year FFP and overall survival (OS) were 79% and 91%, respectively. The IPS was prognostic for both FFP (p=.0035) and OS (p<.0001), with 5-y FFP ranging from 66% to 86% and 5-y OS ranging from 74% to 98% (Table 1). In univariate analysis only stage IV (p=.003) and hemoglobin (P=.001) were prognostic for FFP. Albumin (p=.054), age (p=.082) and WBC (p=.094) were borderline significant, but gender (p=.329) and lymphocyte count (P=.496) appeared to have a weaker prognostic value for FFP. Only stage IV (HR=1.63, CI 1.10-2.40, p=.014) and hemoglobin (HR=1.73, CI 1.17-2.57, p=.006) were prognostic for FFP in a multivariate Cox regression. ConclusionThe IPS remains prognostic for patients with advanced stage HL treated in a more modern era. However, it does not identify risk groups with sufficiently good or poor outcome to justify deviation from standard therapy. Identification of truly low or high risk populations will require supplementation with molecular markers and/or the use of early PET scanning. Caution should be used when comparing results from current clinical trials to historic controls, since more recent outcomes with standard therapy are clearly superior to those previously reported. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PET Scan Results of NCCTG N0489: Epratuzumab and Rituximab in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone Chemotherapy (ER-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma.

Abstract 137 Background:FDG-PET/CT after 2–4 cycles of chemotherapy has been shown to be predictive of outcome in patients with aggressive lymphoma. This multicenter NCCTG phase II study was carried out to assess efficacy of ER-CHOP in newly diagnosed DLBCL; functional response as measured by FDG-PET/CT was done after 2 cycles and after 6 cycles of therapy. Methods:Patients received immunochemotherapy on the following schedule: epratuzumab 360 mg/m2, rituximab 375 mg/m2, and standard dose CHOP every 3 weeks for 6 cycles. FDG-PET/CT was done after 2 cycles and again after 6 cycles of therapy. All PET scans were centrally reviewed by an expert in nuclear medicine who was blinded to the outcome of the patients. Results:107 patients were accrued from Feb 2006 to Aug 2007. 27 patients were ineligible resulting in 80 eligible patients. Baseline patient characteristics for the eligible patients included median age 60 (range 21–82); 56% were male. 80% had advanced stage; 73% had an elevated LDH. Performance score was 0–1 in 71 pts and 2–3 in 9 pts. IPI was 0–1 in 18 pts (23%), 2 in 22 pts (28%), 3 in 29 pts (36%) and 4–5 in 11 pts (14%). PET scans were available on 76 patients (95%); 3 patients completed treatment but scans were unavailable and 1 died prior to cycle 2 PET. The PET CR rate after 2 cycles was 79%. The PET CR rate after 6 cycles was 90%. Using an intent to treat (ITT) analysis, 67 patients (87%) achieved PET CR of which 61 (79%) also completed all 6 cycles of treatment. Based on interim PET after 2 cycles, the EFS at 24 months (EFS24) was 73% for the PET negative patients vs 60% for the PET positive patients (p=0.25); OS at 24 months (OS24) was 83% vs 73% for the PET negative and positive pts, respectively (p=0.17). In comparison, EFS24 for patients with a negative PET after 6 cycles was 80% vs 57% for those with a positive PET (p=0.11); OS24 was 92% vs 57%, respectively (p=0.01). In intent to treat (ITT) analysis, patients that achieved a functional CR had improved overall survival (OS24 = 84%) and event free survival (EFS24 = 74%) compared to patients that failed to achieve a functional CR (OS24 = 50%, EFS24 = 40%, p=0.01 and p=0.006 respectively). Conclusions:ER-CHOP every 21 days × 6 cycles results in a functional CR rate of 87%. Early PET scan during therapy does not significantly predict outcome. Achievement of PET negativity by completion of therapy is associated with a good outcomePredictive ability of PET scan results from Cycle 2 and Cycle 6 of ER-CHOP in relation to 24-months EFS and OSEvaluation time-point according to ER-CHOP cyclesCR rate [1]PET scan result24 mos. EFS24 mos. OSCycle 278% (54/69)NEG73%83%POS60%73%Cycle 690% (61/68)NEG80%92%**POS57%57%Overall (ITT)87% (67/77)NEG74%*84%**POS40%50%[1]A PET-negative patient is considered a CR.*Statistically significant difference between PET-negative and PET-positive patients (P=0.006).**Statistically significant difference between PET-negative and PET-positive patients (P=0.01). [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The 18F-FDG SUVmax Reduction After Two Cycles of R-CHOP Regimen Predicts Progression Free Survival of Patients with Diffuse Large B-Cell Lymphoma.

Abstract 2931Poster Board II-907 Introduction:PET assessment of early response allows to predict outcome of patients with DLBCL, but the more accurate criteria for early PET interpretation remain to be define. So we evaluated the prognostic value of PET after two cycles of immuno-chemotherapy and compared a semiquantitative approach using FDG uptake reduction, with two methods of visual analysis. Patients and methods:Forty five consecutive patients with newly diagnosed DLBCL treated in a single institution with rituximab and CHOP or CHOP-like regimen underwent 18F-FDG PET at baseline (PET0) and after 2 cycles of induction treatment (PET2). Images were interpreted visually according to two separate methods: - Juweid criteria (JCO 2007; 25: 571) (visual analysis-1) – A visual comparison of the FDG uptake between the residual mass and the normal hepatic tissue, a PET being considered as positive when the uptake of at least one residual mass was found greater than the liver (visual analysis-2). The quantitative approach was based on the lymphoma FDG uptake estimated by the maximal standardized uptake value (SUVmax) corrected to body weight. The SUV reduction between PET0 and PET2 (ΔSUVmax) was calculated for each patient. The ΔSUVmax cut-off was estimated to 65% by ROC analysis. Results:Patient median age was 50 years (range, 24 – 79) and 37 patients (73%) were younger than 61 years. The age-adjusted IPI score was, 2 or 3, 1 and 0 in 26 (49%), 16 (36%) and 7 (16%) patients respectively. With a median follow-up of 25 months, 6 (13%) out of 45 patients progressed or relapsed after treatment and 4 died from progressive disease. According to the visual analysis-1, PET2 was interpreted as negative in 16 (36%) patients and positive in the 29 remaining patients. Using the visual analysis-2, PET2 was negative in 25 cases (56%) and positive in 20 cases. The quantitative analysis showed a ΔSUVmax < 65% in 9 patients and a ΔSUVmax >= 65% in 36 patients (80%). The estimated efficiency of the three methods to predict patient outcome is detailed below:Visual analysis-1Visual analysis-2ΔSUVmaxpSensitivity83%83%67%NSSpecificity38%*62% ¤87%* ¤* 0.0001 ¤0.05Negative predictive value94%96%94%NSPositive predictive value17%25%44%NSAccuracy44%*64% ¤84% * ¤* 0.0002 ¤0.05The probability of 2-years progression-free survival (PFS) for patients with a negative PET2 according to the visual analysis was slightly higher than those with a positive PET2 when using as well the Juweid criteria (93% vs 83%; p = 0.3), as the visual analysis-2 (95% vs 75%: p = 0.04).However, the quantitative aproach allows to better identify and split up the population of patients with a good outcome from those with a poor outcome, since the 2-years PFS was 56% in patients with a ΔSUVmax reduction less than 65% compared to a 94% 2-years PFS probability in patients with a ΔSUVmax higher than 65% (p=0.0009). A multivariate analysis was performed including the IPI score and the ΔSUVmax reduction as explanatory variables for PFS, showing that the PET2 result assessed by the ΔSUVmax reduction remains the only independant prognosis factor for PFS (p = 0.008; RR = 10). Conclusion:SUV-based assessment of PET after two courses of immuno-chemotherapy is more reliable to patient outcome than visual analysis. The SUVmax reduction is an early prognostic factor for DLBCL patients that may help to reduce false positive interpretations, and provides a useful tool to guide risk-adapted treatment. Disclosures:No relevant conflicts of interest to declare.

Pet dander and perennial allergic rhinitis: Therapeutic options

Pet allergy may now be the most common perennial allergen in the United States based on recent skin-prick testing data. This trend corresponds with the rise (from 56 to 63%) in U.S. households having indoor pets over the past 10 years. Furthermore small, suspended, particulate animal allergens may be found in 90% of all homes and most public indoor areas. Although the most important cat and dog allergens are Fel d 1 and Can f 1, respectively, there are five well-described allergens for both cats and dogs. The effects of early life domestic pet and endotoxin exposure and subsequent clinical sensitivity remain controversial. Given that only the rare pet-allergic patient is willing to give away his/her pet, it is important to take an evidence-based approach to environmental control. Unfortunately, the benefits from changes in the environment that have been shown in research studies relate more to a reduction of allergens than symptoms. The pharmacotherapy for pet allergy will vary based on whether this is episodic or perennial allergic rhinitis (PAR) and on the severity of the symptoms. A stepwise approach for management, using both mono- and combination therapy, is proposed. Allergen immunotherapy, the only disease-modifying treatment available, may be the best therapeutic recommendation for patients with moderate to severe pet-induced PAR.

OP14.03: Longitudinal study of maternal insulin-like growth factor-I and uterine artery Doppler

Objective: To evaluate the performance of screening for preeclampsia (PET) in women who had both first and second trimester uterine artery (UtA) Doppler. Methods: This longitudinal study involved 3090 asymptomatic pregnant women who had UtA pulsatility index (PI) routinely at 11–14 and 20–25 weeks gestation. Demographic characteristics was also recorded contemporary. Multiple regression analysis was used to evaluate which of the maternal variables and Doppler findings were significant predictors of early-onset PET. Receiveroperating characteristics curves were used to evaluate the value as screening of different combined predictive models. Results: There were 93 (3.0%) women who later developed PET, including 30 women who delivered before 34 weeks gestation (early PET). Early and late PET differed substantially in their UtA PI findings during the first and second trimester of pregnancy. Multiple regression analysis showed that increased body mass index, previous PET, UtA PI at 11–14 and 20–25 weeks gestation, and the change in UtA resistance between the first and second trimester were significantly associated with the appearance of early PET. The detection rate of early PET for a 10% false positive rate in screening by maternal characteristics and first trimester UtA PI only and by a combination with a ratio between both UtA Dopplers was 50% and 82%, respectively. However, second trimester UtA PI alone was able to detect about 90% of women who subsequently developed early cases. Conclusion: This study has confirmed that the severe the PET the lower the magnitude of change in uterine artery dilatation between the first and second trimester of pregnancy. In addition, although the best methods to predict early PET is still the second trimester uterine artery Doppler, a combination between maternal findings, UtA Doppler at 11–14 weeks gestation and the ratio of changes between both trimesters should be also a good screening test for early PET. Supported by Fondecyt No 1090245

Impact of PET on the Radiation Treatment of Hodgkins Lymphoma

Hodgkins lymphoma (HL) is a lymphoproliferative malignancy that frequently affects young people. Because patients with HL are often cured, this neoplasm serves as a clinical laboratory for investigating the late effects of cancer therapy. The “hot” issues today are, in advanced stages, how to identify the best strategy to reduce the rate of resistant diseases and, in the early stages, how to minimize late toxicity due to both chemotherapy and radiotherapy (RT). Literature data revealed that PET as a very promising tool in the management of HL. The main applications of FDG-PET in HL are in staging, therapy monitoring, response assessing and follow-up. Recent data show that early PET seems to play a role in predicting the treatment outcome. In RT FDG-PET improves the accuracy in the disease localization and staging with changes in radiation treatment planning in one third of patients with early-stage HL. It also reduces the subjectivity in lymphoma RT field determination, one of the major causes of uncertainty in radiation treatments. The impact of FDGPET will be greater as more conformal RT is planned. In conclusion, the highly curable early stage Hodgkin lymphomas require careful evaluation and balance of the available treatments, in order to achieve a really individualized solution, reducing radiation doses and/or fields dimension and using new advanced techniques.

Early Changes in 2-Deoxy-2-[18F]Fluoro-d-Glucose Metabolism in Squamous-Cell Carcinoma During Chemotherapy in Vivo and In Vitro

The aim of this study was to investigate early changes in uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) in vivo and in vitro in a squamous-cell carcinoma (SCC) cell line originating from a human head and neck SCC during cytotoxic therapy with respect to metabolism in tumor cells and in surrounding stromal tissue. In 60 nude mice with xenografted SCC, 50 animals were treated with cisplatin. Early changes in the tumor FDG uptake following therapy were evaluated sequentially with phosphor imaging. Using this technique, areas with focal hypermetabolism were detected. The cells creating the focal hypermetabolism were then identified histopathologically on the corresponding sections. In addition, early FDG uptake versus the number of viable tumor cells was measured in vitro following cisplatin treatment. An early transient increase in FDG uptake in tumor cells was seen on day 1 in treated tumors, followed by a rapid decrease confirmed by subsequent tumor regression. This metabolic flare was present in all treated tumors but not in the controls. In vitro, an increase in FDG uptake per cell was observed. Our results provide new insights into the early metabolic changes in squamous-cell carcinomas subjected to cytotoxic therapy and thus contribute to the discussion on the feasibility of early predictive PET studies.

Evaluation of early sequential 18F-FDG PET imaging as a prognostic indicator and predictor of response to platinum and pemetrexed chemotherapy in malignant pleural mesothelioma (MPM)

e14534 Background: Recent evidence has suggested that baseline SUV and metabolic response measured on sequential PET scans early in the course of chemotherapy may predict for survival and response to chemotherapy. Methods: Patients with MPM suitable for platinum/pemetrexed chemotherapy were studied. Baseline pre-chemotherapy PET and CT scans were performed with a further PET scan before cycle 2. CT scans were repeated mid-treatment and at the end of 6 cycles. PET response was determined by measuring the change in the maximum and mean SUV, PET Vol (volume of tumor above SUV threshold of 3.5) and Total Lesion Glycolysis (TLG, calculated as PET Vol x SUV Max). Metabolic response (MR), as measured by a 25% drop in SUV Max, SUV Mean, PET Vol and TLG was compared to overall survival (OS) and to subsequent response to chemotherapy on CT. CT scans were read using Modified RECIST criteria and CT response was compared to OS. Results: 21 patients had baseline PET scans of whom 17 had a further PET before cycle 2. 19 patients had CT scans evaluable by Modified RECIST criteria. Baseline SUV Max and SUV Mean were found to predict for OS. Median survival was 17.2 months for patients with SUV Max less than 15 versus 6 months for those with SUV Max greater than 15 (p=0.0193). Median survival was 14.1 months for patients with SUV Mean less than 5 versus 6.5 months for those with SUV Mean greater than 5 (p=0.0681). MR defined by SUV Max, SUV Mean, PET Vol or TLG did not predict for OS. MR on PET correlated poorly with CT response with Kappa values of 0.01, 0.05, 0.15 and 0.31 for MR defined by SUV Max, PET Vol, SUV Mean and TLG respectively. CT response using Modified RECIST criteria correlated significantly with OS. Patients with partial response (PR), stable disease (SD) and progressive disease (PD) had median survivals of 25.6 months, 8.6 months and 4.6 months respectively (p=0.0072) Conclusions: MR measured by SUV Max, SUV Mean, PET Volume and TLG on early sequential PET scans did not correlate with CT assessed response to chemotherapy or OS. Baseline SUV Max &gt;15 and SUV Mean &gt;5 were indicative of poor prognosis. CT response as measured by Modified RECIST criteria correlated significantly with OS. No significant financial relationships to disclose.

Noninvasive 64Cu-ATSM and PET/CT Assessment of Hypoxia in Rat Skeletal Muscles and Tendons During Muscle Contractions

The purpose of the present study was to investigate exercise-related changes in oxygenation in rat skeletal muscles and tendons noninvasively with PET/CT and the hypoxia-selective tracer (64)Cu-diacetyl bis(N(4)-methylthiosemicarbazone) (ATSM) and to quantitatively study concomitant changes in gene expression of 2 hypoxia-related genes, hypoxia-inducible factor 1alpha (HIF1alpha) and carbonic anhydrase III (CAIII). Two groups of Wistar rats performed 1-leg contractions of the calf muscle by electrostimulation of the sciatic nerve. After 10 min of muscle contractions, (64)Cu-ATSM was injected and contractions were continued for 20 min. PET/CT of both hind limbs was performed immediately and 1 h after the contractions. The exercise group (n = 8) performed only muscle contractions as described, whereas the other group, exercise plus cuff (n = 8), in addition underwent cuff-induced hypoxia during the first PET/CT scan. Standardized uptake values (SUVs) were calculated for the Achilles tendons and triceps surae muscles and were correlated to gene expression of HIF1alpha and CAIII using real-time polymerase chain reaction. Immediately after the contractions, uptake of (64)Cu-ATSM was significantly increased, by approximately 1.5-fold in muscles and 1.3-fold in tendons, compared with resting conditions. The significant increase was maintained in late PET scans in stimulated muscles and tendons independently of cuff application. In muscles, SUV correlated significantly with gene expression of HIF1alpha and CAIII, whereas this coherence was not found in tendons. We found enhanced uptake of (64)Cu-ATSM in both early and late PET scans, thereby supporting the possibility that (64)Cu-ATSM registers exercise-induced transient hypoxia in both skeletal muscles and force-transmitting tendons. The fact that skeletal muscles but not tendons showed upregulation of HIF1alpha and CAIII could indicate that healthy tendons are less responsive than skeletal muscles to low levels of oxygen.