Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy.

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.

Lymph Node Assessment in Prostate Cancer: Evaluation of Iodine Quantification With Spectral Detector CT in Correlation to PSMA PET/CT.

PURPOSE: The aims of this study were to evaluate spectral detector CT (SDCT)-derived iodine concentration (IC) of lymph nodes diagnosed as metastatic and benign in prostate-specific membrane antigen (PSMA) PET/CT and to assess its potential use for lymph node assessment in prostate cancer. PATIENTS AND METHODS: Thirty-four prostate cancer patients were retrospectively included: 16 patients with and 18 without lymph node metastases as determined by PSMA PET/CT. Patients underwent PSMA PET/CT as well as portal venous phase abdominal SDCT for clinical cancer follow-up. Only scan pairs with a stable nodal status indicated by constant size as well as comparable prostate-specific antigen (PSA) levels were included. One hundred benign and 96 suspected metastatic lymph nodes were annotated and correlated between SDCT and PSMA PET/CT. Iodine concentration in SDCT-derived iodine maps and SUVmax in ultra-high definition reconstructions from PSMA PET/CT were acquired based on the region of interest. RESULTS: Metastatic lymph nodes as per PSMA PET/CT showed higher IC than nonmetastatic nodes (1.9 ± 0.6 mg/mL vs 1.5 ± 0.5 mg/mL, P < 0.05) resulting in an AUC of 0.72 and sensitivity/specificity of 81.3%/58.5%. The mean short axis diameter of metastatic lymph nodes was larger than that of nonmetastatic nodes (6.9 ± 3.6 mm vs 5.3 ± 1.3 mm; P < 0.05); a size threshold of 1 cm short axis diameter resulted in a sensitivity/specificity of 12.8%/99.0%. There was a significant yet weak positive correlation between SUVmax and IC (rs = 0.25; P < 0.001). CONCLUSIONS: Spectral detector CT-derived IC was increased in lymph nodes diagnosed as metastatic in PSMA PET/CT yet showed considerable data overlap. The correlation between IC and SUVmax was weak, highlighting the role of PSMA PET/CT as important reference imaging modality for detection of lymph node metastases in prostate cancer patients.

Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.

BACKGROUND: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR. METHODS: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination. RESULTS: Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. CONCLUSIONS: Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.

Volumetric assessment of mediastinal lymphoma masses in Hodgkin lymphoma.

The large mediastinal mass (LMM) at initial staging represents a risk factor in Hodgkin lymphoma (HL) and is measured by X-ray. Depending on location of the LMM, different results can occur regardless of the initial lymphoma volume. To assess this risk factor more accurately, we evaluated the method of volumetry in 77 patients of HD13/14 study of the German Hodgkin Study Group. Furthermore, volume calculations based on three or only one diameter, were performed to simplify volume assessment. Inter-rater reliability was good for all methods. The 3-diameter measurement produced larger volumes than volumetric assessment with an intraclass correlation coefficient (ICC) of 0.93, which could be improved to 0.95 by multiplying volumes with a correction factor of 0.86. The 1-dimensional measurement strongly overestimated the volume with an ICC of 0.7. In conclusion, the simplified volume estimation based on 3 largest diameters provides a reliable concept for the staging of HL patients.

Quantitative assessment of 18F-FDG PET in patients with Hodgkin lymphoma: is it significantly affected by contrast-enhanced computed tomography attenuation correction?

OBJECTIVE: The reliability of visual and quantitative response assessment may be impaired owing to inconsistent scanning protocols and image reconstruction methods of 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) PET. Hence, this study investigates the effect of contrast-enhanced computed tomography (CT) attenuation correction in patients with Hodgkin lymphoma. PATIENTS AND METHODS: In 10 consecutive patients undergoing either staging or response assessment, F-FDG PET images were attenuation-corrected once on the basis of unenhanced CT and additionally using contrast-enhanced CT. Reconstruction was performed in both cases with ordered subset expectation maximization (OSEM) and ultra-high definition (UHD) algorithm. While maximum and peak standardized uptake value (SUV) were obtained from tumour tissue (lesionSUVmax and lesionSUVpeak), maximum and mean SUVs were determined within the background regions liver (liverSUVmax and liverSUVmean) and mediastinal blood pool (mbpSUVmax and mbpSUVmean). RESULTS: After switching to contrast-enhanced CT attenuation correction, lesionSUVmax and lesionSUVpeak increased on average by 2.55±3.24 (P=0.018) and 3.64±3.22% (P=0.008), respectively, with OSEM and by 4.59±5.49 (P=0.005) and 3.84±5.65% (P=0.005), respectively, with UHD reconstruction. LiverSUVmax and liverSUVmean showed a mean rise of 7.15±4.27 (P=0.005) and 6.97±2.18% (P=0.005), respectively, in the OSEM data sets and of 7.24±6.59 (P=0.017) and 6.29±2.83% (P=0.005), respectively, in the UHD images. The average increases of mbpSUVmax and mbpSUVmean were 10.82±4.89 (P=0.005) and 12.40±3.73% (P=0.005), respectively, after OSEM, compared with 13.11±14.93 (P=0.005) and 11.50±12.19% (P=0.005), respectively, after UHD reconstruction. CONCLUSION: As the use of CT contrast fluids results in a stronger SUV increase within the liver and mediastinal blood pool than within lymphoma tissue, this may have clinical consequences regarding visual and quantitative response assessment. Ideally, CT scans for PET attenuation correction should therefore be performed in the absence of a contrast agent.

PET/CT for Lymphoma Post-therapy Response Assessment in Hodgkin Lymphoma and Diffuse Large B-cell Lymphoma.

Over the course of many decades, combined chemotherapy and radiotherapy adapted to the stage of disease have become the optimal and standard treatment for Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma. Besides achieving optimized cure rates of the underlying disease, reduction of toxicity has become a major goal. Since the introduction of FDG-PET for the staging and restaging of patients with lymphoma, a high predictive value of F-18-FDG-PET in response assessment has been observed. Several PET-response-guided therapy regimens have already been established, and even more PET-adapted study designs are being tested in large study groups. PET has a very high negative predictive value following chemotherapy, and radiotherapy can be safely omitted in PET-negative patients with HL after effective chemotherapy with regimens such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in advanced stages. As "state-of-the-art" PET-guided therapy is based on the results of large clinical trials, the reliability of end-of-treatment PET as a basis for abandoning radiotherapy in early and intermediate HL stages remains to be shown. As in HL, the predictive value of FDG-PET after induction therapy of diffuse large B-cell lymphoma is higher than that of CT alone so that we obtain relevant prognostic information unavailable through anatomical imaging. Recent results from trials in aggressive non-HL with a de-escalating strategy suggest that radiotherapy may be safely omitted if FDG-PET is negative after standard chemoimmunotherapy. Since 2007, FDG-PET at end of treatment is integrated into the International Working Group criteria and became the imaging tool of choice for response assessment in aggressive lymphoma. Robust and reproducible interpretation criteria are being used both in the ongoing clinical trials and in daily routine. The recommended five-point scale has become the standard in PET response assessment, with the caveat that the consequence of a PET scan may be influenced by foregoing and following treatments.

Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.

PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Assessment of tumor size reduction improves outcome prediction of positron emission tomography/computed tomography after chemotherapy in advanced-stage Hodgkin lymphoma.

PURPOSE: Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT). PATIENTS AND METHODS: The analysis set consisted of 739 patients with residues≥2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkin's disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkin's disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression. RESULTS: In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%). CONCLUSION: Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse.

18-Fluorodeoxyglucose positron emission tomography/computed tomography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma.

Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2-5 cycles), and were analyzed visually using a 5-point scale (5PS) and quantitatively using the maximum standardized uptake value (SUV(max)) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV(50)) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5-30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV(50), whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL.

Role of [18F]-fluoro-2-deoxy-D-glucose positron emission tomography in early and late therapy assessment of patients with advanced Hodgkin lymphoma treated with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone.

The prognostic value of positron emission tomography (PET) in early therapy response assessment, after completion of chemotherapy and 3 months after the end of treatment in advanced Hodgkin lymphoma (HL) remains to be defined. We report the results of 69 patients with first presentation of advanced HL. [18F]-fluoro-2-deoxy-d-glucose (FDG)-PET scan was performed after four cycles (PET-4), on completion of chemotherapy after 6/8 cycles (PET-6/8) and 3 months after the completion of chemotherapy (PET 3-months). Median follow-up was 55 months. The negative predictive value (NPV) for PET-4, PET-6/8 and PET 3-months was 98%, 95% and 97%, respectively. The 4-year progression-free survival (PFS) for PET-4 negative (n = 51) and PET-4 positive (n = 18) patients was 96% and 78%, respectively (p = 0.016). The 4-year PFS for PET-6/8 negative (n = 59) and PET-6/8 positive (n = 9) patients was 95% and 78%, respectively (p = 0.046). Patients with a large mediastinal mass constituted nearly all of the PET-4 positive (16/18) and PET-6/8 positive (8/9) patients. After radiotherapy of PET-6/8 positive patients, PET 3-months was negative in 64 (97%) and positive in two (3%) patients. PET 3-months after the end of chemotherapy was of limited value when the interim PET-4 was negative. Interim PET after four cycles of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP) is a strong prognostic marker for PFS in advanced HL.

Early and late therapy response assessment with [18F]fluorodeoxyglucose positron emission tomography in pediatric Hodgkin's lymphoma: analysis of a prospective multicenter trial.

PURPOSE: In adult Hodgkin's lymphoma (HL) risk stratification after early therapy response assessment with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) seems to allow tailoring therapy with less toxicity for patients with adequate metabolic response. This study delivers the first prospective data on the potential of FDG-PET for response assessment in pediatric HL. PATIENTS AND METHODS: FDG-PET was performed in 40 pediatric HL patients before polychemotherapy (PET-1), after two cycles of polychemotherapy (PET-2), and after completion of polychemotherapy (PET-3). Mean follow-up was 46 months (range, 26 to 72 months). RESULTS: At early and late response assessment, the proportion of PET-negative patients was significantly higher compared with those patients with negative findings in conventional imaging methods (CIMs; PET-2, 26 of 40 v CIM-2, one of 40; P < .001; PET-3, 21 of 29 v CIM-3, four of 29; P < .001). Sensitivity and negative predictive value were 100% for early and late therapy response assessment by PET. Both patients suffering a relapse during follow-up were identified by PET-2/3, whereas one of these patients was not detected by CIM-3. PET was superior to CIMs with regard to specificity in early and late therapy response assessment (68% v 3%, and 78% v 11%, respectively; both P < .001). Specificity of early therapy response assessment by PET was improved to 97% by quantitative analysis of maximal standardized uptake value reduction using a cutoff value of 58%. CONCLUSION: Pediatric HL patients with a negative PET in response assessment have an excellent prognosis while PET-positive patients have an increased risk for relapse.

Mean and maximum standardized uptake values in [18F]FDG-PET for assessment of histopathological response in oesophageal squamous cell carcinoma or adenocarcinoma after radiochemotherapy.

PURPOSE: To evaluate the potential of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the assessment of histopathological response and survival after neoadjuvant radiochemotherapy in patients with oesophageal cancer. PATIENTS AND METHODS: In 2005 and 2006, 55 patients (43 men, 12 women; median age 60 years) with locally advanced oesophageal cancer (cT3-4 Nx M0; 24 with squamous cell carcinoma, 31 with adenocarcinoma) underwent transthoracic en bloc oesophagectomy after completion of treatment with cisplatin, 5-fluorouracil, and radiotherapy ad 36 Gy in a prospective clinical trial. Of the 55 patients, 21 (38%) were classified as histopathological responders (<10% vital residual tumour cells) and 34 (62%) as nonresponders. FDG-PET was performed before (PET 1) and 3-4 weeks after the end (PET 2) of radiochemotherapy with assessment of maximum and average standardized uptake values (SUV) for correlation with histopathological response and survival. RESULTS: Histopathological responders had a slightly higher baseline SUV than nonresponders (p<0.0001 between PET 1 and PET 2 for responders and nonresponders) and the decrease was more prominent in responders. Except for SUVmax in patients with squamous cell carcinoma neither baseline nor preoperative SUV nor percent SUV reduction correlated significantly with histopathological response. Histopathological responders had a 2-year overall survival of 91 +/- 9% and nonresponders a survival of 53 +/- 10% (p = 0.007). CONCLUSION: Our study does not support recent reports that FDG-PET predicts histopathological response and survival in patients with locally advanced oesophageal cancer treated by neoadjuvant radiochemotherapy.