Lymphoma: The Added Value of Radiomics, Volumes and Global Disease Assessment.

Lymphoma represents a condition that holds promise for cure with existing treatment modalities; nonetheless, the primary clinical obstacle lies in advancing therapeutic outcomes by pinpointing high-risk individuals who are unlikely to respond favorably to standard therapy. In this article, the authors will delineate the significant strides achieved in the lymphoma field, with a particular emphasis on the 3 prevalent subtypes: Hodgkin lymphoma, diffuse large B-cell lymphomas, and follicular lymphoma.

End of induction [18F]FDG PET is prognostic for progression-free survival and overall survival in follicular lymphoma patients enrolled in the FOLL12 trial.

PURPOSE: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [18F]FDG PET (PET) in follicular lymphoma patients. METHODS: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS). RESULTS: Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003). CONCLUSION: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients.

Predictive value on advance hodgkin lymphoma treatment outcome of end-of treatment FDG PET/CT in the HD0607 clinical trial.

The Lugano classification for response assessment in lymphoma recommends the use of the 5-point-scale Deauville Score (DS) to assess response evaluation of end-of-treatment FDG-PET/CT (eotPET) in Hodgkin Lymphoma (HL); nevertheless, there is a paucity of data on its accuracy and reproducibility. We focus here on the cohort of advanced stage IIb-IV HL patients enrolled in the HD0607 clinical trial (NCT identifier 00795613) that having had a negative interim PET performed 6 cycles of ABVD (Doxorubicin, Vinblastine, Vincristine and Dacarbazine) and then performed an eotPET. Negative patients were randomized to radiotherapy and no further treatment while positive patients were treated based on local policies. eotPET was re-evaluated independently by two readers evaluated and progression free survival was analysed (PFS). eotPET of 254 patients were analysed. The median follow-up was 43 months. The best receiver operator characteristics cut-off values to distinguish positive and negative patients was 4. The area-under-the-curve was 0.81 (95%CI, 0.70-0.91). Three-years PFS was 0.95 (95% CI 0.90-0.97) in eotPET negative and 0.22 (95% CI 0.11-0.43) in eotPET positive. DS demonstrated a good reproducibility of positivity/negativity between the readers consensus and local site evaluation where the agreement occurred on 95.0% of patients. The present study demonstrates that eotPET is an accurate tool to predict treatment outcome in HL and confirms the appropriateness of the Lugano classification for eotPET evaluation.

The 18F phantom clinical trials qualification for 18F-FDG-PET scanning adopted by GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea). / Cualificación de fantomas 18F para ensayos clínicos con imagen PET/TC-18F-FDG adoptada por GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea).

INTRODUCTION AND OBJECTIVES: Since different PET/CT (Positron Emission Tomography/Computed Tomography) scanners give different qualitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of PET/CT in prospective multi-centre clinical trials. Within this work we will show the results carried out in performing CTQ in Spain. MATERIALS AND METHODS: We set up, under the auspices of Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GELTAMO), a CTQ program consisting of the acquisition and analysis of 18F uniformity and image quality phantoms for the reduction of inter-scanner variability (ISV). The ISV was estimated on background activity concentration (BAC) and sphere to background ratio (SBR) and defined as their 95% confidence level. RESULTS: Twenty-six out of 27 (96%) scanners fulfilled the CTQ requirements. The CTQ was fulfilled at the first round in 27% of the cases, while in 38%, 15% and 20%, two, three or more than three iterations, were required, respectively. The mean CTQ time was (1.8 ± 1.4) months (range: 0.3-4.6). The ISV in BAC and SBR were 20.3% and 67.7%. CONCLUSIONS: The CTQ proven to be a reliable tool to reduce ISV. This enabled to set-up clinical trials in which PET/CT was used to evaluate different clinical endpoints.

Dose prescription in SBRT for early-stage non-small cell lung cancer: are we all speaking the same language?

INTRODUCTION: Stereotactic body radiation therapy is increasingly used in the treatment of early-stage lung cancers. Guidelines provide indications regarding the constraints to the organs at risk (OARs) and the minimum coverage of the planning target volume but do not suggest optimal dose distribution. Data on dose distribution from the different published series are not comparable due to different prescription modalities and reported dose parameters. METHODS: We conducted a review of the published data on dose prescription, focusing on the role of homogeneity on local tumor control, and present suggestions on how to specify and report the prescriptions to permit comparisons between studies or between cases from different centers. CONCLUSIONS: To identify the dose-prescription modality that better correlates with oncologic outcomes, future studies should guarantee a close uniformity of dose distribution between cases and complete dose parameters reporting for treatment volumes and OARs.

Concomitant semi-quantitative and visual analysis improves the predictive value on treatment outcome of interim 18F-fluorodeoxyglucose/positron-emission tomography in advanced Hodgkin lymphoma.

BACKGROUND: Qualitative assessment using the Deauville five-point Scale (DS) is the gold standard for interim and end-of treatment positron-emission tomography (PET) interpretation in lymphoma. In the present study we assessed the reliability and the prognostic value of different semi- quantitative parameters in comparison with DS for interim PET (iPET) interpretation in Hodgkin lymphoma (HL). METHODS: A cohort of 82 out of 260 patients with advanced stage HL enrolled in the International Validation Study (IVS), scored as 3 to 5 by the expert panel was included in the present report. Two nuclear medicine physicians blinded to patient history, clinical data and treatment outcome reviewed independently the iPET using the following parameters: DS, SUVmax, SUVpeak of the most active lesion, Qmax (ratio of SUVmax of the lesion to liver SUVmax) and Qres (ratio of SUVpeak of the lesion to liver SUVmean). The optimal sensitivity, specificity, positive and negative predictive value to predict treatment outcome was calculated for all the above parameters with the receiver operator characteristics analysis. RESULTS: The prognostic value of all parameters were similar, the best cut-off value being 4 for DS (area under the curve [AUC], 0.81 95% CI: 0.72-0.90), 3.81 for SUVmax (AUC 0.82 95% CI: 0.73-0.91), 3.20 for SUVpeak (AUC 0.86 95% CI: 0.77-0.94), 1.07 for Qmax (AUC 0.84 95% CI: 0.75-0.93) and 1.38 for Qres (AUC 0.84 95% CI: 0.75-0.93). The reproducibility of different parameters was similar as the inter-observer variability measured with Cohen's kappa were 0.93 (95% CI: 0.84-1.01) for the DS, 0.88 (0.77-0.98) for SUVmax, 0.82 (0.70-0.95) for SUVpeak, 0.85 (0.74-0.97) for Qres and 0.78 (0.65-0.92) for Qmax. Due to the high specificity of SUVpeak (0.87) and to the good sensitivity of DS (0.86), upon the use of both parameters the positive predictive value increased from 0.65 of the DS alone to 0.79. When both parameters were positive in iPET, 3-years Failure-Free Survival (FFS) was significantly lower compared to patients whose iPET was interpreted with qualitative parameters only (DS 4 or 5): 21% vs. 35%. On the other hand, the FFS of patients with negative results was not significantly different (88% vs. 86%). CONCLUSIONS: In this study we demonstrated that, combining semi-quantitative parameters with SUVpeak to a pure qualitative interpretation key with DS, it is possible to increase the positive predictive value of iPET and to identify with higher precision the patients subset with a very dismal prognosis. However, these retrospective findings should be confirmed prospectively in a larger patient cohort.

Predictive value of Prostate Specific Antigen variations in the last week of salvage radiotherapy for biochemical recurrence of prostate cancer after surgery: A practical approach.

BACKGROUND: About a third of patients who underwent radical prostatectomy for prostate cancer (Pca) develop a biochemical failure (BF) within 10 years from surgery, and about a half of them receive salvage radiation therapy (SRT). Factors to predict risk to relapse after SRT are still lacking. Dynamic models, based on the assessment of changes in Prostate Specific Antigen (PSA) postsurgery seem to show good reliability. AIMS: The goal of the study was to identify a simple analytical method for the postsalvage radiation therapy biochemical failure (post-SRTBF) prediction before the end of the SRT, regardless of the PSA value at the beginning of the treatment (PSA start), measuring the PSA values at the start and 1 week before the end of SRT. METHODS: In a series of 83 patients treated with SRT for BF of Pca we measured PSA values at the first day and 1 week before the end of SRT. These values were used to define an analytical method for the post-SRTBF prediction. RESULTS: PSA value in patients without post-SRTBF show a significant difference in term of difference during the SRT with respect to patients with post-SRTBF. Starting from this difference, we identified a simple and practical analytical method for the post-SRTBF prediction before the end of the SRT. The data corresponds with the model and the analytical method is highly predictive (Sensitivity = 81%, Specificity = 85%, Accuracy = 83%). CONCLUSION: This study offers a new tool to early predict Pca relapse overtime and to select patients who can benefit from an early additional systemic treatment.

The impact of time-of-flight, resolution recovery, and noise modelling in reconstruction algorithms in non-solid-state detectors PET/CT scanners: - multi-centric comparison of activity recovery in a 68Ge phantom.

The reconstruction algorithms implemented on PET/CT scanners offer gain in activity recovery of small lesions at an extent that is not full known yet. METHODS: A cylindrical phantom with warm background and hot spheres filled with a 68Ge epoxy was acquired with four non-state-solid-detectors PET/CT scanners: mCT, Ingenuity TF, Discovery 710, and IQ. Images were reconstructed switching on and off time-of-flight (TOF), point spread function (PSF) modelling, and Bayesian penalised likelihood (BPL). Images were reconstructed with the default parameters recommended by the manufacturers. The recovery coefficient (RCmax), defined as the ratio of the measured maximum activity concentration in each sphere and the actual one, and the coefficient of variation (CoVBAC) defined as the ratio of the standard deviation and the average of background activity concentration were measured. RESULTS: While with IR alone, complete recovery of the activity concentration is achieved down to the 22 mm diameter's sphere, with TOF, TOF + PSF and BPL it is achieved down to the 17 mm diameter one. At smaller dimensions, the difference among the various studied reconstruction algorithms is substantial for the 13- and 17-mm diameters' spheres for all scanners and for all reconstructions with a considerable gain in RCmax when PSF and BPL are used. At 10 mm diameter's sphere the difference among the algorithms is significantly reduced, except for BPL which still guarantees a gain in RCmax.

Dual-point FDG-PET/CT for treatment response assessment in Hodgkin lymphoma, when an FDG-avid lesion persists after treatment.

FDG-PET/CT (PET) is now considered the standard imaging tool for Hodgkin Lymphoma (HL) staging and restaging. However a CT-detected residual mass at the end of therapy (EoT) is still a challenge for PET interpretation. The aim of our study was to improve the overall accuracy of EoT PET/CT by using a dynamic dual-point scanning at 60 and 120 after FDG injection (2P-PET/CT). Fifty-one HL patients showing a single residual FDG-avid mass (SFAM) at EoT PET/CT were included in the study in Italy and Poland. Treatment was ABVD, ABVD followed by BEACOPP or ABVD plus radiotherapy. Only patients with a SFAM and a Deauville score (DS) > 2 in EoT PET/CT were included in the study. Two independent nuclear medicine reviewed images with a semi-quantitative analysis (SUVMax and retention index, RI) and a visual scoring according to DS. Compared to standard PET, 2P-PET/CT showed only a modest increase in NPV and PPV, from 0.87 to 0.89 and of the PPV from 0.67 to 0.71, respectively. Increase of the overall accuracy became substantial upon including in the analysis only patients whose images were acquired in strict adhesion to original protocol of 2P-PET/CT scanning: (t 120'-6040 min): the sensitivity increased from 0.60 to 1.00, PPV from 0.75 to 0.83 and NPV from 0.89 to 1. This study, with caution for the small number of patients included, seems to suggest that 2P-PET/CT could increase the overall accuracy of EoT PET/CT in correctly classifying treatment response in HL with a persisting SFAM at EoT.

Monitoring response in lymphomas: qualitative, quantitative, or what else?

The Deauville criteria (DC) shall always be used to report interim and final PET and to assign metabolic response categories in FDG-avid lymphoma. A recent review article supports the role of quantitative extension of the DC to improve response assessment in lymphoma. We analyze different quantitative approach, to help physician to better distinguish what has to be done in every day clinical practice respect to what represent interesting insights and ongoing research. Respect to DC, all the proposed quantitative approaches obtained in retrospective studies, requires mature follow-up and a validation in independent cohorts of lymphoma patients. Moreover, the sensitivity of the system, not the adequate specificity of the tracer and the biology of the disease together with the DC, influence the accuracy of PET/CT. In conclusions, in current clinical practice, the DC, validated in a large cohort of lymphoma patients, represent the standard criteria for PET interpretation.

Automatic liver detection and standardised uptake value evaluation in whole-body Positron Emission Tomography/Computed Tomography scans.

BACKGROUND AND OBJECTIVE: Standardised Uptake Value (SUV), in clinical research and practice, is a marker of tumour avidity in Positron Emission Tomography/Computed Tomography (PET/CT). Since many technical, physical and physiological factors affect the SUV absolute measurement, the liver uptake is often used as reference value both in quantitative and semi-quantitative evaluation. The purpose of this investigation was to automatically detect the liver position in whole-body PET/CT scans and extract its average SUV value. METHODS: We developed an algorithm, called LIver DEtection Algorithm (LIDEA), that analyses PET/CT scans, and under the assumption that the liver is a large homogeneous volume near the centre of mass of the patient, finds its position and automatically places a region of interest (ROI) in the liver, which is used to calculate the average SUV. The algorithm was validated on a population of 630 PET/CT scans coming from more than 60 different scanners. The SUV was also calculated by manually placing a large ROI in the liver. RESULTS: LIDEA identified the liver with a 97.3% sensitivity with PET/CT images only and reached a 98.9% correct detection rate when using the co-registered CT scan to avoid liver misidentification in the right lung. The average liver SUV obtained with LIDEA was successfully validated against its manual assessment, with no systematic difference (0.11 ±â€¯0.36 SUV units) and a R2=0.89 correlation coefficient. CONCLUSIONS: LIDEA proved to be a reliable tool to automatically identify and extract the average SUV of the liver in oncological whole-body PET/CT scans.

Early Chemotherapy Intensification With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Positive Interim Positron Emission Tomography/Computed Tomography Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Trial.

Purpose To investigate the progression-free survival (PFS) of patients with advanced Hodgkin lymphoma (HL) after a risk-adapted treatment strategy that was based on a positive positron emission tomography scan performed after two doxorubicin, vinblastine, vincristine, and dacarbazine (ABVD) cycles (PET2). Patients and Methods Patients with advanced-stage (IIB to IVB) HL were consecutively enrolled. After two ABVD cycles, PET2 was performed and centrally reviewed according to the Deauville five-point scale. Patients with a positive PET2 were randomly assigned to four cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) followed by four cycles of standard BEACOPP with or without rituximab. Patients with a negative PET2 continued ABVD, and those with a large nodal mass at diagnosis (≥ 5 cm) in complete remission with a negative PET at the end of chemotherapy were randomly assigned to radiotherapy or no further treatment. The primary end point was 3-year PFS. Results Of 782 enrolled patients, 150 (19%) had a positive and 630 (81%) a negative PET2. The 3-year PFS of all patients was 82%. The 3-year PFS of those with a positive and negative PET2 was 60% and 87%, respectively ( P < .001). The 3-year PFS of patients with a positive PET2 assigned to BEACOPP with or without rituximab was 63% versus 57% ( P = .53). In 296 patients with both interim and post-ABVD-negative PET who had a large nodal mass at diagnosis, radiotherapy was randomly added after chemotherapy without a significant PFS improvement (97% v 93%, respectively; P = .29). The 3-year overall survival of all 782 patients was 97% (99% and 89% for PET2 negative and positive, respectively). Conclusion The PET-driven switch from ABVD to escalated BEACOPP is feasible and effective in high-risk patients with advanced-stage HL.

Development of standardized image interpretation for 68Ga-PSMA PET/CT to detect prostate cancer recurrent lesions.

METHODS: After primary treatment, biochemical relapse (BCR) occurs in a substantial number of patients with prostate cancer (PCa). PET/CT imaging with prostate-specific membrane antigen based tracers (68Ga-PSMA) has shown promising results for BCR patients. However, a standardized image interpretation methodology has yet to be properly agreed. The aim of this study, which was promoted and funded by European Association of Nuclear Medicine (EANM), is to define standardized image interpretation criteria for 68Ga-PSMA PET/CT to detect recurrent PCa lesions in patients treated with primary curative intent therapy (radical prostatectomy or radiotherapy) who presented a biochemical recurrence. In the first phase inter-rater agreement between seven readers from seven international centers was calculated on the reading of 68Ga-PSMA PET/CT images of 49 patients with BCR. Each reader evaluated findings in five different sites of recurrence (local, loco-regional lymph nodes, distant lymph nodes, bone, and other). In the second phase the re-analysis was limited to cases with poor, slight, fair, or moderate agreement [Krippendorff's (K) alpha<0.61]. Finally, on the basis of the consensus readings, we sought to define a list of revised consensus criteria for 68Ga-PSMA PET/CT interpretation. RESULTS: Between-reader agreement for the presence of anomalous findings in any of the five sites was only moderate (K's alpha: 0.47). The agreement improved and became substantial when readers had to judge whether the anomalous findings were suggestive for a pathologic, uncertain, or non-pathologic image (K's alpha: 0.64). K's alpha calculations for each of the five sites of recurrence were also performed and evaluated. First Delphi round was thus conducted. A more detailed definition of the criteria was proposed by the project coordinator, which was then discussed and finally agreed by the seven readers. After the second Delphi round only four cases of disagreement still remained. These were evaluated for a final round, allowing a final agreement table to be written. CONCLUSION: We hope that by developing these consensus guidelines on the interpretation of 68Ga-PSMA PET/CT, clinicians reporting these studies will be able to provide more consistent clinical reports and that within clinical trials, abnormality classifications will be harmonized, allowing more robust assessment of its diagnostic performance.

The (68)Ge phantom-based FDG-PET site qualification program for clinical trials adopted by FIL (Italian Foundation on Lymphoma).

PURPOSE: The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life. METHODS: We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of (18)F and (68)Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR). RESULTS: The use of a (68)Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the (18)F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with (68)Ge and (18)F respectively. CONCLUSIONS: The (68)Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.

The Strategies to Homogenize PET/CT Metrics: The Case of Onco-Haematological Clinical Trials.

Positron emission tomography (PET) has been a widely used tool in oncology for staging lymphomas for a long time. Recently, several large clinical trials demonstrated its utility in therapy management during treatment, paving the way to personalized medicine. In doing so, the traditional way of reporting PET based on the extent of disease has been complemented by a discrete scale that takes in account tumour metabolism. However, due to several technical, physical and biological limitations in the use of PET uptake as a biomarker, stringent rules have been used in clinical trials to reduce the errors in its evaluation. Within this manuscript we will describe shortly the evolution in PET reporting, examine the main errors in uptake measurement, and analyse which strategy the clinical trials applied to reduce them.