Monitoring metabolic response using FDG PET-CT during targeted therapy for metastatic colorectal cancer.

INTRODUCTION: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient's unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. METHODS: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. RESULTS: On baseline FDG PET-CT, 124 measurable "target" lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. CONCLUSIONS: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs.

Combined Metabolically Active Tumor Volume and Early Metabolic Response Improve Outcome Prediction in Metastatic Colorectal Cancer.

Stratification of metastatic colorectal cancer (mCRC) patients is mostly based on clinical and biologic characteristics. This study aimed to validate the prognostic value of 18F-FDG PET/CT-based biomarkers such as baseline whole-body metabolically active tumor volume (WB-MATV) and early metabolic response (mR) in mCRC. Methods: The development cohort included chemorefractory mCRC patients enrolled in 2 prospective Belgian multicenter trials evaluating last-line treatments (multikinase inhibitors). The validation cohort included mCRC patients from an Italian center treated with chemotherapy and bevacizumab as first-line. Baseline WB-MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. Early mR assessment was performed following usual response criteria (response threshold of 30% [PERCIST-30%], response threshold of 15% [PERCIST-15%], European Organization for Research and Treatment of Cancer) and the so-called CONSIST method, which defines response as a decrease of SULmax ≥ 15% for all target lesions. Baseline WB-MATV and early mR assessment were investigated along with usual clinical factors and correlated with overall survival (OS) and progression-free survival (PFS). Results: Clinical factors, baseline WB-MATV, and early mR were evaluable in 192 of 239 and 94 of 125 patients of the development and validation cohorts, respectively. Except for PERCIST-30%, all response methods were equivalent in terms of outcome prediction, and CONSIST was found to be the most accurate. Baseline WB-MATV and early mR using the CONSIST method were independent prognostic parameters after adjustment for clinical factors in the development and validation sets for both OS (hazard ratio [HR] WB-MATV: 1.87 [95% CI, 1.17-2.97], P = 0.005, and HR early mR: 1.79 [95% CI, 1.08-2.95], P = 0.02 for the validation set) and PFS (HR WB-MATV: 1.94 [95% CI, 1.27-2.97], P = 0.002, and HR early mR: 1.69 [95% CI, 1.04-2.73], P = 0.03 for the validation set). Conclusion: Baseline WB-MATV and early mR are strong independent prognostic biomarkers for OS and PFS in mCRC, regardless of treatment received. Therefore, combining these biomarkers improves risk stratification for OS and PFS in mCRC.

Interim PET Evaluation in Diffuse Large B-Cell Lymphoma Using Published Recommendations: Comparison of the Deauville 5-Point Scale and the ΔSUVmax Method.

The value of interim 18F-FDG PET/CT (iPET)-guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the change-in-SUVmax (ΔSUVmax) approach-2 methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial, iPET scans of 596 patients originally evaluated using the ΔSUVmax method were available for post hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the ΔSUVmax approach is characterized as a relative reduction of the SUVmax between baseline and iPET staging of less than or equal to 66%. We investigated the 2 methods' correlation and concordance by Spearman rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the prespecified cutoffs. Time-dependent receiver-operating-characteristic curve analysis provided information on the methods' respective discrimination performance. Results: Deauville score and ΔSUVmax approach differed in their iPET-based prognosis. The ΔSUVmax approach outperformed the Deauville score in terms of discrimination performance-most likely because of a high number of false-positive decisions by the Deauville score. Cutoff-independent discrimination performance remained low for both methods, but cutoff-related analyses showed promising results. Both favored the ΔSUVmax approach, for example, for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval, 2.22-4.46) for ΔSUVmax and 1.70 (95% confidence interval, 1.29-2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cutoff of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The ΔSUVmax criterion of a relative reduction in SUVmax of less than or equal to 66% should be considered as an alternative.

[18F]-Fluorodeoxyglucose Positron Emission Tomography/CT to Assess the Early Metabolic Response in Patients with Hormone Receptor-Positive HER2-Negative Metastasized Breast Cancer Treated with Cyclin-Dependent 4/6 Kinase Inhibitors.

INTRODUCTION: Addition of cyclin-dependent 4/6 kinase (CDK4/6) inhibitors to endocrine therapy is standard of care in the treatment of women with advanced hormone receptor-positive HER2-negative breast cancer. However, the predictive factors for the treatment response to CDK4/6 inhibitor therapy are poorly elucidated. Early changes in the by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake of tumors receiving different kinds of therapy have proven to reliably predict treatment outcomes in a variety of malignancies. Therefore, the feasibility of early metabolic response assessment to predict the long-term treatment response to CDK4/6 inhibitor therapy was evaluated in the present study. METHODS: Eight patients underwent FDG-PET/CT before and after the initiation of CDK4/6 inhibitor therapy (ribociclib, palbociclib or abemcaciclib). CDK4/6 inhibitor therapy was combined with either aromatase inhibition or fulvestrant. The median interval between the treatment start (including baseline PET) and the follow-up PET examination was 14 days. Conventional radiographic staging was performed 3 months after the start of CDK4/6 inhibitor therapy. The percentual changes in molecular tumor volume, SUVpeak, the summed SUVpeak of up to 5 metastases (PERCIST-5), and total lesion glycolysis (TLG) were calculated for each patient. RESULTS: Three patients showed progressive disease after 3 months of CDK4/6 inhibitor therapy, whereas 5 patients showed disease control (3 stable disease and 2 partial remission). Disease control was maintained in these patients (follow-up range 7-22 months). Patients with disease control had a significantly greater decline in TLG (-55.3 vs. 16.7%; p < 0.05). The same was true for the PERCIST-5 (-21.9 vs. 11.3%, p < 0.05). All patients with progressive TLG showed treatment failure and/or a poor outcome. CONCLUSION: Elevated TLG on early FDG-PET seems to be associated with long-term treatment failure and a poor outcome in patients undergoing CDK4/6 inhibitor therapy for metastatic breast cancer. Early findings indicate a potential prognostic value of early FDG-PET in this setting and warrant a prospective evaluation.

Association between textural and morphological tumor indices on baseline PET-CT and early metabolic response on interim PET-CT in bulky malignant lymphomas.

PURPOSE: We investigated whether metabolic, textural, and morphological tumoral indices evaluated on baseline PET-CT were predictive of early metabolic response on interim PET-CT in a cohort of patients with bulky Hodgkin and non-Hodgkin malignant lymphomas. METHODS: This retrospective study included 57 patients referred for initial PET-CT examination. In-house dedicated software was used to delineate tumor contours using a fixed 30% threshold of SUV max and then to compute tumoral metabolic parameters (SUV max, mean, peak, standard deviation, skewness and kurtosis, metabolic tumoral volume (MTV), total lesion glycolysis, and area under the curve of the cumulative histogram), textural parameters (Moran's and Geary's indices, energy, entropy, contrast, correlation derived from the gray-level co-occurrence matrix, area under the curve of the power spectral density, auto-correlation distance, and granularity), and shape parameters (surface, asphericity, convexity, surfacic extension, and 2D and 3D fractal dimensions). Early metabolic response was assessed on interim PET-CT using the Deauville 5-point scale and patients were ranked according to the Lugano classification as complete or not complete metabolic responders. The impact of the segmentation method (alternate threshold at 41%) and image resolution (Gaussian postsmoothing of 3, 5, and 7 mm) was investigated. The association of the proposed parameters with early response was assessed in univariate and multivariate analyses. Their added predictive value was explored using supervised classification by support vector machines (SVM). We evaluated in leave-one-out cross-validation three SVMs admitting as input features (a) MTV, (b) MTV + histological type, and (c) MTV + histology + relevant texture/shape indices. RESULTS: Features associated with complete metabolic response were low MTV (P = 0.01), low TLG (P = 0.003), high power spectral density AUC (P = 0.007), high surfacic extension (P = 0.006), low 2D fractal dimension (P = 0.007), and low 3D fractal dimension (P = 0.003). The prognostic value of these metrics was optimal with the 30% segmentation threshold and overall was progressively altered with decreasing image resolution. In cross-validation, the SVM accounting for texture and shape achieved the highest predictive value with ROC AUC of 0.82 and 80% accuracy (compared with 0.68 and 61% for MTV, and 0.65 and 68% for MTV + histology). CONCLUSIONS: The combination of usual prognostic factors with appropriately chosen textural and shape parameters evaluated on baseline PET-CT improves the prediction of early metabolic response in bulky lymphoma.