Longitudinal studies of the 18F-FDG kinetics after ipilimumab treatment in metastatic melanoma patients based on dynamic FDG PET/CT.

BACKGROUND: Immunotherapy has raised the issue of appropriate treatment response evaluation, due to the unique mechanism of action of the immunotherapeutic agents. Aim of this analysis is to evaluate the potential role of quantitative analysis of 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) data in monitoring of patients with metastatic melanoma undergoing ipilimumab therapy. METHODS: 25 patients with unresectable metastatic melanoma underwent dynamic PET/CT (dPET/CT) of the thorax and upper abdomen as well as static, whole body PET/CT with 18F-FDG before the start of ipilimumab treatment (baseline PET/CT), after two cycles of treatment (interim PET/CT) and at the end of treatment after four cycles (late PET/CT). The evaluation of dPET/CT studies was based on semi-quantitative (standardized uptake value, SUV) calculation as well as quantitative analysis, based on two-tissue compartment modeling and a fractal approach. Patients' best clinical response, assessed at a mean of 59 weeks, was used as reference. RESULTS: According to their best clinical response, patients were dichotomized in those demonstrating clinical benefit (CB, n = 16 patients) and those demonstrating no clinical benefit (no-CB, n = 9 patients). No statistically significant differences were observed between CB and no-CB regarding either semi-quantitative or quantitative parameters in all scans. On contrary, the application of the recently introduced PET response evaluation criteria for immunotherapy (PERCIMT) led to a correct classification rate of 84% (21/25 patients). CONCLUSION: Quantitative analysis of 18F-FDG PET data does not provide additional information in treatment response evaluation of metastatic melanoma patients receiving ipilimumab. PERCIMT criteria correlated better with clinical response.

Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies.

BACKGROUND: PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma and other malignancies. Arthralgia is an underestimated side effect of PD-1 antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced arthralgia. PATIENTS AND METHODS: We retrospectively included patients with metastatic cutaneous malignancies treated with pembrolizumab or nivolumab ± ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013 and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and if indicated, rheumatologic consultation. RESULTS: 26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7-780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment. Patients with arthralgia showed a better treatment response and improved PFS and OS. CONCLUSION: Arthralgia is frequent during PD1ab treatment. The clinical picture varies between synovitis of predominantly large joints, progressive osteoarthritis and arthralgia without evident joint damage. Vast majority of cases can be satisfactorily managed by NSAID and/or low-dose corticosteroids.

Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab.

PURPOSE: Evaluation of response to immunotherapy is a matter of debate. The aim of the present study was to evaluate the response of metastatic melanoma to treatment with ipilimumab by means of 18F-FDG PET/CT, using the patients' clinical response as reference. METHODS: The final cohort included in the analyses consisted of 41 patients with metastatic melanoma who underwent 18F-FDG PET/CT before and after administration of ipilimumab. After determination of the best clinical response, the PET/CT scans were reviewed and a separate independent analysis was performed, based on the number and functional size of newly emerged 18F-FDG-avid lesions, as well as on the SUV changes after therapy. RESULTS: The median observation time of the patients after therapy was 21.4 months (range 6.3-41.9 months). Based on their clinical response, patients were dichotomized into those with clinical benefit (CB) and those without CB (No-CB). The CB group (31 patients) included those with stable disease, partial remission and complete remission, and the No-CB group (10 patients) included those with progressive disease. The application of a threshold of four newly emerged 18F-FDG-avid lesions on the posttherapy PET/CT scan led to a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%. This cut-off was lower for lesions with larger functional diameters (three new lesions larger than 1.0 cm and two new lesions larger than 1.5 cm). SUV changes after therapy did not correlate with clinical response. Based on these findings, we developed criteria for predicting clinical response to immunotherapy by means of 18F-FDG PET/CT (PET Response Evaluation Criteria for Immunotherapy, PERCIMT). CONCLUSION: Our results show that a cut-off of four newly emerged 18F-FDG-avid lesions on posttherapy PET/CT gives a reliable indication of treatment failure in patients under ipilimumab treatment. Moreover, the functional size of the new lesions plays an important role in predicting the clinical response. Validation of these results in larger cohorts of patients is warranted.

The role of interim 18F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma.

PURPOSE: The aim of the present study was to assess the value of interim 18F-FDG PET/CT performed after the first two cycles of ipilimumab treatment in the prediction of the final clinical response to this type of immunotherapy. METHODS: The study group comprised 41 patients with unresectable metastatic melanoma scheduled for ipilimumab therapy. Whole-body 18F-FDG PET/CT was performed before the start of ipilimumab treatment (baseline PET/CT) and after the initial two cycles of ipilimumab treatment (interim PET/CT). Evaluation of patient response to treatment was based on the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria for PET as well as the recently proposed PET Response Evaluation Criteria for Immunotherapy (PERCIMT). The patients' best clinical response, assessed at a median of 21.4 months (range 6.3-41.9 months) was used as reference. RESULTS: According to their best clinical response, the patients were divided into two groups: those showing clinical benefit (CB) including stable disease, partial response and complete response (31 patients), and those showing no clinical benefit (no-CB including progressive disease (10 patients). According to the EORTC criteria, interim PET/CT demonstrated progressive metabolic disease (PMD) in 20 patients, stable metabolic disease (SMD) in 11 patients, partial metabolic response (PMR) in 8 patients, and complete metabolic response (CMR) in 2 patients. According to the PERCIMT, interim PET/CT demonstrated PMD in 9 patients, SMD in 24 patients, PMR in 6 patients and CMR in 2 patients. On the basis of the interim PET, the patients were divided in a similar manner to the division according to clinical response into those showing metabolic benefit (MB) including SMD, PMR and CMR, and those showing no metabolic benefit (no-MB) including PMD. According to this dichotomization, the EORTC criteria showed a sensitivity (correctly predicting CB) of 64.5%, a specificity (correctly predicting no-CB) of 90.0%, a positive predictive value (PPV) of 95.2%, a negative predictive value (NPV) of 45.0% and an accuracy of 70.7% in predicting best clinical response. The PERCIMT showed a sensitivity of 93.6%, a specificity of 70.0%, a PPV of 90.6%, a NPV of 77.8% and an accuracy of 87.8%. The McNemar test showed that the PERCIMT had a significantly higher sensitivity than EORTC criteria (p = 0.004), while there was no significant difference in specificity (p = 0.5). The agreement between the two sets of criteria was poor (McNemar test p = 0.001, and accordingly kappa = 0.46). CONCLUSION: The application of the recently proposed PERCIMT to interim 18F-FDG PET/CT provides a more sensitive predictor of final clinical response to immunotherapy than the application of the EORTC criteria in patients with metastatic melanoma.

Fluorine-18-FDG PET/CT in a patient with angiomyolipoma: Response to mammalian target of rapamycin inhibitor therapy.

We report on a 27 years old female patient who was referred to our department for whole-body as well as dynamic positron emission tomography/computed tomography (dPET/CT) scan of the upper and middle abdomen with fluorine-18-fluorodeoxy glucose (18F-FDG), for further evaluation of a mass in the left adrenal gland region. Positron emission tomography showed a suspicious, enlarged, hypermetabolic mass with an average standardized uptake value (SUV) of 4.5 and a maximum SUV of 5.9. The patient was referred for biopsy, which revealed an angiomyolipoma, a perivascular epithelioid cell tumor (PEComa) of the adrenal gland. Perivascular epithelioid cell tumors are mesenchymal tumors consisting of blood vessels, smooth muscles and fat cells. The patient received anti-proliferative treatment with Afinitor, a mammalian target of rapamycin (mTOR) inhibitor, and was referred again one month after onset of therapy for early response assessment. The follow-up 18F-FDG PET/CT scan showed a nearly complete resolution of the previously detected adrenal mass, with very low tracer uptake and a decrease in its functional volume. Fluorine- 18-FDG PET/CT can be used for treatment response evaluation of angiomyolipoma treated with mTOR-inhibitors.

The value of different 18F-FDG PET/CT baseline parameters in risk stratification of stage I surgical NSCLC patients.

OBJECTIVE: Administration of postoperative chemotherapy to patients with completely resected stage I NSCLC is still a matter of debate. The aim of the present study was to evaluate the value of different baseline 18F-FDG PET parameters in identifying surgical stage I NSCLC patients who are at high risk of recurrence, and thus are indicated for further postoperative treatment. METHODS: This is a retrospective study, which included 49 patients (28 males, 21 females) with the median age of 69 years (range 28-84), who had pathologically proven stage I NSCLC. All patients underwent 18F-FDG PET/CT at baseline followed by complete surgical resection of the tumor (R0). Baseline SUVmax, MTV and TLG were measured. Patients' follow-up records were retrospectively reviewed, and DFS (disease-free survival) was assessed. For each parameter, the most accurate cut-off value for the prediction of recurrence was calculated using the ROC curve analysis and the Youden index. DFS was evaluated for patients above and below the calculated cut-off value using the Kaplan-Meier method and the difference in survival between the two groups was estimated using the log-rank test. RESULTS: Median observation time of the patients after surgery was 28.7 months (range 3.5-58.8 months). 9 patients developed recurrence. The calculated cut-off values for SUVmax, MTV and TLG were 6, 6.6 and 33.6, respectively. Using these cut-offs, the observed sensitivity for SUVmax, MTV and TLG for prediction of recurrence was 100%, 89% and 89%, respectively, while the observed specificity was 43%, 73% and 65%, respectively. The difference in survival between patients below and above the cut-off value was statistically significant in all three studied parameters. The highest AUC was observed for MTV (AUC = 0.825, p = 0.003), followed by TLG (AUC = 0.789, p = 0.007), and lastly SUVmax (AUC = 0.719, p = 0.041). ROC curve analysis showed that volumetric parameters had better predictive performance than SUVmax as regards recurrence. CONCLUSION: PET-derived parameters at baseline were predictive of recurrence in stage I surgical NSCLC patients. Moreover, the metabolic volume of the tumor was the most significant parameter for this purpose among the studied indices.

Quantitative analysis of 18F-NaF dynamic PET/CT cannot differentiate malignant from benign lesions in multiple myeloma.

A renewed interest has been recently developed for the highly sensitive bone-seeking radiopharmaceutical 18F-NaF. Aim of the present study is to evaluate the potential utility of quantitative analysis of 18F-NaF dynamic PET/CT data in differentiating malignant from benign degenerative lesions in multiple myeloma (MM). 80 MM patients underwent whole-body PET/CT and dynamic PET/CT scanning of the pelvis with 18F-NaF. PET/CT data evaluation was based on visual (qualitative) assessment, semi-quantitative (SUV) calculations, and absolute quantitative estimations after application of a 2-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD). In total 263 MM lesions were demonstrated on 18F-NaF PET/CT. Semi-quantitative and quantitative evaluations were performed for 25 MM lesions as well as for 25 benign, degenerative and traumatic lesions. Mean SUVaverage for MM lesions was 11.9 and mean SUVmax was 23.2. Respectively, SUVaverage and SUVmax for degenerative lesions were 13.5 and 20.2. Kinetic analysis of 18F-NaF revealed the following mean values for MM lesions: K1 = 0.248 (1/min), k3 = 0.359 (1/min), influx (Ki) = 0.107 (1/min), FD = 1.382, while the respective values for degenerative lesions were: K1 = 0.169 (1/min), k3 = 0.422 (1/min), influx (Ki) = 0.095 (1/min), FD = 1. 411. No statistically significant differences between MM and benign degenerative disease regarding SUVaverage, SUVmax, K1, k3 and influx (Ki) were demonstrated. FD was significantly higher in degenerative than in malignant lesions. The present findings show that quantitative analysis of 18F-NaF PET data cannot differentiate malignant from benign degenerative lesions in MM patients, supporting previously published results, which reflect the limited role of 18F-NaF PET/CT in the diagnostic workup of MM.