Abstract
Simple SummaryThe fractal dimension (FD) and the multifractal spectrum (MFS) are nonlinear quantitative measures which express the heterogeneity in the distribution of the tracer, F-18-fluorodeoxyglucose, (18F-FDG), in the body of patients suffering from metastatic melanoma. Given the well-documented, high accumulation of the tracer in tumor/metastatic sites, the measures expressing the tracer distribution also express the extent of metastases in the body. As such, FD and MFS can be employed to detect the presence of melanoma and to monitor the therapeutic outcome using the PET-CT follow-up digitized scans of the patients. In the present study, the FD and MFS measures of patients are evaluated before and during treatment with PD-1 inhibitors and are compared with the corresponding values of healthy controls. The MFS predictions agree with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while the FD agrees in 77% of all cases. Therefore, the quantitative MFS is proposed as an additional, alternative biomarker for monitoring the immunotherapy outcome in melanoma patients, after treatment with PD-1 inhibitors.Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients’ clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered.
Highlights
Recent advances in immunotherapy have revolutionized cancer therapy and offer the possibility to activate the immune system against cancer cells
immune checkpoint inhibitors (ICI) treatment started with the use of the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor ipilimumab, an antibody with response rates between 10% and 15% and long-term survival of approximately 20% [3,4]
In a previous analysis of our group, we studied a cohort of 31 patients suffering from metastatic melanoma under treatment with ipilimumab monotherapy [17]
Summary
Recent advances in immunotherapy have revolutionized cancer therapy and offer the possibility to activate the immune system against cancer cells. The use of immune checkpoint inhibitors (ICI) showed a dramatic improvement in the management of patients with metastatic melanoma leading in higher response rates and a prolongation of patient survival [1,2]. ICI treatment started with the use of the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor ipilimumab, an antibody with response rates between 10% and 15% and long-term survival of approximately 20% [3,4]. In 2014, two programmed cell death protein (PD-1) inhibitors, pembrolizumab and nivolumab, were approved by the Food and Drug Administration and were used as a monotherapy or in combination with ipilimumab. Larkin et al reported on a median overall survival of more than 60.0 months for the combined use of nivolumab plus ipilimumab as compared with. Survival at 5 years was 52% for the combination of nivolumab and ipilimumab, 44% for nivolumab and 26% for ipilimumab [5]
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