Emiel A De Jaeghere1, Frederiek Laloo2, Lien Lippens3, Mieke Van Bockstal4, Kathia De Man2, Eline Naert5, Jo Van Dorpe6, Koen Van de Vijver7, Philippe Tummers8, Amin Makar9, Pieter J L De Visschere10, Olivier De Wever11, Frédéric Amant12, Hannelore G Denys13, Katrien Vandecasteele14. 1. Medical Oncology, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium; Laboratory of Experimental Cancer Research (LECR), Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium. Electronic address: emiel.dejaeghere@ugent.be. 2. Radiology and Nuclear Medicine, Department of Diagnostic Sciences, Ghent University Hospital, Belgium. 3. Medical Oncology, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium; Laboratory of Experimental Cancer Research (LECR), Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium. 4. Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. 5. Medical Oncology, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium. 6. Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Pathology, Department of Diagnostic Sciences, Ghent University Hospital, Belgium. 7. Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium; Pathology, Department of Diagnostic Sciences, Ghent University Hospital, Belgium. 8. Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium; Gynecology, Department of Human Structure and Repair, Ghent University Hospital, Belgium. 9. Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium; Gynecology, Department of Human Structure and Repair, Ghent University Hospital, Belgium. 10. Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium; Radiology and Nuclear Medicine, Department of Diagnostic Sciences, Ghent University Hospital, Belgium. 11. Laboratory of Experimental Cancer Research (LECR), Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium. 12. Centers Gynecologic Oncology Amsterdam, Netherlands Cancer Institute and Amsterdam University Medical Center, Amsterdam, The Netherlands; Department of Oncology, KU Leuven, Leuven, Belgium. 13. Medical Oncology, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium. 14. Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Gynecological Pelvic Oncology Network (GYPON), Ghent, Belgium; Radiation Oncology, Department of Human Structure and Repair, Ghent University Hospital, Belgium.
Abstract
OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.
OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.