Functional imaging to promote individualized and targeted therapy in endometrial cancer
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Background: Endometrial carcinoma is the most common pelvic malignancy in the Western world and the incidence is increasing. Endometrial carcinomas are surgically staged according to FIGO 2009 criteria, and the lack of robust preoperative staging methods results in overtreatment of this patient population, mostly by unnecessary invasive surgery and lymphadenectomy in patients with localized disease. New imaging methods are highly warranted to aid more accurate preoperative staging and thus potentially reduce unwanted post-operative side effects, decrease the amount of unnecessary resource-demanding surgery and to provide better individualized therapy for this patient group. Aims: Promote individualized treatment, reduce morbidity and facilitate implementation of targeted therapy among endometrial carcinoma patients by investigating functional and structural imaging biomarkers in pre-operatively acquired MRI and FDG-PET/CT. Methods: All patients with histologically confirmed endometrial carcinoma at Haukeland University Hospital were consecutively referred to pre-operative MRI and/or FDG-PET/CT for a period of four years. Images were individually read by two to four radiologists and nuclear medicine physicians conducting staging and image quantifications in a standard imaging report. Results were compared to the results of surgical staging regarding the tumors depth of myometrial invasion, cervical stromal involvement and the presence of lymph node metastases, these three criteria being well-established parameters predicting aggressiveness of disease and survival in endometrial cancer. Main Results: The evaluation of the staging criteria depth of myometrial invasion, cervical stromal involvement and the presence of lymph node metastases on pre- operative 1.5T MRI are prone to considerable inter-observer variability (κ=0.4, 0.5 and 0.6, respectively), and the staging accuracy is variable with a sensitivity (specificity) of 80%, 63% and 38% respectively (53%, 94% and 100%, respectively). For image quantifications, the inter-observer agreement is good (ICC=0.56-0.98) and the measured parameters show significant correlations to established staging criteria. Tumor apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI) is significantly lower in tumors with deep myometrial invasion (ADC = 0.75 × 10-3mm2/s) compared with tumors with superficial or no myometrial invasion (ADC = 0.85 × 10-3mm2/s; p < 0.001), and the ADC value is negatively correlated to tumor size (p=0.007). Large tumor size measured on preoperative MRI is associated with reduced progression/recurrence free survival (p ≤ 0.005 for all size parameters), and CC diameter has an independent impact on survival (adjusted hazards ratio, 1.04; p = 0.009). FDG-PET/CT is excellent in ruling out lymph node metastases (NPV=97%) and SUVmax, SUVmean, MTV and TLG are significantly related to deep myometrial invasion, presence of lymph node metastases and high histological grade (p<0.015 for all). Calculated optimal cut-off values for MTV in predicting deep myometrial invasion (20 ml) and presence of lymph node metastases (30 ml), yield ORs of 7.8 (p<0.001) and 16.5 (p=0.001), respectively, outperforming the current pre-operative ground for decision-making based on pathology findings in endometrial biopsies. Conclusion: Functional and structural imaging biomarkers from MRI and FDG- PET/CT are promising for preoperative identification of high-risk patients in endometrial carcinoma.
Has partsPaper I: Haldorsen IS, Husby J, Werner H, Magnussen IJ, Rørvik J, Helland H, Trovik J, Salvesen ØO, Espeland A, Salvesen HB: Standard 1.5-T MRI of endometrial carcinomas: modest agreement between radiologists. European Radiology 2012, 22:1601-1611. This article is not available in BORA. The published version is available at: 10.1007/s00330-012-2400-y
Paper II: Husby JA, Salvesen ØO, Magnussen IJ, Trovik J, Bjørge L, Salvesen HB, Haldorsen IS: Tumour apparent diffusion coefficient is associated with depth of myometrial invasion and is negatively correlated to tumour volume in endometrial carcinomas. Clinical Radiology 2015, 70(5):487-94. This article is not available in BORA. The published version is available at: 10.1016/j.crad.2014.12.016
Paper III: Ytre-Hauge S, Husby JA, Magnussen IJ, Werner HM, Salvesen ØO, Bjørge L, Trovik J, Stefansson IM, Salvesen HB, Haldorsen IS: Preoperative tumor size at MRI predicts deep myometrial invasion, lymph node metastases, and patient outcome in endometrial carcinomas. International Journal of Gynecologic Cancer 2015, 25(3):459-66. The article is available in BORA at: http://hdl.handle.net/1956/10957
Paper IV: Husby JA, Reitan BC, Biermann M, Trovik J, Bjørge L, Magnussen IJ, Salvesen ØO, Salvesen HB, Haldorsen IS: Metabolic Tumor Volume on 18F- FDG PET/CT Improves Preoperative Identification of High-Risk Endometrial Carcinoma Patients. Journal of Nuclear Medicine 2015, 56(8):1191-8. This article is not available in BORA. The published version is available at: 10.2967/jnumed.115.159913