Ultra-early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer

Abstract

Background: The authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed.

Methods: Sixty-two cervical cancer patients underwent dynamic contrast-enhanced (DCE) MRI before and during early radiation/chemotherapy (2-2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE-MRI and 3-dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow-up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis.

Results: SI(10%) and 3D volume 2-2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0-6.5 [P = .04] and HR, 1.9; 95% CI, 1.1-3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0-3.5 [P = .03] and HR, 1.9; 95% CI, 1.2-2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death.

Conclusions: MRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy.

Figure 1

A. High DCE at 2.5 weeks of chemo/radiation therapy In this 52-year old woman with stage IIB squamous cell carcinoma of the cervix, MRI was obtained 2.5 weeks after RT start at a dose of 21.6 Gy in 12 fractions and 2 cycles of weekly Cisplatin chemotherapy. The volumetric MRI shows the cervical tumor region (arrows). The DCE MRI shows intense heterogeneous enhancement (arrows). The voxel histogram distribution of DCE demonstrates high and heterogeneous SI of the tumor and a high SI(10%) of 3.13. The patient is alive and well without primary tumor recurrence or metastasis 5 years and 2 months after therapy completion. B. Low DCE at 2.5 weeks of chemo/radiation therapy In this 42-year old woman with stage IIB adenocarcinoma of the cervix, MRI was obtained 2.5 weeks after RT start at a dose of 21.6 Gy in 12 fractions and 2 cycles of weekly Cisplatin chemotherapy. The volumetric MRI shows the cervical tumor region (arrows). The DCE MRI shows very low and heterogeneous enhancement (arrows). Voxel histogram distribution of DCE demonstrates overall much lower SI than in the patient in A. The SI(10%) is 1.70. This patient had primary tumor recurrence 1 month after therapy completion. Pelvic exenteration was attempted but the tumor was unresectable. She died of cervical cancer 12 months later.

Figure 2. ROC analysis of signal intensity percentiles

Receiver Operator Characteristic (ROC) analysis to determine the best signal intensity percentile (SI(%)) for the discrimination of recurrence (solid blue curve) and cancer death (dashed red curve). Area under the curve values of SI(2.5%) to SI(30%) are above 0.70, supporting the usefulness of the SI parameter across a range of percentiles associated with low DCE and indicative of poor perfusion and hypoxia. Consistent with the results of the exploratory study, SI(10%) shows the best discriminating capacity.