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Spatially fractionated radiation therapy (SFRT) has shown promise in generating high tumor response and local control in the treatment of various palliative and locally advanced bulky tumors. SFRT has not yet been studied systematically in cancer of the cervix. Here we report the first series of patients receiving SFRT for advanced/bulky cervical cancer. Ten patients with far-advanced bulky cervical cancer, stage IIIB-IVA (seven squamous cell and three adeno/adenosquamous carcinomas) received lattice radiation therapy (LRT), a variant of SFRT. The LRT regimen consisted of a dose of 24 Gy in three fractions, given to an average of five high-dose spheres within the gross tumor volume (GTV). The dose in the peripheral GTV was limited to 9 Gy in three fractions, using the volumetric modulated arc therapy (VMAT) technique. LRT was followed subsequently by conventionally fractionated external beam irradiation to 44.28 Gy (range: 39.60-45.00 Gy in 1.8 Gy fractions). All patients received concurrent cisplatin chemotherapy. Tumor response was assessed clinically, by morphological imaging (CT, MRI) and 18FDG PET/CT. Tumor control and survival rates were estimated using Kaplan-Meier analysis. All patients had local control at a median follow-up of 16 months (1-77). The two-year disease-specific survival rate was 53.3%. All cancer deaths were due to metastatic failure with local control maintained. Among the three patients who died of disease, all had adeno- or adenosquamous carcinoma histology, and no deaths from disease occurred among the patients with squamous cell carcinoma (P = 0.010). There were no grade ≥3 short-term or long-term treatment-related complications. Intra-treatment morphological tumor regression was highly variable (mean: 54%, range: 6-91%). After therapy, the complete metabolic response was 88.9% (8/9), and one patient out of the nine patients with post-treatment PET-CT had partial response (11.1%). Our preliminary data suggest that LRT-based SFRT is well tolerated in patients with far-advanced bulky cervical cancer and results in favorable tumor responses and high local control. These observations confirm prior reports of favorable tumor control and toxicity outcomes with SFRT in other advanced/bulky malignancies. Our findings are corroborated by high molecular-imaging-based tumor response. These encouraging hypothesis-generating results require cautious interpretation and confirmation with larger patient cohorts, preferably through a multi-institutional controlled randomized clinical trial., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: Robust approaches to quantify tumor heterogeneity are needed to provide early decision support for precise individualized therapy., Purpose: To conduct a technical exploration of longitudinal changes in tumor heterogeneity patterns on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and FDG positron emission tomography / computed tomography (PET/CT), and their association to radiation therapy (RT) response in cervical cancer., Study Type: Prospective observational study with longitudinal MRI and PET/CT pre-RT, early-RT (2 weeks), and mid-RT (5 weeks)., Population: Twenty-one FIGO IB 2 -IVA cervical cancer patients receiving definitive external beam RT and brachytherapy., Field Strength/sequence: 1.5T, precontrast axial T 1 -weighted, axial and sagittal T 2 -weighted, sagittal DWI (multi-b values), sagittal DCE MRI (<10 sec temporal resolution), postcontrast axial T 1 -weighted., Assessment: Response assessment 1 month after completion of treatment by a board-certified radiation oncologist from manually delineated tumor volume changes., Statistical Tests: Intensity histogram (IH) quantiles (DCE SI 10% and DWI ADC 10% , FDG-PET SUV max ) and distribution moments (mean, variance, skewness, kurtosis) were extracted. Differences in IH features between timepoints and modalities were evaluated by Skillings-Mack tests with Holm's correction. Area under receiver-operating characteristic curve (AUC) and Mann-Whitney testing was performed to discriminate treatment response using IH features., Results: Tumor IH means and quantiles varied significantly during RT (SUV mean : ↓28-47%, SUV max : ↓30-59%, SI mean : ↑8-30%, SI 10% : ↑8-19%, ADC mean : ↑16%, P < 0.02 for each). Among IH heterogeneity features, FDG-PET SUV CoV (↓16-30%, P = 0.011) and DW-MRI ADC skewness decreased (P = 0.001). FDG-PET SUV CoV was higher than DCE-MRI SI CoV and DW-MRI ADC CoV at baseline (P < 0.001) and 2 weeks (P = 0.010). FDG-PET SUV kurtosis was lower than DCE-MRI SI kurtosis and DW-MRI ADC kurtosis at baseline (P = 0.001). Some IH features appeared to associate with favorable tumor response, including large early RT changes in DW-MRI ADC skewness (AUC = 0.86)., Data Conclusion: Preliminary findings show tumor heterogeneity was variable between patients, modalities, and timepoints. Radiomic assessment of changing tumor heterogeneity has the potential to personalize treatment and power outcome prediction., Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1388-1396., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: To classify tumor imaging voxels at-risk for treatment failure within the heterogeneous cervical cancer using DCE MRI and determine optimal voxel's DCE threshold values at different treatment time points for early prediction of treatment failure., Material and Method: DCE-MRI from 102 patients with stage IB2-IVB cervical cancer was obtained at 3 different treatment time points: before (MRI 1) and during treatment (MRI 2 at 2-2.5 weeks and MRI 3 at 4-5 weeks). For each tumor voxel, the plateau signal intensity (SI) was derived from its time-SI curve from the DCE MRI. The optimal SI thresholds to classify the at-risk tumor voxels was determined by the maximal area under the curve using ROC analysis when varies SI value from 1.0 to 3.0 and correlates with treatment outcome., Results: The optimal SI thresholds for MRI 1, 2 and 3 were 2.2, 2.2 and 2.1 for significant differentiation between local recurrence/control, respectively, and 1.8, 2.1 and 2.2 for death/survival, respectively., Conclusion: Optimal SI thresholds are clinically validated to quantify at-risk tumor voxels which vary with time. A single universal threshold (SI=1.9) was identified for all 3 treatment time points and remained significant for the early prediction of treatment failure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3-Tesla (3-T) magnetic resonance (MR) image-based cervical-cancer brachytherapy., Methods and Materials: Twenty-three experts in gynecologic radiation oncology contoured the same 3 cervical cancer brachytherapy cases: 1 stage IIB near-complete response (CR) case with a tandem and ovoid, 1 stage IIB partial response (PR) case with tandem and ovoid with needles, and 1 stage IB2 CR case with a tandem and ring applicator. The CT contours were completed before the MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with κ statistics as a measure of agreement between participants. The conformity index was calculated for each of the 6 data sets. Dice coefficients were generated to compare the CT and MR contours of the same case., Results: For all 3 cases, the mean tumor volume was smaller on MR than on CT (P<.001). The κ and conformity index estimates were slightly higher for CT, indicating a higher level of agreement on CT. The Dice coefficients were 89% for the stage IB2 case with a CR, 74% for the stage IIB case with a PR, and 57% for the stage IIB case with a CR., Conclusion: In a comparison of MR-contoured with CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast medium visible on the images at the time of brachytherapy. MR at the time of brachytherapy may be of greatest benefit in patients with large tumors with parametrial extension that have a partial or complete response to external beam. On the basis of these results, a 95% consensus volume was generated for CT and for MR. Online contouring atlases are available for instruction at http://www.nrgoncology.org/Resources/ContouringAtlases/GYNCervicalBrachytherapy.aspx., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Accelerated tumor repopulation has significant implications in low-dose rate (LDR) brachytherapy. Repopulation onset time remains undetermined for cervical cancer. The purpose of this study was to determine the onset time of accelerated repopulation in cervical cancer, using clinical data., Methods and Materials: The linear quadratic (LQ) model extended for tumor repopulation was used to analyze clinical data and magnetic resonance imaging-based three-dimensional tumor volumetric regression data from 80 cervical cancer patients who received external beam radiotherapy (EBRT) and LDR brachytherapy. The LDR dose was converted to EBRT dose in 1.8-Gy fractions by using the LQ formula, and the total dose ranged from 61.4 to 99.7 Gy. Patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least χ(2) method was used to fit the TCP data with two free parameters: onset time (T(k)) of accelerated repopulation and number of clonogens (K), while other LQ model parameters were adopted from the literature, due to the limited patient data., Results: Among the 11 patient groups, TCP varied from 33% to 100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment duration were associated with higher TCP. Using the LQ model, we achieved the best fit with onset time T(k) of 19 days and K of 139, with uncertainty ranges of (11, 22) days for T(k) and (48, 1822) for K, respectively., Conclusion: This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from clinical data by using the LQ model. Our study verifies the fact that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted., (Published by Elsevier Inc.)

Objectives: The definitive treatment of early-stage cervical cancer involves multidisciplinary decision making. This expert panel was convened to reach consensus on the selection of appropriate therapies based on patient and disease characteristics at presentation., Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or the treatment., Results: Three clinical variants were developed to represent common scenarios in the treatment of early-stage cervical cancer. Group members reached consensus on the appropriateness of therapeutic options. This process yielded numerical ratings and descriptive commentary., Conclusions: This manuscript represents the consensus opinion of an expert panel based on a survey of all available medical literature. This manuscript may be used to inform the clinical decision making of physicians involved in the treatment of early-stage cervical cancer.

Purpose: Treatment response in cancer has been monitored by measuring anatomic tumor volume (ATV) at various times without considering the inherent functional tumor heterogeneity known to critically influence ultimate treatment outcome: primary tumor control and survival. This study applied dynamic contrast-enhanced (DCE) functional MRI to characterize tumors' heterogeneous subregions with low DCE values, at risk for treatment failure, and to quantify the functional risk volume (FRV) for personalized early prediction of treatment outcome., Methods and Materials: DCE-MRI was performed in 102 stage IB(2)-IVA cervical cancer patients to assess tumor perfusion heterogeneity before and during radiation/chemotherapy. FRV represents the total volume of tumor voxels with critically low DCE signal intensity (<2.1 compared with precontrast image, determined by previous receiver operator characteristic analysis). FRVs were correlated with treatment outcome (follow-up: 0.2-9.4, mean 6.8 years) and compared with ATVs (Mann-Whitney, Kaplan-Meier, and multivariate analyses)., Results: Before and during therapy at 2-2.5 and 4-5 weeks of RT, FRVs >20, >13, and >5 cm(3), respectively, significantly predicted unfavorable 6-year primary tumor control (p = 0.003, 7.3 × 10(-8), 2.0 × 10(-8)) and disease-specific survival (p = 1.9 × 10(-4), 2.1 × 10(-6), 2.5 × 10(-7), respectively). The FRVs were superior to the ATVs as early predictors of outcome, and the differentiating power of FRVs increased during treatment., Discussion: Our preliminary results suggest that functional tumor heterogeneity can be characterized by DCE-MRI to quantify FRV for predicting ultimate long-term treatment outcome. FRV is a novel functional imaging heterogeneity parameter, superior to ATV, and can be clinically translated for personalized early outcome prediction before or as early as 2-5 weeks into treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The use of adjuvant treatment(s) following initial hysterectomy and retroperitoneal nodal harvesting of patients with clinical stage I and II cervical carcinoma is (are) presently based on the pathological assessment of surgical specimens. This report sought to delineate further the clinical application of potential therapeutic interventions and associated follow-up investigations of this patient cohort., Methods: The American College of Radiology (ACR) Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journal and the application of a well-established consensus methodology (modified Delphi) to rate appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment., Results: From this process, 5 unique clinical variants were developed. These scenarios pertained to options of adjuvant radiation therapy and chemotherapy, methods of delivery of radiotherapy to optimize target volume coverage while simultaneously minimizing radiation exposure of adjacent healthy organs, and recommendations for patient follow-up care. Group members reached consensus of topic ratings in descending order of importance. A risk assessment breakdown was established to highlight the most likely indications for adjuvant treatment(s)., Conclusion: This assembly by the ACR of physicians involved in the management of patients with early stage cervical cancer was able to describe appropriateness criteria to aid other practitioners in selecting reasonable implementation of postoperative therapies and subsequent surveillance studies. These guidelines await further validation and refinement by both current and future prospectively randomized clinical studies regarding this patient population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aim: To test and evaluate direct sagittal-plane tumor delineation for MRI-based image-guided brachytherapy (IGBT) planning for patients with cervical cancer., Materials and Methods: An image registration method based on the sagittal source MR images was developed and employed in ten patients with an indwelling ring/tandem applicator. The gross tumor volume (GTV) was delineated separately on the sagittal (GTV-S) and axial images (GTV-A). GTV conformity indices and dose-volume histogram analyses were compared among GTV-S and GTV-A (paired t-test)., Results: Image quality and delineation in the sagittal images was graded superior to the axial images. The ratio of common volume of the axial and sagittal volumes to that of the axial volume was 0.77 +/- (standard deviation) 0.2. The GTV-S mean volume (19.6 +/- 13.8 mL) was significantly larger than the GTV-A mean volume (10.3 +/- 7.3 mL, p=0.003). The GTV-S mean D99 (5.2 +/- 2.5 Gy) was significantly lower than the GTV-A mean D99 (6.9 +/- 2.7 Gy, p=0.013). The GTV-S mean D90 (6.8 +/- 2.8 Gy) was significantly lower than the GTV-A mean D90 (8.5 +/- 3.1 Gy, p=0.016)., Conclusions: Registration of the sagittal source MRI and contouring the GTV directly on the sagittal images is feasible and practical for IGBT. Consistently larger sagittal GTVs may be explained by the better visualization and more continuous tumor topology in the sagittal plane, compared to the discrete oblique sectioning of the uterus/tumor and partial volume loss in the axial plane.

Background: The objectives of this study were to investigate outcome prediction by measuring absolute tumor volume and regression ratios using serial magnetic resonance imaging (MRI) during radiation therapy (RT) for cervical cancer and to develop algorithms capable of identifying patients at risk of a poor therapeutic outcome., Methods: Eighty patients with stage IB2 through IVA cervical cancer underwent 4 MRI scans: before RT (MRI1), during RT at 2 to 2.5 weeks (MRI2) at 4 to 5 weeks (MRI3), and 1 to 2 months after RT (MRI4). The median follow-up was 6.2 years (range, 0.2-9.4 years). Tumor volumes at MRI1, MRI2, MRI3, and MRI4 (V1, V2, V3, and V4, respectively) and tumor regression ratios (V2/V1, V3/V1, and V4/V1) were measured by 3-dimensional volumetry. Predictive metrics based on tumor volume/regression parameters were correlated with ultimate clinical outcomes, including tumor local recurrence (LR) and dying of disease (DOD). Predictive power was evaluated using the Mann-Whitney test, sensitivity/specificity analyses, and Kaplan-Meier analyses., Results: Both tumor volume and regression ratio were strongly correlated with LR (P=.06, P = 5×10(-4), P=1×10(-6), and P=2×10(-8) for V1, V2, V3, and V4, respectively; and P=7×10(-5), P=1×10(-6), and P=1×10(-8) for V2/V1, V3/V1, and V4/V1, respectively) and DOD (P=.015, P=.004, P=.001, and P=3×10(-4) for V1, V2, V3, and V4, respectively; and P=.03, P=.009, and P=3×10(-4) for V2/V1, V3/V1, and V4/V1, respectively). Algorithms that combined tumor volumes and regression ratios improved predictive power (sensitivity, 61%-89%; specificity, 79%-100%). The strongest predictor, pre-RT volume and regression ratio at MRI3 (V1>40 cm3 and V3/V1>20%, respectively), achieved 89% sensitivity, 87% specificity, and 88% accuracy for LR and achieved 54% sensitivity, 83% specificity, and 73% accuracy for DOD., Conclusions: The current results suggested that tumor volume/regression parameters obtained during primary therapy are useful in predicting LR and DOD. Both tumor volume and regression ratio provided important information as early outcome predictors that may guide early intervention for patients with cervical cancer who are at high risk of treatment failure., (Copyright © 2010 American Cancer Society.)

Purpose: To study the temporal changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns during the radiation therapy (RT) course and their influence on local control and survival in cervical cancer., Methods and Materials: DCE-MRI was performed in 98 patients with Stage IB(2)-IVA cervical cancer before RT (pre-RT) and during early RT (20-25 Gy) and mid-RT (45-50 Gy). Signal intensity (SI) from the DCE-MRI time-SI curve was derived for each tumor voxel. The poorly perfused low-DCE tumor subregions were quantified as lower 10th percentiles of SI (SI10). Local control, disease-specific survival, and overall survival were correlated with DCE parameters at pre-RT, early RT, and mid-RT. Median follow-up was 4.9 (range, 0.2-9.0) years., Results: Patients (16/98) with initial pre-RT high DCE (SI10 >or=2.1) had 100% 5-year local control, 81% disease-specific survival, and 81% overall survival, compared with only 79%, 61%, and 55%, respectively, in patients with pre-RT low DCE. Conversion from pre-RT low DCE to high DCE in early RT (28/82 patients) was associated with higher local control, disease-specific survival, and overall survival (93%, 74%, and 67%, respectively). In comparison with all other groups, outcome was worst in patients with persistently low DCE from pre-RT throughout the mid-RT phase (66%, 44%, and 43%; p = 0.003, 0.003, and 0.020; respectively)., Conclusion: Longitudinal tumor perfusion changes during RT correlate with treatment outcome. Persistently low perfusion in pre-RT, early RT, and mid-RT indicates a high risk of treatment failure, whereas outcome is favorable in patients with initially high perfusion or subsequent improvements of initially low perfusion. These findings likely reflect reoxygenation and may have potential for noninvasive monitoring of intra-treatment radio-responsiveness and for guiding adaptive therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

In this paper, we present a method of quantifying the heterogeneity of cervical cancer tumors for use in radiation treatment outcome prediction. Features based on the distribution of masked wavelet decomposition coefficients in the tumor region of interest (ROI) of temporal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were used along with the imaged tumor volume to assess the response of the tumors to treatment. The wavelet decomposition combined with ROI masking was used to extract local intensity variations in the tumor. The developed method was tested on a data set consisting of 23 patients with advanced cervical cancer who underwent radiation therapy; 18 of these patients had local control of the tumor, and five had local recurrence. Each patient participated in two DCE-MRI studies: one prior to treatment and another early into treatment (2-4 weeks). An outcome of local control or local recurrence of the tumor was assigned to each patient based on a posttherapy follow-up at least 2 years after the end of treatment. Three different supervised classifiers were trained on combinational subsets of the full wavelet and volume feature set. The best-performing linear discriminant analysis (LDA) and support vector machine (SVM) classifiers each had mean prediction accuracies of 95.7%, with the LDA classifier being more sensitive (100% vs. 80%) and the SVM classifier being more specific (100% vs. 94.4%) in those cases. The K-nearest neighbor classifier performed the best out of all three classifiers, having multiple feature sets that were used to achieve 100% prediction accuracy. The use of distribution measures of the masked wavelet coefficients as features resulted in much better predictive performance than those of previous approaches based on tumor intensity values and their distributions or tumor volume alone.

Purpose: To assess individual volumetric tumor regression pattern in cervical cancer during therapy using serial four-dimensional MRI and to define the regression parameters' prognostic value validated with local control and survival correlation., Methods and Materials: One hundred and fifteen patients with Stage IB(2)-IVA cervical cancer treated with radiation therapy (RT) underwent serial MRI before (MRI 1) and during RT, at 2-2.5 weeks (MRI 2, at 20-25 Gy), and at 4-5 weeks (MRI 3, at 40-50 Gy). Eighty patients had a fourth MRI 1-2 months post-RT. Mean follow-up was 5.3 years. Tumor volume was measured by MRI-based three-dimensional volumetry, and plotted as dose(time)/volume regression curves. Volume regression parameters were correlated with local control, disease-specific, and overall survival., Results: Residual tumor volume, slope, and area under the regression curve correlated significantly with local control and survival. Residual volumes >or=20% at 40-50 Gy were independently associated with inferior 5-year local control (53% vs. 97%, p <0.001) and disease-specific survival rates (50% vs. 72%, p = 0.009) than smaller volumes. Patients with post-RT residual volumes >or=10% had 0% local control and 17% disease-specific survival, compared with 91% and 72% for <10% volume (p <0.001)., Conclusion: Using more accurate four-dimensional volumetric regression analysis, tumor response can now be directly translated into individual patients' outcome for clinical application. Our results define two temporal thresholds critically influencing local control and survival. In patients with >or=20% residual volume at 40-50 Gy and >or=10% post-RT, the risk for local failure and death are so high that aggressive intervention may be warranted., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

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.

Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S(2) < 0.70 vs. S(2) > or = 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T(1/2) < 22 days versus T(1/2) > or = 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S(2) < 0.70 versus S(2) > or = 0.70 (P = 0.025), and 87% vs. 52% with T(1/2) < 22 days versus T(1/2) > or = 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy.

Purpose: The tumor oxygenation status is likely influenced by two major factors: local tumor blood supply (tumor perfusion) and its systemic oxygen carrier, hemoglobin (Hgb). Each has been independently shown to affect the radiotherapy (RT) outcome in cervical cancer. This study assessed the effect of local tumor perfusion, systemic Hgb levels, and their combination on the treatment outcome in cervical cancer., Methods and Materials: A total of 88 patients with cervical cancer, Stage IB2-IVA, who were treated with RT/chemotherapy, underwent serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before RT, at 20-22 Gy, and at 45-50 Gy. The DCE-MRI perfusion parameters, mean and lowest 10th percentile of the signal intensity distribution in the tumor pixels, and the Hgb levels, including pre-RT, nadir, and mean Hgb (average of weekly Hgb during RT), were correlated with local control and disease-specific survival. The median follow-up was 4.6 years., Results: Local recurrence predominated in the group with both a low mean Hgb (<11.2 g/dL) and low perfusion (lowest 10th percentile of signal intensity <2.0 at 20-22 Gy), with a 5-year local control rate of 60% vs. 90% for all other groups (p = .001) and a disease-specific survival rate of 41% vs. 72% (p = .008), respectively. In the group with both high mean Hgb and high perfusion, the 5-year local control rate and disease-specific survival rate was 100% and 78%, respectively., Conclusion: These results suggest that the compounded effects of Hgb level and tumor perfusion during RT influence the radioresponsiveness and survival in cervical cancer patients. The outcome was worst when both were impaired. The management of Hgb may be particularly important in patients with low tumor perfusion.

Purpose: To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival., Materials and Methods: Three MRI examinations were obtained in 101 patients before and during therapy (at 2-2.5 and 4-5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3-dimensional volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t test, Kaplan-Meier analysis, and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 0.2-9.4 years)., Results: Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2 to 2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of > or =30 cm(3) in the MRI obtained at 2 to 2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, P = 0.006) and disease-free-survival rate (47% vs. 79%, P = 0.001), respectively., Conclusions: Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2 to 2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation, and the bulk of residual presumably therapy-resistant tumor, requires future study.

Objective: The purpose of this study was to evaluate the patterns and distribution of tumor shape and its temporal change during radiation therapy (RT) in cervical cancer and the effect of tumor configuration changes on the correlation between region of interest (ROI)-based and diameter-based MRI tumor measurement., Materials and Methods: Serial MRI examinations (T1-weighted and T2-weighted images) were performed in 60 patients (age range, 29-75 years; mean, 53.3 years) with advanced cervical cancer (stages IB2-IVB/recurrent) who were treated with RT at four time points: start of RT, during RT (at 2-2.5 and at 4-5 weeks of RT), and post-RT. Tumor configuration was classified qualitatively into oval, lobulated, and complex based on MR film review. Two methods of tumor volume measurement were compared: ellipsoid computation of three orthogonal diameters (diameter based) and ROI volumetry by delineating the entire tumor volume on the MR workstation (ROI based). Temporal changes of tumor shape and the respective tumor volumes measured by the two methods were analyzed using linear regression analysis., Results: Most tumors (70%) had a non-oval (lobulated and complex) shape before RT and became increasingly irregular during and after RT: 84% at 2-2.5 weeks of RT (p = 0.037), 86% (p = 0.025) at 4-5 weeks, and 96% post-RT (p = 0.010), compared with 70% pre-RT. Diameter-based and ROI-based measurement correlated well before RT (r = 0.89) but not during RT (r = 0.68 at 2-2.5 weeks, r = 0.67 at 4-5 weeks of RT)., Conclusion: Most cervical cancers are not oval in shape pretherapy, and they become increasingly irregular during and after therapy because of nonconcentric tumor shrinkage. ROI-based volumetry, which can optimally measure irregular volumes, may provide better response assessment during treatment than diameter-based measurement.

Radiation therapy for cervical cancer involves a team of specialists, including diagnostic radiologists (DRs), radiation oncologists (ROs), and medical physicists (MPs), to optimize imaging-based radiation therapy planning. The purpose of the study was to investigate the interobserver variations in tumor delineation on MR images of cervical cancer within the same and among different specialties. Twenty MRI cervical cancer studies were independently reviewed by two DRs, two ROs, and two MPs. For every study, each specialist contoured the tumor regions of interest (ROIs) on T2-weighted Turbo Spin Echo sagittal images on all slices containing tumor, and the total tumor volume was computed for statistical analysis. Analysis of variance (ANOVA) was used to compare the differences in tumor volume delineation among the observers. A graph of all tumor-delineated volumes was generated, and differences between the maximum and minimum volumes over all the readers for each patient dataset were computed. Challenges during the evaluation process for tumor delineation were recorded for each specialist. Interobserver variations of delineated tumor volumes were significant (p < 0.01) among all observers based on a repeated measures ANOVA, which produced an F(5,95) = 3.55. The median difference between the maximum delineated volume and minimum delineated volume was 33.5 cm3 (which can be approximated by a sphere of 4.0 cm diameter) across all 20 patients. Challenges noted for tumor delineation included the following: (1) partial voluming by parametrial fat at the periphery of the uterus; (2) extension of the tumor into parametrial space; (3) similar signal intensity of structures proximal to the tumor such as ovaries, muscles, bladder wall, bowel loops, and pubic symphysis; (4) postradiation changes such as heterogeneity and necrosis; (5) susceptibility artifacts from bowels and vaginal tampons; (6) presence of other pathologies such as atypical myoma; (7) factors that affect pelvic anatomy, including the degree of bladder distension, bowel interposition, uterine malposition, retroversion, and descensus. Our limited study indicates significant interobserver variation in tumor delineation. Despite rapid progress in technology, which has improved the resolution and precision of image acquisition and the delivery of radiotherapy to the millimeter level, such "human" variations (at the centimeter level) may overshadow the gain from technical advancement and impact treatment planning. Strategies of standardization and training in tumor delineation need to be developed.

Purpose: Recently, imaging-based tumor volume before, during, and after radiation therapy (RT) has been shown to predict tumor response in cervical cancer. However, the effectiveness of different methods and timing of imaging-based tumor size assessment have not been investigated. The purpose of this study was to compare the predictive value for treatment outcome derived from simple diameter-based ellipsoid tumor volume measurement using orthogonal diameters (with ellipsoid computation) with that derived from more complex contour tracing/region-of-interest (ROI) analysis 3D tumor volumetry., Methods and Materials: Serial magnetic resonance imaging (MRI) examinations were prospectively performed in 60 patients with advanced cervical cancer (Stages IB2-IVB/recurrent) at the start of RT, during early RT (20-25 Gy), mid-RT (45-50 Gy), and at follow-up (1-2 months after RT completion). ROI-based volumetry was derived by tracing the entire tumor region in each MR slice on the computer work station. For the diameter-based surrogate "ellipsoid volume," the three orthogonal diameters (d1, d2, d3) were measured on film hard copies to calculate volume as an ellipsoid (d1 x d2 x d3 x pi/6). Serial tumor volumes and regression rates determined by each method were correlated with local control, disease-free and overall survival, and the results were compared between the two measuring methods. Median post-therapy follow-up was 4.9 years (range, 2.0-8.2 years)., Results: The best method and time point of tumor size measurement for the prediction of outcome was the tumor regression rate in the mid-therapy MRI examination (at 45-50 Gy) using 3D ROI volumetry. For the pre-RT measurement both the diameter-based method and ROI volumetry provided similar predictive accuracy, particularly for patients with small (<40 cm3) and large (> or =100 cm3) pre-RT tumor size. However, the pre-RT tumor size measured by either method had much less predictive value for the intermediate-size (40-99 cm3) tumors, which accounted for the majority of patients (55%). Tumor regression rate (fast vs. slow) obtained during mid-RT (45-50 Gy), which could only be appreciated by 3D ROI volumetry, had the best outcome prediction rate for local control (84% vs. 22%, p < 0.0001) and disease-free survival (63% vs. 20%, p = 0.0005). Within the difficult to classify intermediate pre-RT size group, slow ROI-based regression rate predicted all treatment failures (local control rate: 0% vs. 91%, p < 0.0001; disease-free survival: 0% vs. 73%, p < 0.0001). Mid-RT regression rate based on simple diameter measurement did not predict outcome. The early-RT and post-RT measurements were least useful with either measuring method., Conclusion: Our preliminary data suggest that for the prediction of treatment outcome in cervical cancer, initial tumor volume can be estimated by simple diameter-based measurement obtained from film hard copies. When initial tumor volume is in the intermediate size range, ROI volumetry and an additional MRI during RT are needed to quantitatively analyze tumor regression rate for the prediction of treatment outcome.

Purpose: To evaluate temporal changes in signal intensity (SI) and degree of contrast enhancement (CE) of bone marrow in lumbosacral vertebrae inside and outside the radiation therapy (RT) field., Materials and Methods: Twenty-three patients with advanced uterine cervical cancer who were treated with RT were prospectively evaluated. Each patient underwent four dynamic magnetic resonance (MR) studies: before RT, 2 and 4 weeks after initiation of RT, and 4 weeks after completion of RT. SI and CE were calculated in all four studies of each patient., Results: Bone marrow inside the RT field showed steady and marked increase in precontrast SI and early and transient increase in CE at 2 weeks after initiation of RT followed by progressive and marked decrease in CE at 4 weeks after initiation of RT and 4 weeks after completion of RT. Bone marrow outside the RT field showed slight increase in precontrast SI and steady and moderate decrease in CE to a lesser degree without early increase as seen in bone marrow inside the RT field., Conclusion: RT causes an increase in precontrast SI predominantly in bone marrow inside the RT field. However, a decrease in CE is seen in bone marrow not only inside but also outside the RT field.