Joseph F. Montebello

Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer

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 ≥30 cm3 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.

Longitudinal Changes in Tumor Perfusion Pattern during the Radiation Therapy Course and its Clinical Impact in Cervical Cancer

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.

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

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.

Serial therapy-induced changes in tumor shape in cervical cancer and their impact on assessing tumor volume and treatment response

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.

Skin cancer in patients with chronic radiation dermatitis

The cases of 76 patients with chronic radiation dermatitis resulting from low-dose ionizing radiation for benign disease were reviewed retrospectively for risk factors leading to the development of neoplasia. The patients were studied with respect to original hair color, eye color, sun reactive skin type, benign disease treated, area treated, age at treatment, and age at development of first skin cancer. Analysis of data showed 37% of patients had sun-reactive skin type I, 27% had type II, and 36% had type III. Types IV through VI were not represented. There appeared to be an overrepresentation of types I and II. Increased melanin pigmentation may therefore be either directly or indirectly protective against the development of skin cancers in patients who have received low-dose superficial ionizing radiation for benign disease. The sun-reactive skin type of patients with chronic radiation dermatitis may be used as a predictor of skin cancer risk when the total dose of ionizing radiation is not known.

Predicting outcomes in cervical cancer: a kinetic model of tumor regression during radiation therapy.

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.

Sequential magnetic resonance imaging of cervical cancer

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.

Synergistic Effects of Hemoglobin and Tumor Perfusion on Tumor Control and Survival in Cervical Cancer

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.

Effect of edema, relative biological effectiveness, and dose heterogeneity on prostate brachytherapy

Many factors influence response in low-dose-rate (LDR) brachytherapy of prostate cancer. Among them, edema, relative biological effectiveness (RBE), and dose heterogeneity have not been fully modeled previously. In this work, the generalized linear-quadratic (LQ) model, extended to account for the effects of edema, RBE, and dose heterogeneity, was used to assess these factors and their combination effect. Published clinical data have shown that prostate edema after seed implant has a magnitude (ratio of post- to preimplant volume) of 1.3-2.0 and resolves exponentially with a half-life of 4-25 days over the duration of the implant dose delivery. Based on these parameters and a representative dose-volume histogram (DVH), we investigated the influence of edema on the implant dose distribution. The LQ parameters (alpha=0.15 Gy(-1) and alpha/beta=3.1 Gy) determined in earlier studies were used to calculate the equivalent uniform dose in 2 Gy fractions (EUD2) with respect to three effects: edema, RBE, and dose heterogeneity for 125I and 103Pd implants. The EUD2 analysis shows a negative effect of edema and dose heterogeneity on tumor cell killing because the prostate edema degrades the dose coverage to tumor target. For the representative DVH, the V100 (volume covered by 100% of prescription dose) decreases from 93% to 91% and 86%, and the D90 (dose covering 90% of target volume) decrease from 107% to 102% and 94% of prescription dose for 125I and 103Pd implants, respectively. Conversely, the RBE effect of LDR brachytherapy [versus external-beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy] enhances dose effect on tumor cell kill. In order to balance the negative effects of edema and dose heterogeneity, the RBE of prostate brachytherapy was determined to be approximately 1.2-1.4 for 125I and 1.3-1.6 for 103Pd implants. These RBE values are consistent with the RBE data published in the literature. These results may explain why in earlier modeling studies, when the effects of edema, dose heterogeneity, and RBE were all ignored simultaneously, prostate LDR brachytherapy was reported to show an overall similar dose effect as EBRT and HDR brachytherapy, which are independent of edema and RBE effects and have a better dose coverage.

Interobserver variation in cervical cancer tumor delineation for image-based radiotherapy planning among and within different specialties.

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. PACS number(s):