Sarah Roels

Value of Diffusion-Weighted Magnetic Resonance Imaging for Prediction and Early Assessment of Response to Neoadjuvant Radiochemotherapy in Rectal Cancer: Preliminary Results

PURPOSE To evaluate diffusion-weighted magnetic resonance imaging (DWI) for response prediction before and response assessment during and early after preoperative radiochemotherapy (RCT) for locally advanced rectal cancer (LARC). METHODS AND MATERIALS Twenty patients receiving RCT for LARC underwent MRI including DWI before RCT, after 10-15 fractions and 1 to 2 weeks before surgery. Tumor volume and apparent diffusion coefficient (ADC; b-values: 0-1000 s/mm(2)) were determined at all time points. Pretreatment tumor ADC and volume, tumor ADC change (∆ADC), and volume change (∆V) between pretreatment and follow-up examinations were compared with histopathologic findings after total mesorectal excision (pathologic complete response [pCR] vs. no pCR, ypT0-2 vs. ypT3-4, T-downstaging or not). The discriminatory capability of pretreatment tumor ADC and volume, ∆ADC, and ∆V for the detection of pCR was compared with receiver operating characteristics analysis. RESULTS Pretreatment ADC was significantly lower in patients with pCR compared with patients without (in mm(2)/s: 0.94 ± 0.12 × 10(-3) vs. 1.19 ± 0.22 × 10(-3), p = 0.003), yielding a sensitivity of 100% and specificity of 86% for detection of pCR. The volume reduction during and after RCT was significantly higher in patients with pCR compared with patients without (in %: ΔV(during): -62 ± 16 vs. -33 ± 16, respectively, p = 0.015; and ΔV(post): -86 ± 12 vs. -60 ± 21, p = 0.012), yielding a sensitivity of 83% and specificity of 71% for the ΔV(during) and, respectively, 83% and 86% for the ΔV(post). The ∆ADC during (ΔADC(during)) and after RCT (ΔADC(post)) showed a significantly higher value in patients with pCR compared with patients without (in %: ΔADC(during): 72 ± 14 vs. 16 ± 12, p = 0.0006; and ΔADC(post): 88 ± 35 vs. 26 ± 19, p = 0.0011), yielding a sensitivity and specificity of 100% for the ΔADC(during) and, respectively, 100% and 93% for the ΔADC(post). CONCLUSIONS These initial findings indicate that DWI, using pretreatment ADC, ΔADC(during), and ΔADC(post) may be useful for prediction and early assessment of pathologic response to preoperative RCT of LARC, with higher accuracy than volumetric measurements.

The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer

Abstract Purpose. To investigate the use of FDG-PET/CT before, during and after chemoradiotherapy (CRT) and diffusion-weighted magnetic resonance imaging (DW-MRI) before CRT for the prediction of pathological response (pCR) in rectal cancer patients. Material and methods. Twenty-two rectal cancer patients treated with long course CRT were included. An FDG-PET/CT was performed prior to the start of CRT, after 10 to 12 fractions of CRT and five weeks after the end of CRT. The tumor was delineated using a gradient based delineation method and the maximal standardized uptake values (SUVmax) were calculated. A DW-MRI was performed before start of CRT. Mean apparent diffusion coefficients (ADC) were determined. The ΔSUVmax during and after CRT and the initial ADC values were correlated to the histopathological findings after total mesorectal excision (TME). Results. ΔSUVmax during and after CRT significantly correlated with the pathological response to treatment (during CRT: ΔSUVmax = 59% ± 12% for pCR vs. 25% ± 27% if no pCR, p=0.0036; post-CRT: 90% ± 11 for pCR vs. 63% ± 22 if no pCR p=0.013). ROC curve analysis revealed an optimal threshold for ΔSUVmax of 40% during CRT and 76% after CRT. The initial ADC value was also significantly correlated with pCR (0.94 ± 0.12 × 10−3 mm2/s for pCR vs. 1.2 ± 0.24 × 10−3 mm2/s, p=0.002) and ROC curve analysis revealed an optimal threshold of 1.06 × 10−3 mm2/s. Combining the provided ΔSUVmax thresholds during and after CRT increased specificity of the prediction (sensitivity 100% and specificity 94%). The combination of the thresholds for the initial ADC value and the ΔSUVmax during CRT increased specificity of the prediction to a similar level (sensitivity of 100% and specificity of 94%). Conclusions. The combination of the different time points and the different imaging modalities increased the specificity of the response assessment both during and after CRT.

Biological image-guided radiotherapy in rectal cancer: Is there a role for FMISO or FLT, next to FDG?

Purpose. The purpose of this study is to investigate the use of PET/CT with fluorodeoxyglucose (FDG), fluorothymidine (FLT) and fluoromisonidazole (FMISO) for radiotherapy (RT) target definition and evolution in rectal cancer. Materials and methods. PET/CT was performed before and during preoperative chemoradiotherapy (CRT) in 15 patients with resectable rectal cancer. PET signals were delineated and CT images on the different time points were non-rigidly registered. Mismatch analyses were carried out to quantify the overlap between FDG and FLT or FMISO tumour volumes (TV) and between PET TVs over time. Results. Ninety sequential PET/CT images were analyzed. The mean FDG, FLT and FMISO-PET TVs showed a tendency to shrink during preoperative CRT. On each time point, the mean FDG-PET TV was significantly larger than the FMISO-PET TV but not significantly larger than the mean FLT-PET TV. There was a mean 65% mismatch between the FMISO and FDG TVs obtained before and during CRT. FLT TVs corresponded better with the FDG TVs (25% mismatch before and 56% during CRT). During CRT, on average 61% of the mean FDG TV (7 cc) overlapped with the baseline mean TV (15.5 cc) (n=15). For FLT, the TV overlap was 49% (n=5) and for FMISO only 20% of the TV during CRT remained inside the contour at baseline (n=10). Conclusion. FDG, FLT and FMISO-PET reflect different functional characteristics that change during CRT in rectal cancer. FLT and FDG show good spatial correspondence, while FMISO seems less reliable due to the non-specific FMISO uptake in normoxic tissue and tracer diffusion through the bowel wall. FDG and FLT-PET/CT imaging seem most appropriate to integrate in preoperative RT for rectal cancer.

Biological image-guided radiotherapy in rectal cancer: challenges and pitfalls.

PURPOSE To investigate the feasibility of integrating multiple imaging modalities for image-guided radiotherapy in rectal cancer. PATIENTS AND METHODS Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) were performed before, during, and after preoperative chemoradiotherapy (CRT) in patients with resectable rectal cancer. The FDG-PET signals were segmented with an adaptive threshold-based and a gradient-based method. Magnetic resonance tumor volumes (TVs) were manually delineated. A nonrigid registration algorithm was applied to register the images, and mismatch analyses were carried out between MR and FDG-PET TVs and between TVs over time. Tumor volumes delineated on the images after CRT were compared with the pathologic TV. RESULTS Forty-five FDG-PET/CT and 45 MR images were analyzed from 15 patients. The mean MRI and FDG-PET TVs showed a tendency to shrink during and after CRT. In general, MRI showed larger TVs than FDG-PET. There was an approximately 50% mismatch between the FDG-PET TV and the MRI TV at baseline and during CRT. Sixty-one percent of the FDG-PET TV and 76% of the MRI TV obtained after 10 fractions of CRT remained inside the corresponding baseline TV. On MRI, residual tumor was still suspected in all 6 patients with a pathologic complete response, whereas FDG-PET showed a metabolic complete response in 3 of them. The FDG-PET TVs delineated with the gradient-based method matched closest with pathologic findings. CONCLUSIONS Integration of MRI and FDG-PET into radiotherapy seems feasible. Gradient-based segmentation is recommended for FDG-PET. Spatial variance between MRI and FDG-PET TVs should be taken into account for target definition.

Double blind randomized phase II study with radiation+5-fluorouracil+/-celecoxib for resectable rectal cancer

PURPOSE To assess the feasibility and efficacy of the COX-2 inhibitor celecoxib in conjunction with preoperative chemoradiation for patients with locally advanced rectal cancer in a double blind randomized phase II study. MATERIALS AND METHODS Thirty-five patients of the initially planned 80 patients with locally advanced rectal cancer were treated with preoperative radiation (45 Gy; 1.8 Gy/fraction, 5 days/week) combined with 5-fluorouracil (continuous infusion, 225 mg/m(2)/day) and celecoxib (2 x 400 mg/day) or placebo. Pathological response and toxicity of study treatment were evaluated, as well as expression of COX-2 and Ki67 in tumor tissue and IL-6 in plasma as possible molecular correlates and predictors of response to treatment. RESULTS Patients treated with celecoxib tended to show a better response (61%) when compared to those treated with placebo (35%), although not significant (p=0.13). T-downstaging and N-downstaging were also slightly higher with celecoxib. Plasma IL-6 levels and intratumoral COX2 or Ki67 were altered by chemoradiation, but were not further altered by celecoxib treatment and therefore not useful for prediction of treatment benefit. Celecoxib therapy in conjunction with chemoradiation was not associated with additional toxicity and seemed to help mitigate therapy-related pain. CONCLUSIONS Addition of celecoxib to preoperative chemoradiation is feasible for patients with locally advanced rectal cancer. To study the individual effect of COX-2 inhibitors on pathological response phase III studies are required.

Do refined consensus guidelines improve the uniformity of clinical target volume delineation for rectal cancer? Results of a national review project

In a previous national central review project, 74% of the rectal cancer clinical target volumes (CTVs) needed a modification. In a follow-up initiative, we evaluated whether the use of refined international consensus guidelines improves the uniformity of CTV delineation in clinical practice.

Validation of nonrigid registration for multi-tracer PET-CT treatment planning in rectal cancer radiotherapy

The goal of radiotherapy is to deliver maximal dose to the tumor and minimal dose to the surrounding tissue. This requires accurate target definition. In sites were the tumor is difficult to see on the CT images, such as for rectal cancer, PET-CT imaging can be used to better define the target. If the information from multiple PETCT images with different tracers needs to be combined, a nonrigid registration is indispensable to compensate for rectal tissue deformations. Such registration is complicated by the presence of different volumes of bowel gas in the images to be registered. In this paper, we evaluate the performance of different nonrigid registration approaches by looking at the overlap of manually delineated rectum contours after registration. Using a B-spline transformation model, the results for two similarity measures, sum of squared differences and mutual information, either calculated over the entire image or on a region of interest are compared. Finally, we also assess the effect of the registration direction. We show that the combination of MI with a region of interest is best able to cope with residual rectal contrast and differences in bowel filling. We also show that for optimal performance the registration direction should be chosen depending on the difference in bowel filling in the images to be registered.

SU‐DD‐A4‐01: Nonrigid Registration of Mesorectal Region for PET Signal Follow‐Up During Radiation Therapy

Purpose: We wish to achieve maximum registration performance in the region around the tumor for patients with rectal cancer to assess the changes in PET signal due to radiotherapy.Method and Materials: A nonrigid registration was performed on nine PET‐CT images of three patients with rectal cancer. We use a B‐spline transformation model with mutual information as similarity criterion. The registration is performed in a multiresolution framework. To exclude the influence of differences in bladder filling, registration was limited to the mesorectum, delineated at planning time, by only calculating the similarity criterion for the control points inside the mesorectum. In the last multiresolution stages of the registration, a small, local volume constraint was used to regularize the deformation field inside the tumor region. Validation was performed by comparing volume overlap (Dice Similarity Coefficient or DSC), centroid distance and volume change of the manually delineated rectum contour for all slices where tumor was actually seen on the FDG‐PET. Results: When using the region of interest, volume overlap increases while centroid distance decreases for all registrations. The mean DSC when using the entire image for registrations was 0.68 compared to 0.79 when only registering inside the mesorectum. The mean centroid distance decreased from 4.40mm to 3.30mm. The mean volume difference decreased from 28.11% to 14.09%. Conclusion: Results show that by limiting the registration to the mesorectum, a much higher volume overlap for the rectum can be seen. Also, by regularizing the deformation field around the tumor in the last stages of the registration, a slight increase in rectum correspondence is found. The results of these registrations can be used to evaluate the PET signal around the tumor over time.