A phase I-II study on the combination of rapamycin and short course radiotherapy in rectal cancer.

PURPOSE: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of the combination of rapamycin, an mTOR inhibitor, with short-course radiotherapy in rectal cancer patients. Antitumor activity, changes in metabolic activity and perfusion on imaging, and changes in phosphorylation status of the mTOR pathway were also assessed. MATERIALS AND METHODS: Patients with primary resectable rectal cancer were treated with short-course hypofractionated radiotherapy (5×5 Gy) combined with oral rapamycin 1 week before and during radiotherapy, followed by surgical resection. RESULTS: Thirteen patients were entered in phase I. One patient developed a dose-limiting toxicity, consisting of a grade 4 leak and grade 4 bleeding. Because of an unexpected high rate of grade 3 postoperative toxicity, it was decided to treat patients with delayed surgery in phase II. Primary endpoint for phase II was tumor blood flow (K(trans)) assessed by perfusion CT. Thirty-one patients were treated with the MTD of 6 mg rapamycin daily. One patient (3%) developed a pathological complete response (pCR) and 3 patients (10%) had a ypT1N0 tumor at the time of resection. No change in tumor perfusion was observed on perfusion CT, but a significant decrease of metabolic activity was found on PET-scan. CONCLUSIONS: The combination of short-course radiotherapy and rapamycin turned out to be feasible, provided that the interval between neo-adjuvant treatment and surgical resection is at least 6 weeks. Although from this cohort no clear increase in pCR could be observed, a clear metabolic response after rapamycin run-in was observed, indicating a biological activity of this drug in rectal cancer.

FDG-PET-CT reduces the interobserver variability in rectal tumor delineation.

BACKGROUND AND PURPOSE: Previously, we showed a good correlation between pathology and an automatically generated PET-contour in rectal cancer. This study analyzed the effect of the use of PET-CT scan on the interobserver variation in GTV definition in rectal cancer and the influence of PET-CT on treatment volumes. MATERIALS AND METHODS: Forty two patients diagnosed with rectal cancer underwent an FDG-PET-CT for radiotherapy planning. An automatic contour was created on PET-scan using the source-to-background ratio. The GTV was delineated by 5 observers in 3 rounds: using CT and MRI, using CT, MRI and PET and using CT, MRI and PET auto-contour. GTV volumes were compared and concordance indices (CI) were calculated. Since the GTV is only a small portion of the treatment volume in rectal cancer, a separate analysis was performed to evaluate the influence of PET on the definition of the CTV used in daily clinical practice and the caudal extension of the treatment volumes. RESULTS: GTV volumes based on PET were significantly smaller. CIs increased significantly using PET and the best interobserver agreement was observed using PET auto-contours. Furthermore, we found that in up to 29% of patients the CTV based on PET extended outside the CTV used in clinical practice. The caudal border of the treatment volume can be tailored using PET-scan in low seated tumors. Influence of PET on the position of the caudal border was most pronounced in high seated tumors. CONCLUSION: PET-CT increases the interobserver agreement in the GTV definition in rectal cancer, helps to avoid geographical misses and allows tailoring the caudal border of the treatment volume.

PET-based treatment response evaluation in rectal cancer: prediction and validation.

PURPOSE: To develop a positron emission tomography (PET)-based response prediction model to differentiate pathological responders from nonresponders. The predictive strength of the model was validated in a second patient group, treated and imaged identical to the patients on which the predictive model was based. METHODS AND MATERIALS: Fifty-one rectal cancer patients were prospectively included in this study. All patients underwent fluorodeoxyglucose (FDG) PET-computed tomography (CT) imaging both before the start of chemoradiotherapy (CRT) and after 2 weeks of treatment. Preoperative treatment with CRT was followed by a total mesorectal excision. From the resected specimen, the tumor regression grade (TRG) was scored according to the Mandard criteria. From one patient group (n = 30), the metabolic treatment response was correlated with the pathological treatment response, resulting in a receiver operating characteristic (ROC) curve based cutoff value for the reduction of maximum standardized uptake value (SUV(max)) within the tumor to differentiate pathological responders (TRG 1-2) from nonresponders (TRG 3-5). The applicability of the selected cutoff value for new patients was validated in a second patient group (n = 21). RESULTS: When correlating the metabolic and pathological treatment response for the first patient group using ROC curve analysis (area under the curve = 0.98), a cutoff value of 48% SUV(max) reduction was selected to differentiate pathological responders from nonresponders (specificity of 100%, sensitivity of 64%). Applying this cutoff value to the second patient group resulted in a specificity and sensitivity of, respectively, 93% and 83%, with only one of the pathological nonresponders being false positively predicted as pathological responding. CONCLUSIONS: For rectal cancer, an accurate PET-based prediction of the pathological treatment response is feasible already after 2 weeks of CRT. The presented predictive model could be used to select patients to be considered for less invasive surgical interventions or even a "wait and see" policy. Also, based on the predicted response, early modifications of the treatment protocol are possible, which might result in an improved clinical outcome.

Residual metabolic tumor activity after chemo-radiotherapy is mainly located in initially high FDG uptake areas in rectal cancer.

PURPOSE: Recent literature suggests that tumor cells and areas within tumors with a high initial FDG uptake might be more resistant to (chemo)radiotherapy ((C)RT). This study was undertaken to test this hypothesis in rectal cancer using rigid and non-rigid image registration. PATIENTS AND METHODS: Twenty-eight patients, diagnosed with locally advanced rectal cancer and referred for pre-operative treatment with CRT were included in this study. All patients underwent FDG-PET-CT imaging prior to and after CRT. Rigid and non-rigid image registration was performed to compensate organ deformations between the pre- and post-treatment PET-CT scans. The tumor was contoured on both PET-scans using SUV iso-contouring based on the SBR-method. The voxels with residual increased FDG uptake were studied and correlated to their pre-treatment FDG uptake level. Two SUV-volume-histograms were made based on the pre-treatment PET-data, one for the voxels within the pre-treatment tumor PET-based iso-contour and one for the voxels within the PET-based iso-contour of the residual tumor non-rigidly registered onto the pre-treatment scan. RESULTS: For the voxels with a pre-treatment FDG uptake of >50% of SUV(max), 70.6±5.6% of the voxels were still metabolic active in the residual tumor, whereas for voxels with an FDG uptake of <50% of SUV(max) only 51.1±6.7% were present in the metabolic active residual tumor. CONCLUSION: This study presents areas in rectal tumors with an initially high FDG uptake to be most likely to show residual disease after CRT. This could indicate a higher (C)RT-resistance for tumor regions with a high FDG uptake prior to treatment.

FDG-PET provides the best correlation with the tumor specimen compared to MRI and CT in rectal cancer.

PURPOSE: To compare CT-, MR- and PET-CT based tumor length measurements in rectal cancer with pathology. PATIENTS AND METHODS: Twenty-six rectal cancer patients underwent both MR and PET-CT imaging followed by short-course radiotherapy (RT 5×5 Gy) and surgery within 3 days after RT. Tumor length was measured manually and independently by 2 observers on CT, MR and PET. PET-based tumor length measurements were also generated automatically using the signal-to-background-ratio (SBR) method. All measurements were correlated with the tumor length on the pathological specimen. RESULTS: CT-based measurements did not show a valuable correlation with pathology. MR-based measurements correlated only weakly, but still significantly (Pearson correlation=0.55 resp. 0.57; p<0.001). Manual PET measurements reached a good correlation with pathology, but less strong (Pearson correlation 0.72 and 0.76 for the two different observers) than automatic PET-CT based measurements, which provided the best correlation with pathology (Pearson correlation of 0.91 (p<0.001)). Bland-Altman analysis demonstrated in general an overestimation of the tumor diameter using manual measurements, while the agreement of automatic contours and pathology was within acceptable ranges. A direct comparison of the different modalities revealed a significant better precision for PET-based auto-contours as compared to all other measurements. CONCLUSION: Automatically generated PET-CT based contours show the best correlation with the surgical specimen and thus provide a useful and powerful tool to accurately determine the largest tumor dimension in rectal cancer. This could be used as a quick and reliable tool for target delineation in radiotherapy. However, a 3D volume analysis is needed to confirm these results.

Evaluation of early metabolic responses in rectal cancer during combined radiochemotherapy or radiotherapy alone: sequential FDG-PET-CT findings.

BACKGROUND AND PURPOSE: The purpose of this study was to prospectively investigate metabolic changes of rectal tumors after 1 week of treatment of either radiochemotherapy (28 x 1.8 Gy+Capecitabine) (RCT) or hypofractionated radiotherapy (5 x 5 Gy) alone (RT). MATERIALS AND METHODS: Fourty-six rectal cancer patients, 25 RCT- and 21 RT-patients, were included in this study. Sequential FDG-PET-CT scans were performed for each of the included patients both prior to treatment and after the first week of treatment. Consecutively, the metabolic treatment response of the tumor was evaluated. RESULTS: For the patients referred for pre-operative RCT, significant reductions of SUV(mean) (p<0.001) and SUV(max) (p<0.001) within the tumor were found already after the first week of treatment (8 Gy biological equivalent dose (BED). In contrast, 1 week of treatment with RT alone did not result in significant changes in the metabolic activity of the tumor (p=0.767, p=0.434), despite the higher applied RT dose of 38.7 Gy BED. CONCLUSIONS: Radiochemotherapy of rectal cancer leads to significant early changes in the metabolic activity of the tumor, which was not the case early after hypofractionated radiotherapy alone, despite the higher radiotherapy dose given. Thus, the chemotherapeutic agent Capecitabine might be responsible for the early metabolic treatment responses during radiochemotherapy in rectal cancer.

Blood glucose level normalization and accurate timing improves the accuracy of PET-based treatment response predictions in rectal cancer.

PURPOSE: To quantify the influence of fluctuating blood glucose level (BGLs) and the timing of PET acquisition on PET-based predictions of the pathological treatment response in rectal cancer. MATERIAL AND METHODS: Thirty patients, diagnosed with locally advanced-rectal-cancer (LARC), were included in this prospective study. Sequential FDG-PET-CT investigations were performed at four time points during and after pre-operative radiochemotherapy (RCT). All PET-data were normalized for the BGL measured shortly before FDG injection. The metabolic treatment response of the tumor was correlated with the pathological treatment response. RESULTS: During RCT, strong intra-patient BGL-fluctuations were observed, ranging from -38.7 to 95.6%. BGL-normalization of the SUVs revealed differences ranging from -54.7 to 34.7% (p < 0.001). Also, a SUV(max) time-dependency of 1.30 +/- 0.66 every 10 min (range: 0.39-2.58) was found during the first 60 min of acquisition. When correlating the percent reduction of SUV(max) after 2 weeks of RCT with the pathological treatment response, a significant increase (p = 0.027) in the area under the curve of ROC-curve analysis was found when normalizing the PET-data for the measured BGLs, indicating an increase of the predictive strength. CONCLUSIONS: This study strongly underlines the necessity of BGL-normalization of PET-data and a precise time-management between FDG injection and the start of PET acquisition when using sequential FDG-PET-CT imaging for the prediction of pathological treatment response.

Accurate prediction of pathological rectal tumor response after two weeks of preoperative radiochemotherapy using (18)F-fluorodeoxyglucose-positron emission tomography-computed tomography imaging.

PURPOSE: To determine the optimal time point for repeated (18)F-fluorodeoxyglucose-positron emission tomography (PET)-CT imaging during preoperative radiochemotherapy (RCT) and the best predictive factor for the prediction of pathological treatment response in patients with locally advanced rectal cancer. METHODS AND MATERIALS: A total of 30 patients referred for preoperative RCT treatment were included in this prospective study. All patients underwent sequential PET-CT imaging at four time points: prior to therapy, at day 8 and 15 during RCT, and shortly before surgery. Tumor metabolic treatment responses were correlated with the pathological responses by evaluation of the tumor regression grade (TRG) and the pathological TN (ypT) stage of the resected specimen. RESULTS: Based on their TRG evaluations, 13 patients were classified as pathological responders, whereas 17 patients were classified as pathological nonresponders. The response index (RI) for the maximum standardized uptake value (SUV(max)) on day 15 of RCT was found to be the best predictive factor for the pathological response (area under the curve [AUC] = 0.87) compared to the RI on day 8 (AUC = 0.78) or the RI of presurgical PET imaging (AUC = 0.66). A cutoff value of 43% for the reduction of SUV(max) resulted in a sensitivity of 77% and a specificity of 93%. CONCLUSIONS: The SUV(max)-based RI calculated after the first 2 weeks of RCT provided the best predictor of pathological treatment response, reaching AUCs of 0.87 and 0.84 for the TRG and the ypT stage, respectively. However, a few patients presented with peritumoral inflammatory reactions, which led to mispredictions. Exclusion of these patients further enhanced the predictive accuracy of PET imaging to AUCs of 0.97 and 0.89 for TRG and ypT, respectively.

Evaluation of three different CT simulation and planning procedures for the preoperative irradiation of operable rectal cancer.

PURPOSE: To find the best procedure regarding quality and work load for treatment planning in operable non-locally advanced rectal cancer using 3D CT-based information. METHODS: The study population consisted of 62 patients with non-locally advanced tumours, as defined by MRI in the lower (N=16), middle (N=25) and upper (N=21) rectum referred for preoperative short-course radiotherapy. In procedure 1 (Pr1), planning in one central plane was performed (field borders/shielding based on bony anatomy). In procedure 2 (Pr2), field borders were determined by 2 markers for the extension of the CTV in the cranial and ventral direction. Dose optimization was performed in one central and two border planes. In procedure 3(Pr3) the PTV volume (CTV was contoured on CT) received conformal treatment (3D dose optimization). RESULTS: Conformity index reached 1.6 for Pr3 vs. 2.2 for Pr2 (p<0.001). PTV coverage was 87%, 94%, 99% in Pr1, Pr2, Pr3, respectively (p=0.001). In Pr2 target coverage was below 95% for low/middle tumours. PTV coverage was reduced by narrow field borders (18-23%) and shielding (28%). A total of 43.5% (1-100) of the bladder volume was treated in Pr2 in contrast to 16% (0-68) in Pr3 (p<0.001). The maximum dose was exceeded in 10 patients (26-298 cc) and 2 patients (21-36 cc) in procedures 1 and 2, respectively. The overall time spent by technologists was 86 min for Pr3 vs 17 min in Pr2 and Pr1 (p<0.001), for radiation oncologists this difference was 24 vs 4 min (p<0.001). CONCLUSIONS: Pr1 does not fulfill todays quality requirements. Pr3 provides the best quality at the cost of working time. Pr2 is less time consuming, however, the PTV coverage was insufficient, with also much larger treatment volumes. An optimization of the PTV coverage in Pr2 even further enlarged the treatment volume.