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.

Repeated positron emission tomography-computed tomography and perfusion-computed tomography imaging in rectal cancer: fluorodeoxyglucose uptake corresponds with tumor perfusion.

PURPOSE: The purpose of this study was to analyze both the intratumoral fluorodeoxyglucose (FDG) uptake and perfusion within rectal tumors before and after hypofractionated radiotherapy. METHODS AND MATERIALS: Rectal cancer patients, referred for preoperative hypofractionated radiotherapy (RT), underwent FDG-positron emission tomography (PET)-computed tomography (CT) and perfusion-CT (pCT) imaging before the start of hypofractionated RT and at the day of the last RT fraction. The pCT-images were analyzed using the extended Kety model, quantifying tumor perfusion with the pharmacokinetic parameters K(trans), v(e), and v(p). The mean and maximum FDG uptake based on the standardized uptake value (SUV) and transfer constant (K(trans)) within the tumor were correlated. Also, the tumor was subdivided into eight subregions and for each subregion the mean and maximum SUVs and K(trans) values were assessed and correlated. Furthermore, the mean FDG uptake in voxels presenting with the lowest 25% of perfusion was compared with the FDG uptake in the voxels with the 25% highest perfusion. RESULTS: The mean and maximum K(trans) values were positively correlated with the corresponding SUVs (ρ = 0.596, p = 0.001 and ρ = 0.779, p < 0.001). Also, positive correlations were found for K(trans) values and SUVs within the subregions (mean, ρ = 0.413, p < 0.001; and max, ρ = 0.540, p < 0.001). The mean FDG uptake in the 25% highest-perfused tumor regions was significantly higher compared with the 25% lowest-perfused regions (10.6% ± 5.1%, p = 0.017). During hypofractionated radiotherapy, stable mean (p = 0.379) and maximum (p = 0.280) FDG uptake levels were found, whereas the mean (p = 0.040) and maximum (p = 0.003) K(trans) values were found to significantly increase. CONCLUSION: Highly perfused rectal tumors presented with higher FDG-uptake levels compared with relatively low perfused tumors. Also, intratumor regions with a high FDG uptake demonstrated with higher levels of perfusion than regions with a relatively low FDG-uptake. Early after hypofractionated RT, stable FDG uptake levels were found, whereas tumor perfusion was found to significantly increase.

Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging.

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [(18)F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

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.

Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging.

PURPOSE: To develop and validate an accurate predictive model and a nomogram for pathologic complete response (pCR) after chemoradiotherapy (CRT) for rectal cancer based on clinical and sequential PET-CT data. Accurate prediction could enable more individualised surgical approaches, including less extensive resection or even a wait-and-see policy. METHODS AND MATERIALS: Population based databases from 953 patients were collected from four different institutes and divided into three groups: clinical factors (training: 677 patients, validation: 85 patients), pre-CRT PET-CT (training: 114 patients, validation: 37 patients) and post-CRT PET-CT (training: 107 patients, validation: 55 patients). A pCR was defined as ypT0N0 reported by pathology after surgery. The data were analysed using a linear multivariate classification model (support vector machine), and the model's performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: The occurrence rate of pCR in the datasets was between 15% and 31%. The model based on clinical variables (AUC(train)=0.61±0.03, AUC(validation)=0.69±0.08) resulted in the following predictors: cT- and cN-stage and tumour length. Addition of pre-CRT PET data did not result in a significantly higher performance (AUC(train)=0.68±0.08, AUC(validation)=0.68±0.10) and revealed maximal radioactive isotope uptake (SUV(max)) and tumour location as extra predictors. The best model achieved was based on the addition of post-CRT PET-data (AUC(train)=0.83±0.05, AUC(validation)=0.86±0.05) and included the following predictors: tumour length, post-CRT SUV(max) and relative change of SUV(max). This model performed significantly better than the clinical model (p(train)<0.001, p(validation)=0.056). CONCLUSIONS: The model and the nomogram developed based on clinical and sequential PET-CT data can accurately predict pCR, and can be used as a decision support tool for surgery after prospective validation.

PET imaging of hypoxia using [18F]HX4: a phase I trial.

BACKGROUND AND PURPOSE: Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [(18)F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. METHODS: Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [(18)F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. RESULTS: Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). CONCLUSION: The findings of this study showed that [(18)F]HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.

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.

Tumor perfusion increases during hypofractionated short-course radiotherapy in rectal cancer: sequential perfusion-CT findings.

PURPOSE: The purpose of this study was to investigate perfusion of rectal tumors and to determine early responses to short-course hypofractionated radiotherapy (RT). MATERIAL AND METHODS: Twenty-three rectal cancer patients were included, which underwent perfusion-CT imaging before (pre-scan) and after treatment (post-scan). Contrast-enhancement was measured in tumor and muscle tissues and in the external iliac artery. Perfusion was quantified with three pharmacokinetic parameters: K(trans), v(e) and v(p). Perfusion differences between tumor and normal tissue and changes of the pharmacokinetic parameters between both scans were evaluated. RESULTS: The median tumors K(trans) values increased significantly from the pre-scan (0.36+/-0.11 (min(-1))) to the post-scan (0.44+/-0.13 (min(-1))) (p<0.001). Also, histogram analysis showed a shift of tumor voxels from lower K(trans) values towards higher K(trans) values. Furthermore, the median K(trans) values were significantly higher for tumor than for muscle tissue on both the pre-scan (0.10+/-0.05 (min(-1)), p<0.001) and the post-scan (0.10+/-0.04 (min(-1)), p<0.001). In contrast, no differences between tumor and muscle tissues were found for v(e) and v(p). Also, no significant differences were observed for v(e) and v(p) between the two pCT-imaging time-points. CONCLUSIONS: Hypofractionated radiotherapy of rectal cancer leads to an increased tumor perfusion as reflected by an elevated K(trans), possibly improving the bioavailability of cytotoxic agents in rectal tumors, often administered early after radiotherapy treatment.

Comparison between perfusion computed tomography and dynamic contrast-enhanced magnetic resonance imaging in rectal cancer.

PURPOSE: To compare pretreatment scans with perfusion computed tomography (pCT) vs. dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rectal tumors. METHODS AND MATERIALS: Nineteen patients diagnosed with rectal cancer were included in this prospective study. All patients underwent both pCT and DCE-MRI. Imaging was performed on a dedicated 40-slice CT-positron emission tomography system and a 3-T MRI system. Dynamic contrast enhancement was measured in tumor tissue and the external iliac artery. Tumor perfusion was quantified in terms of pharmacokinetic parameters: transfer constant K(trans), fractional extravascular-extracellular space v(e), and fractional plasma volume v(p). Pharmacokinetic parameter values and their heterogeneity (by 80% quantile value) were compared between pCT and DCE-MRI. RESULTS: Tumor K(trans) values correlated significantly for the voxel-by-voxel-derived median (Kendall's tau correlation, tau = 0.81, p < 0.001) and 80% quantile (tau = 0.54, p = 0.04), as well as for the averaged uptake (tau = 0.58, p = 0.03). However, no significant correlations were found for v(e) and v(p) derived from the voxel-by-voxel-derived median and 80% quantile and derived from the averaged uptake curves. CONCLUSIONS: This study demonstrated for the first time that pCT provides K(trans) values comparable to those of DCE-MRI. However, no correlation was found for the v(e) and v(p) parameters between CT and MRI. Computed tomography can serve as an alternative modality to MRI for the in vivo evaluation of tumor angiogenesis in terms of the transfer constant K(trans).

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.

Tumor delineation based on time-activity curve differences assessed with dynamic fluorodeoxyglucose positron emission tomography-computed tomography in rectal cancer patients.

PURPOSE: To develop an unsupervised tumor delineation method based on time-activity curve (TAC) shape differences between tumor tissue and healthy tissue and to compare the resulting contour with the two tumor contouring methods mostly used nowadays. METHODS AND MATERIALS: Dynamic positron emission tomography-computed tomography (PET-CT) acquisition was performed for 60 min starting directly after fluorodeoxyglucose (FDG) injection. After acquisition and reconstruction, the data were filtered to attenuate noise. Correction for tissue motion during acquisition was applied. For tumor delineation, the TAC slope values were k-means clustered into two clusters. The resulting tumor contour (Contour I) was compared with a contour manually drawn by the radiation oncologist (Contour II) and a contour generated using a threshold of the maximum standardized uptake value (SUV; Contour III). RESULTS: The tumor volumes of Contours II and III were significantly larger than the tumor volumes of Contour I, with both Contours II and III containing many voxels showing flat TACs at low activities. However, in some cases, Contour II did not cover all voxels showing upward TACs. CONCLUSION: Both automated SUV contouring and manual tumor delineation possibly incorrectly assign healthy tissue, showing flat TACs, as being malignant. On the other hand, in some cases the manually drawn tumor contours do not cover all voxels showing steep upward TACs, suspected to be malignant. Further research should be conducted to validate the possible superiority of tumor delineation based on dynamic PET analysis.