Jeroen Buijsen

Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer

PURPOSE Neoadjuvant chemoradiotherapy for rectal cancer can result in complete disappearance of tumor and involved nodes. In patients without residual tumor on imaging and endoscopy (clinical complete response [cCR]) a wait-and-see-policy (omission of surgery with follow-up) might be considered instead of surgery. The purpose of this prospective cohort study was to evaluate feasibility and safety of a wait-and-see policy with strict selection criteria and follow-up. PATIENTS AND METHODS Patients with a cCR after chemoradiotherapy were prospectively selected for the wait-and-see policy with magnetic resonance imaging (MRI) and endoscopy plus biopsies. Follow-up was performed 3 to 6 monthly and consisted of MRI, endoscopy, and computed tomography scans. A control group of patients with a pathologic complete response (pCR) after surgery was identified from a prospective cohort study. Functional outcome was measured with the Memorial Sloan-Kettering Cancer Center (MSKCC) bowel function questionnaire and Wexner incontinence score. Long-term outcome was estimated by using Kaplan-Meier curves. RESULTS Twenty-one patients with cCR were included in the wait-and-see policy group. Mean follow-up was 25 ± 19 months. One patient developed a local recurrence and had surgery as salvage treatment. The other 20 patients are alive without disease. The control group consisted of 20 patients with a pCR after surgery who had a mean follow-up of 35 ± 23 months. For these patients with a pCR, cumulative probabilities of 2-year disease-free survival and overall survival were 93% and 91%, respectively. CONCLUSION A wait-and-see policy with strict selection criteria, up-to-date imaging techniques, and follow-up is feasible and results in promising outcome at least as good as that of patients with a pCR after surgery. The proposed selection criteria and follow-up could form the basis for future randomized studies.

Accurate Prediction of Pathological Rectal Tumor Response after Two Weeks of Preoperative Radiochemotherapy Using 18F-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.

Can an FDG-PET/CT predict tumor clearance of the mesorectal fascia after preoperative chemoradiation of locally advanced rectal cancer?

Background and Purpose:More effective preoperative treatment in locally advanced rectal cancer gives rise to a more individualized, conservative surgical treatment strategy. This, however, requires accurate information on tumor response after chemoradiation (CRT). So far, MRI and CT have failed to provide such information. Therefore, the value of a combined FDG-PET/CT in predicting tumor clearance of the mesorectal fascia (MRF) was determined.Patients and Methods:20 rectal cancer patients with MRF tumor invasion underwent preoperative PET/CT before and on average 6.3 weeks after CRT. The SUVmax(maximal standard uptake value) on sequential PET/CT and the shortest distance between the outlined tumor volume and the MRF measured by using autocontouring software on post-CRT PET/CT were registered. The surgical specimen was evaluated for tumor clearance of the MRF and the tumor regression grade (TRG).Results:The TRG significantly corresponded with the SUVmaxchanges induced by CRT (p = 0.025), and showed a trend with the post-CRT SUVmax(TRG 1–2 vs. TRG 3–5: SUVmax= 3.0 vs. 5.0; p = 0.06). However, the pathologically verified tumor clearance of the MRF was not correlated with any of the tested SUV parameters nor with the shortest distance between the residual tumor and the MRF.Conclusion:Post-CRT PET/CT is not a useful tool for evaluating anatomic tumor changes and, therefore, not accurate in predicting tumor clearance of the MRF. However, it might be a useful tool in predicting pathologic tumor response after CRT.Hintergrund und Ziel:Die immer effektivere präoperative Behandlung bei lokal fortgeschrittenem Rektumkarzinom verstärkt den Wunsch nach einer individuelleren, eher konservativen chirurgischen Behandlungsstrategie. Dies setzt jedoch exakte Informationen bezüglich der anatomischen Tumorantwort nach Radiochemotherapie voraus. In dieser Studie wurde der Wert der kombinierten FDG-PET/CT für die Vorhersage einer Tumorrückbildung an der mesorektalen Faszie (MRF) untersucht.Patienten und Methodik:20 Patienten mit Rektumkarzinom und MRT-bestätigter Tumorinvasion der MRF wurden präoperativ mit einer kombinierten FDG-PET/CT vor und im Mittel 6,3 Wochen nach Radiochemotherapie untersucht. Die Tumorvolumina wurden bei beiden PETs/CTs mit Hilfe einer Autokonturierungssoftware eingezeichnet. Der SUVmax(„maximal standard uptake value“) und der kürzeste Abstand zwischen dem eingezeichneten Tumorvolumen und der MRF wurden ermittelt. Das chirurgisch exzidierte Präparat wurde auf eine Tumorrückbildung an der mesorektalen Faszie und den Tumorregressionsgrad (TRG) untersucht.Ergebnisse:Der TRG korrespondierte signifikant mit den durch die Radiochemotherapie induzierten Veränderungen des SUVmax(p = 0,025) und annähernd signifikant mit dem SUVmaxnach Radiochemotherapie (TRG 1–2 vs. TRG 3–5: SUVmax= 3,0 vs. 5,0; p = 0,06). Es ließ sich jedoch keine Korrelation zwischen der pathologisch verifizierten Tumorrückbildung an der MRF und den untersuchten SUV-Parametern sowie dem kürzesten Abstand zwischen Resttumor und MRF feststellen.Schlussfolgerung:Diese Daten legen den Schluss nahe, dass eine wiederholte PET/CT-Untersuchung nach Radiochemotherapie beim Rektumkarzinom nicht in der Lage ist, anatomische Veränderungen so sicher zu ermitteln, dass eine konservativere operative Vorgehensweise zu verantworten wäre. Jedoch erweist sich die PET/CT als sinnvolle Untersuchung zur Vorhersage der pathologischen Tumorantwort nach Radiochemotherapie.

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.

MRI and Diffusion-weighted MRI Volumetry for Identification of Complete Tumor Responders After Preoperative Chemoradiotherapy in Patients With Rectal Cancer: A Bi-institutional Validation Study.

Background: Retrospective single-center studies have shown that diffusion-weighted magnetic resonance imaging (DWI) is promising for identification of patients with rectal cancer with a complete tumor response after neoadjuvant chemoradiotherapy (CRT), using certain volumetric thresholds. Objective: This study aims to validate the diagnostic value of these volume thresholds in a larger, independent, and bi-institutional patient cohort. Methods: A total of 112 patients with locally advanced rectal cancer (2 centers) treated with a long course of CRT were enrolled. Patients underwent standard T2W-magnetic resonance imaging and DWI, both pre- and post-CRT. Two experienced readers independently determined pre-CRT and post-CRT tumor volumes (cm3) on T2W-magnetic resonance image and diffusion-weighted magnetic resonance image by means of freehand tumor delineation. Tumor volume reduction rates (&Dgr;volume) were calculated. Previously determined T2W and DWI threshold values for prevolume, postvolume, and &Dgr;volume were tested to “prospectively” assess their respective diagnostic value in discriminating patients with a complete tumor response from patients with residual tumor. Results: Twenty patients had a complete response. Using the average measurements between the 2 readers, areas under the curve for the pre-/post-/&Dgr;volumes was 0.73/0.82/0.78 for T2W-magnetic resonance imaging and 0.77/0.92/0.86 for DWI, respectively. For T2W-volumetry, sensitivity and specificity using the predefined volume thresholds were 55% and 74% for pre-, 60% and 89% for post-, and 60% and 86% for &Dgr;volume. For DWI volumetry, sensitivity and specificity were 65% and 76% for pre-, 70% and 98% for post-, and 70% and 93% for &Dgr;volume. Conclusions: Previously established DWI volume thresholds can be reproduced with good results. Post-CRT DWI volumetry offers the best results for the detection of patients with a complete response after CRT with an area under the curve of 0.92, sensitivity of 70%, and specificity of 98%.

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.

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 (Kendalls 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).

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.

Active Breathing Control in Combination With Ultrasound Imaging: A Feasibility Study of Image Guidance in Stereotactic Body Radiation Therapy of Liver Lesions

PURPOSE Accurate tumor positioning in stereotactic body radiation therapy (SBRT) of liver lesions is often hampered by motion and setup errors. We combined 3-dimensional ultrasound imaging (3DUS) and active breathing control (ABC) as an image guidance tool. METHODS AND MATERIALS We tested 3DUS image guidance in the SBRT treatment of liver lesions for 11 patients with 88 treatment fractions. In 5 patients, 3DUS imaging was combined with ABC. The uncertainties of US scanning and US image segmentation in liver lesions were determined with and without ABC. RESULTS In free breathing, the intraobserver variations were 1.4 mm in left-right (L-R), 1.6 mm in superior-inferior (S-I), and 1.3 mm anterior-posterior (A-P). and the interobserver variations were 1.6 mm (L-R), 2.8 mm (S-I), and 1.2 mm (A-P). The combined uncertainty of US scanning and matching (inter- and intraobserver) was 4 mm (1 SD). The combined uncertainty when ABC was used reduced by 1.7 mm in the S-I direction. For the L-R and A-P directions, no significant difference was observed. CONCLUSION 3DUS imaging for IGRT of liver lesions is feasible, although using anatomic surrogates in the close vicinity of the lesion may be needed. ABC-based breath-hold in midventilation during 3DUS imaging can reduce the uncertainty of US-based 3D table shift correction.

Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial

BACKGROUND Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma. METHODS In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m2 on day 1), cisplatin (60 mg/m2 on day 1) or oxaliplatin (130 mg/m2 on day 1), and capecitabine (1000 mg/m2 orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m2 orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1·8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m2 orally twice daily on radiotherapy days) and cisplatin (20 mg/m2 intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02. FINDINGS Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61·4 months (IQR 43·3-82·8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1·01 (95% CI 0·84-1·22; p=0·90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment. INTERPRETATION Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies. FUNDING Dutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.