Magnetic resonance imaging (MRI) in advanced rectal cancer (UICC stages II to IV) before and after neoadjuvant radiochemotherapy – its significance from the surgical point of view.

Magnetic resonance imaging (MRI) in advanced rectal cancer (UICC stages II to IV) before and after neoadjuvant radiochemotherapy – its significance from the surgical point of view. Hasibullah Habibi Abstract Background: In Germany treatment of advanced rectal cancer (clinically staged as UICC stages II to IV) consists of radical surgery (to achieve R0-status), preoperative radiation (RT) combined with chemotherapy (CTx) (to induce tumor remission) and postoperative CTx (to reduce metastatic spread). In several clinical studies this ap-proach has demonstrated improvement of survival accompanied by acceptable qual-ity of life. For successful conduction of multimodality treatment comprehensive STAGING as well as RE-STAGING procedures are mandatory. These include rectal endosonog-raphy (rES, as preferred by colorectal surgeons) and pelvic magnetic resonance im-aging (MRI, as performed by specialized radiologists). But in daily clinical practice, the significance of MRI diagnostic is still under debate, especially from the sur-geons` point of view. Purpose: In this thesis importance and accuracy of MRI (using a standard MRI 1.5 Tesla apparatus) at STAGING, RE-STAGING and for treatment monitoring were evaluated in three patients` cohorts (in total n=184 patients) with adenocarcinoma of the rectum (cUICC stages II to IV). All patients had received treatment at the Univer-sity Medical Center of the Georg August University of Goettingen (Lower Saxony, Germany) within interdisciplinary clinical trials. Patients and methods: Between 04/2005 and 01/2010 36 patients of patients` co-hort A (control) received MRI at STAGING (MRI-1) followed by rectal cancer surgery performed as partial or total mesorectal excision (PME- or TME-surgery). In 60 pa-tients (patients` cohort B1) TME-surgery was conducted after completion of preoper-ative RT combined with 5-Fluorouracil (5-FU) CTx and in further 64 patients (pa-tients` cohort B2) after RT combined with 5-FU+Oxaliplatin CTx. In both patients` groups, B1 and B2, a RE-STAGING MRI-2 was performed preoperatively using the established imaging protocol of MRI-1. Furthermore, between 03/2011 and 08/2013 24 patients (patients` cohort C) were treated with intensified preoperative RT com-bined with 5-FU+Oxaliplatin and followed by 3 cycles of FOLFOX CTx. After comple-tion of RCT a RE-STAGING MRI-2 was conducted. After application of modified FOLFOX CTx a second RE-STAGING (MRI-3) followed preoperatively. After PME-/TME-surgery including anterior (ARR), low anterior (LARR) and (extend-ed) abdomino-perineal resections (APR) pathological (p) confirmed tumor (T-), lymphnode (N- or LN-), residual (R-) and circumferential resection status (CRM-status) and other relevant clinico-pathological parameters were correlated with MRI-findings according to MERCURY-criteria and TNM-/UICC-classification system (8th and 10th edition). Furthermore, RCT+/-CTx-induced downcategorizing of UICC- and T-stages as well as the rate of pathological confirmed tumor regression grading (TRG, according to Dworak et al., 1997) were assessed. This TRG classification ranged from no regression (TRG 0 and TRG 1), intermediate regression (TRG 2 and TRG 3) to complete remission (TRG 4, equivalent to ypCR or ypT0). At STAGING MRI findings (mr) were classified according to the TNM-/UICC-system (e.g. mrT-, mrN-, mrCRM-, mrTRG- status) and were compared to rES and several other clinico-pathological findings. Treatment associated shrinkage of tumor extent was measured by comparing the craniocaudal tumor length (in mm) in MRI-1 vs MRI-2 vs MRI-3. Furthermore, general tumor response to treatment was categorized using modified RECIST-criteria (complete (CR) and partial (PR) remission, stable (SD) or progressive (PD) disease). In patients` cohort C, all results were correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) parameters after follow-up of 48 months (Median) using Kaplan-Meier-Logrank regression analyses. Further-more time-to-treatmet-failure (TTF) was determined. For all cohorts MRI findings at STAGING (and RE-STAGING) were compared to postoperative histopathological findings as the reference gold standard. Binary STAGING (and RE-STAGING) parameters such as ≥ mrT3-status, ymrCR- (ymrT0), residual lymph node metastasis (LNM-) status as well as ymrCRM-status were demonstrated in four fields blackboards. Sensitivtity, specificity, the positive and negative predictive value as well as accuracy were calculated. Results: In patients` cohort A (control) the mrT-status (MRI-1) was pathologically confirmed in 47%. The rate of overstaging was 37% and of understaging was 16%. The mrLN-status was correctly diagnosed in 42% of patients. In 53% an overstaging and in 5% an understaging was detectable. The mrCRM-status was correctly predict-ed in 92% at STAGING. In contrast, rES demonstrated a true prediction of uT-status in 60% of cases. The uT-status overstaging rate resulted in 30% and the uT- under-staging in 10%, respectively. For determination of the prognostic endpoint ≥T3-status, the sensitivity was 85% (MRI-1) and 91% (rES), the specificity in both 0% and the accuracy was 58% (MRT-1) and 63% (rES), respectively. Prediction of LNM in MRI-1 was possible with sensitivity of 86%, specificity of 17% and accuracy of 42%. For CRM positivity as preoperatively predicted by MRI, the sensitivity was 0%, the specificity 100%, the NPV 95% and the accuracy 95%, too. Finally, MRI-1 excluded early at STAGING any postoperatively detectable CRM positivity. For correctly classified ≥ uT3-status at rES STAGING sensitivity amounted 91%, specificity 0%, PPV 69%, NPV 0% and the accuracy was 63%. In prediction of LNM (uN+ status in rES) the sensitivity was 70%, the specificity 45%, the NPV 75% and the accuracy 53%. In contrast to the excellent MRI findings according to the CRM, there was no adequate information with rES available. In patients` cohort B the T-status and LN-status were correctly classified both by MRI-1 and rES in 65% and 58%, respectively. At STAGING with rES, rectal cancers were appraised uT2 tumors in 5%, uT3 tumors in 93% and uT4 tumors in 2%. MRI-1 evaluated mrT2 tumors in 7%, mrT3 tumors in 65% and mrT4 rectal cancer in 28% of cases. In contrast to rES with a detection rate of LNM in 75% of patients, STAGING MRI-1 allowed a much more precise subclassification of LN-status as shown in 14% mrN0-, in 66% mrN1- and in 20% mrN2-status of patients, respectively. A positive CRM (mrCRM+) was diagnosed in 55% of patients at STAGING in MRI-1. Preopera-tively, Re-STAGING MRI-2 (after RCT) correctly predicted ypT-status in 51% (52 of 101 patients). The ymrT-overstaging was 43% and ymrT-understaging was 6%. In MRI-2 ymrLN-status was correctly diagnosed in 60% of patients. The rate of ymrLN-overstaging resulted in 34%. Comparing MRI-1 with MRI-2, there was no change in the number of ymrT3 rectal cancers after RCT in patients` cohort B, but the amount of ymrT4 cancers decreased from 29% to 12%. Furthermore the percentage of ymrT2 tumors increased from 7% to 19%. In 5% of patients ymrT0-status (mrCR) was de-tectable. However, MRI-2 allowed prediction of RCT-induced tumor regression and verified significant reduction of craniocaudal tumor length compared to MRI-1 (p<0.001). Additionally, assessment of ymrLN-status predicted a RCT-induced re-gression in nearly 30% of cases and was confirmed as ypUICC-downstaging after pathological work-up of the resected rectal specimens. In patients` cohort C, MRI-3 showed an ypUICC-downstaging in 67% of patients after intensified multimodality treatment. At least, an ypCR (ypTN0-status) rate of 17% was verified. In 20% of rectal cancer specimens no viable cancer cells could be de-tected (ypT0-status). Furthermore very encouraging survival data (data given in re-stricted mean survival time ± SE) could be achieved. At last day of observation post-operative DFS resulted in 49.3 ± 5.8 months, TTF in 57.1 ± 5.4 months and CSS in 62 ± 4.2 months, respectively. The OS was 54.7 ± 5.1 months. After intensified RCT followed by 3 cycles of mFOLFOX-CTx a significant reduction in craniocaudal tumor extent was detectable comparing findings of MRI-1 vs MRI-3 (p<0.001). This treatment-induced tumor shrinkage was even predictable after com-pletion of RCT comparing tumor findings of MRI-1 to MRI-2 as well as between MRI-2 to MRI-3 (p