Hilka Rothe

High-Grade Acute Organ Toxicity During Preoperative Radiochemotherapy as Positive Predictor for Complete Histopathologic Tumor Regression in Multimodal Treatment of Locally Advanced Rectal Cancer*

Purpose:To test for a possible correlation between high-grade acute organ toxicity during preoperative radiochemotherapy and complete tumor regression after total mesorectal excision in multimodal treatment of locally advanced rectal cancer.Patients and Methods:From 2001 to 2008, 120 patients were treated. Preoperative treatment consisted of normofractionated radiotherapy at a total dose of 50.4 Gy, and either two cycles of 5-fluorouracil (5-FU) or two cycles of 5-FU and oxaliplatin. Toxicity during treatment was monitored weekly, and any toxicity CTC (Common Toxicity Criteria) ≥ grade 2 of enteritis, proctitis or cystitis was assessed as high-grade organ toxicity for later analysis. Complete histopathologic tumor regression (TRG4) was defined as the absence of any viable tumor cells.Results:A significant coherency between high-grade acute organ toxicity and complete histopathologic tumor regression was found, which was independent of other factors like the preoperative chemotherapy schedule. The probability of patients with acute organ toxicity ≥ grade 2 to achieve TRG4 after neoadjuvant treatment was more than three times higher than for patients without toxicity (odds ratio: 3.29, 95% confidence interval: [1.01, 10.96]).Conclusion:Acute organ toxicity during preoperative radiochemotherapy in rectal cancer could be an early predictor of treatment response in terms of complete tumor regression. Its possible impact on local control and survival is under further prospective evaluation by the authors’ working group.Ziel:Überprüfung einer möglichen Korrelation zwischen höhergradiger akuter Organtoxizität während präoperativer Radiochemotherapie und kompletter Tumorregression nach totaler mesorektaler Exzision in der multimodalen Behandlung von lokal fortgeschrittenen Rektumkarzinomen.Patienten und Methodik:Im Zeitraum von 2001 bis 2008 wurden 120 Patienten behandelt. Die präoperative Behandlung bestand aus einer normofraktionierten Radiotherapie mit einer Gesamtdosis von 50,4 Gy und entweder zwei Zyklen 5-Fluorouracil (5-FU) oder zwei Zyklen 5-FU und Oxaliplatin. Die Toxizität während der Behandlung wurde wöchentlich untersucht. Jede Toxizität ≥ Grad 2 nach CTC (Common Toxicity Criteria) in Form von Enteritis, Proktitis oder Zystitis wurde dabei als höhergradige Organtoxizität gewertet und für spätere Analysen verwendet. Bei vollständigem histopathologischen Tumoransprechen (TRG4) konnten im Operationspräparat nach neoadjuvanter Therapie keine vitalen Tumorzellen mehr identifiziert werden.Ergebnisse:Es fand sich eine signifikante Korrelation zwischen höhergradiger akuter Organtoxizität und kompletter Tumorregression, und zwar in multivariater Analyse unabhängig von anderen Faktoren wie z.B. dem präoperativen Chemotherapieregime. Die Wahrscheinlichkeit für die Patienten mit höhergradigen Nebenwirkungen, eine histopathologische Komplettremission zu entwickeln, war mehr als dreimal höher als für Patienten ohne Toxizität (Odds-Ratio: 3,29, 95%-Konfidenzintervall: [1,01, 10,96]).Schlussfolgerung:Höhergradige akute Organtoxizität während präoperativer Radiochemotherapie bei Patienten mit multimodaler Therapie lokal fortgeschrittener Rektumkarzinome könnte einen frühen Prädiktor für das Ansprechen auf die Therapie in Bezug auf die histopathologische Remission darstellen. Ob dieser Parameter auch für die lokale Kontrolle sowie das Gesamtüberleben prädiktiv sein kann, wird in weiteren prospektiven Untersuchungen durch die Arbeitsgruppe der Autoren untersucht.

Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival.

Purpose: Valid molecular markers need to be implemented in clinical trials to fulfill the demand of a risk-adapted and more individualized multimodal therapy of locally advanced primary rectal cancer. In this study, the expression of the inhibitor-of-apoptosis (IAP) protein survivin was evaluated in pretreatment biopsies and corresponding posttreatment resection specimens, and was correlated to histo-pathological tumor characteristics and clinical follow-up. Patients and Methods: One hundred sixteen patients with stage II/III rectal cancer treated with 5-FU–based neoadjuvant radiochemotherapy (RCT) at a single university medical centre within the German Rectal Cancer Trials were investigated. Survivin expression in pretreatment biopsies and surgical resection specimens were determined by immunohistochemistry by two independent institutions and correlated with histopathologic parameters, tumor recurrences, disease-free (DFS), and overall cancer-specific survival (CSS). Results: In pretreatment biopsies, a higher survivin expression correlated with advanced ypT (P = 0.026) and ypUICC (P = 0.05) stage as well as DFS (P = 0.038) after preoperative RCT. High posttreatment survivin levels were associated with advanced ypT stage (P = 0.03) and residual lymph node metastases (P = 0.04). Moreover, neoadjuvant RCT resulted in a significant downregulation of survivin expression (P < 0.0001). A failure of RCT-induced downregulation was associated with development of distant metastases (P = 0.0056) and cancer-related death (P = 0.026), and correlated significantly with DFS (P = 0.011*/0.02**) and CSS (P = 0.0017*/0.01**) in uni-* and multivariate** analyses. Conclusions: Survivin expression displays a marker with prognostic utility in rectal cancers. These results underline the potential of survivin to monitor individual response to RCT and encourage anti-survivin strategies in multimodal rectal cancer therapy within future randomized clinical trials. Clin Cancer Res; 17(6); 1623–31. ©2010 AACR.

Irradiation as preparative regimen for hepatocyte transplantation causes prolonged cell cycle block.

Purpose: Hepatocyte transplantation following liver irradiation (IR) and partial hepatectomy (PH) leads to extensive liver repopulation. We investigated the changes in the liver induced by IR explaining the loss of reproductive integrity in endogenous hepatocytes. Materials and methods: Right lobules of rat liver underwent external beam IR (25 Gy). A second group was subjected to additional 33% PH of the untreated left liver lobule. Liver specimens and controls were analyzed for DNA damage, apoptosis, proliferation and cell cycle related genes (1 hour to up to 12 weeks). Results: Double strand breaks (phosphorylated histone H2AX) induced by IR rapidly declined within hours and were no longer detectable after 4 days. No significant apoptosis was noted and steady mRNA levels (B-cell lymphoma 2-associated X protein (BAX), caspase 3 and 9) were in line with the lack of DNA fragmentation. However, gene expression of p53 and p21 in irradiated liver tissue increased. Transcripts of cyclin D1, proliferating cell nuclear antigen (PCNA), and cyclin B augmented progressively, whereas cyclin E was only affected moderately. Following PH, irradiated livers displayed persistently high protein levels of p21 and cyclin D1. However, cell divisions were infrequent, as reflected by low PCNA levels up to four weeks. Conclusion: IR leads to a major arrest in the G1/S phase and to a lesser extent in the G2/M transition of the cell cycle, resulting in reduced regenerative response following PH. The persistent block of at least four weeks may promote preferential proliferation of transplanted hepatocytes in this milieu.

Lymph node metastases in rectal cancer after preoperative radiochemotherapy: impact of intramesorectal distribution and residual micrometastatic involvement.

Introduction:After neoadjuvant chemoradiation (CRT), the pathologic determined lymph node (LN) status is the most important prognostic factor in rectal cancer patients. Here we assessed the prognostic impact of residual LN micrometastases (<0.2 cm) and the intramesorectal distribution of LN metastases. Patients and Methods:Surgical specimens from 81 patients with cUICC II/III rectal cancer undergoing neoadjuvant CRT and total mesorectal excision within the German Rectal Cancer Trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was paraffin embedded and screened microscopically. The number and distribution of mesorectal LN macrometastases and micrometastases were correlated with disease-free (DFS) and cancer-specific overall survival (CSS). Results:A total of 2412 LNs were detected (mean 29.8±13.7). Twenty-five patients had residual LN metastases (ypN+). The incidence of metastases in the peritumoral mesorectum was higher (7.7%) than that proximal to the tumor (1.5%), whereas no metastases were identified below the tumor level. Patients with both proximal and peritumoral involvement showed a significantly reduced CSS (hazard ratio=5.4; P<0.05). Fourteen patients with ypN+ status (56%) had micrometastases, 9 patients (36%) had only micrometastatic involvement. Patients with nodal macrometastases had a reduced DFS (P<0.01) and CSS (P<0.005) as compared with ypN0 patients, whereas residual micrometastases had no influence on survival. Conclusions:Despite the high incidence of residual LN micrometastases they did not seem to have a prognostic impact in this series. Micrometastases might indicate responsive tumors to CRT with a more favorable biology. The intramesorectal distribution of LN metastases had a prognostic impact and should be validated in further studies.

Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: do we have indications for individual risk stratification?

BackgroundResponse to preoperative radiochemotherapy (RCT) in patients with locally advanced rectal cancer is very heterogeneous. Pathologic complete response (pCR) is accompanied by a favorable outcome. However, most patients show incomplete response. The aim of this investigation was to find indications for risk stratification in the group of intermediate responders to RCT.MethodsFrom a prospective database of 496 patients with rectal adenocarcinoma, 107 patients with stage II/III cancers and intermediate response to preoperative 5-FU based RCT (ypT2/3 and TRG 2/3), treated within the German Rectal Cancer Trials were studied. Surgical treatment comprised curative (R0) total mesorectal excision (TME) in all cases. In 95 patients available for statistical analyses, residual transmural infiltration of the mesorectal compartment, nodal involvement and histolologic tumor grading were investigated for their prognostic impact on disease-free (DFS) and overall survival (OS).ResultsResidual tumor transgression into the mesorectal compartment (ypT3) did not influence DFS and OS rates (p = 0.619, p = 0.602, respectively). Nodal involvement after preoperative RCT (ypN1/2) turned out to be a valid prognostic factor with decreased DFS and OS (p = 0.0463, p = 0.0236, respectively). Persistent tumor infiltration of the mesorectum (ypT3) and histologic tumor grading of residual tumor cell clusters were strongly correlated with lymph node metastases after neoadjuvant treatment (p < 0.001).ConclusionsAdvanced transmural tumor invasion after RCT does not affect prognosis when curative (R0) resection is achievable. Residual nodal status is the most important predictor of individual outcome in intermediate responders to preoperative RCT. Furthermore, ypT stage and tumor grading turn out to be additional auxiliary factors. Future clinical trials for risk-adapted adjuvant therapy should be based on a synopsis of clinicopathologic parameters.

Gold markers for tumor localization and target volume delineation in radiotherapy for rectal cancer

Background and Purpose:In locally advanced rectal cancer, neoadjuvant radiochemotherapy is indicated. To improve target volume definition for radiotherapy planning, the potential of implanted gold markers in the tumor region was evaluated.Patients and Methods:In nine consecutive patients, two to three gold markers were implanted in the tumor region during rigid rectoscopy. Computed tomography scans were performed during treatment planning. All electronic portal imaging devices (EPIDs) recorded during treatment series were analyzed. All patients underwent complete tumor resection with meticulous histopathologic examination.Results:The gold markers could easily be implanted into the mesorectal tissue at the caudal tumor border without any complications. They were helpful in identifying the inferior border of the planning target volume in order to spare normal tissue (in particular anal structures). No significant shift of the markers was found during the course of therapy. Marker matching of the EPIDs did not improve patient positioning in comparison to bone structure matching. The former position of at least one marker could be identified in all patients during histopathologic examination.Conclusion:The use of gold marker enables a more precise definition of the target volume for radiotherapy in patients with rectal cancer. This could eventually allow a better protection of anal structures of patients with a tumor localization ≥ 5 cm cranial of the anal sphincter. The implantation of the gold markers improved communication between the surgeon, the radiooncologist and the pathologist resulting in intensified exchange of relevant informations.Hintergrund und Ziel:Bei Patienten mit fortgeschrittenem Rektumkarzinom ist eine neoadjuvante Radiochemotherapie indiziert. Um die Definition des Zielvolumens zu verbessern, wurde das Potential von implantierten Goldmarkern in der Tumorregion untersucht.Patienten und Methodik:Bei neun konsekutiven Patienten wurden während der prätherapeutischen starren Rektoskopie zwei bis drei Goldmarker in die Tumorregion implantiert. Für die Bestrahlungsplanung wurden computertomographische Bilder aufgenommen. Alle während der Bestrahlung aufgenommenen Portal-Image-Bilder wurden analysiert. Alle Patienten erhielten eine komplette Tumorresektion mit anschließender histopathologischer Untersuchung.Ergebnisse:Die Goldmarker konnten einfach und komplikationslos in das mesorektale Gewebe am kaudalen Tumorrand gelegt werden. Sie waren hilfreich bei der Identifikation des unteren Tumorrands während der Bestrahlungsplanung, um Normalgewebe (insbesondere die analen Strukturen) bei der Bestrahlung schonen zu können. Es fand sich keine signifikante Verschiebung der absoluten Markerpositionen während der Bestrahlung. Eine Korrektur der Lagerung der Patienten nach Markern ergab keinen Vorteil gegenüber der Korrektur mit knöchernen Landmarken. Die ehemalige Position von mindestens einem Marker konnte bei jedem Patienten in der histopathologischen Untersuchung bestimmt werden.Schlussfolgerung:Die Verwendung von Goldmarkern bei Patienten mit Rektumkarzinom ermöglicht eine präzisere Definition der Zielvolumens für die Bestrahlungsplanung. Dadurch könnten evtl. anale Strukturen bei einer Tumorlage von ≥ 5 cm kranial des Analsphinkters geschont werden. Die Implantation von Goldmarkern verbessert die Kommunikation zwischen Chirurgen, Radioonkologen und Pathologen, was in einem intensivierten Austausch relevanter Informationen resultiert.

Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup.

BACKGROUND: For patients with ycT1/2 rectal carcinomas after neoadjuvant chemoradiotherapy, local excision instead of radical surgery has increasingly been discussed as a way to avoid postoperative morbidity associated with radical surgery. OBJECTIVE: The purpose of this study was to determine the incidence of lymph node metastases in total mesorectal excision specimens with ypT0, ypT1/2, and ypT3/4 rectal cancers. DESIGN: This is a prospective and retrospective cohort study. SETTINGS: This study was conducted in tertiary referral hospitals that are part of the German Rectal Cancer Study Group. PATIENTS: A total of 479 patients with stage II and III rectal cancers treated within phase III trials of the German Rectal Cancer Study Group were evaluated. Specimens from 81 patients treated in the Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society (CAO/ARO/AIO-04) trial were prospectively studied with extensive microscopic screening of the entire mesorectum. The frequency and localization of nodal metastases were specified and compared with those of 398 patients having received neoadjuvant chemoradiation within the CAO/ARO/AIO-94 trial. MAIN OUTCOME MEASURES: Frequency and localization of mesorectal lymph node metastases in patients with ypT0, ypT1/2, or ypT3/4 cancer were measured. RESULTS: A mean number of 28.0 ± 13.7 nodes were detected per specimen within the prospective group. A total of 25% of patients in the ypT1/2 group had nodal metastases compared with 40% in the ypT3/4 group. Patients with node-positive ypT1/2 had a mean number of 2.2 metastases, and 55% of these metastases were located far from the primary lesion in the proximal mesorectum. Within the CAO/ARO/AIO-94 cohort (n = 398), 19% of patients with ypT1/2 (ypT1 = 22%; ypT2 = 18%) had ypN+ status compared with 43% with ypT3/4 cancers (ypT3 = 40%; ypT4 = 73%). LIMITATIONS: Low numbers of patients with ypT0 limited the evaluation of nodal metastases in pathologic complete responders. CONCLUSIONS: Even in good responders (ypT1/2), >20% of rectal carcinomas still harbored residual lymph node metastases. Local excision for patients with ycT1/2 rectal cancers would, thus, miss metastases in a considerable percentage and might involve the risk of significant undertreatment in a number of patients.