Efficacy and quality of life for FOLFOX/bevacizumab +/- irinotecan in first-line metastatic colorectal cancer-final results of the AIO CHARTA trial.

BACKGROUND: FOLFOXIRI plus bevacizumab has demonstrated benefits for metastatic colorectal cancer (mCRC) patients. However, challenges arise in its clinical implementation due to expected side effects and a lack of stratification criteria. METHODS: The AIO "CHARTA" trial randomised mCRC patients into clinical Group 1 (potentially resectable), 2 (unresectable/risk of rapid progression), or 3 (asymptomatic). They received FOLFOX/bevacizumab +/- irinotecan. The primary endpoint was the 9-month progression-free survival rate (PFSR@9). Secondary endpoints included efficacy in stratified groups, QoL, PFS, OS, ORR, secondary resection rate, and toxicity. RESULTS: The addition of irinotecan to FOLFOX/bevacizumab increased PFSR@9 from 56 to 67%, meeting the primary endpoint. The objective response rate was 61% vs. 69% (P = 0.21) and median PFS was 10.3 vs. 12 months (HR 0.83; P = 0.17). The PFS was (11.4 vs. 12.9 months; HR 0.83; P = 0.46) in potentially resectable patients, with a secondary resection rate of 37% vs. 51%. Moreover, Group 3 (asymptomatic) patients had a PFS of 11.1 vs. 16.1 months (HR 0.6; P = 0.14). The addition of irinotecan did not diminish QoL. CONCLUSION: The CHARTA trial, along with other studies, confirms the efficacy and tolerability of FOLFOXIRI/bevacizumab as a first-line treatment for mCRC. Importantly, clinical stratification may lead to its implementation. TRIAL REGISTRATION: The trial was registered as NCT01321957.

Correlation of skin rash and overall survival in patients with pancreatic cancer treated with gemcitabine and erlotinib - results from a non-interventional multi-center study.

BACKGROUND: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. METHODS: This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years). RESULTS: Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. CONCLUSIONS: Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.

Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection. DESIGN: Patients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread. DISCUSSION: Pancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy. Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00006179 .

Y90 Radioembolization in chemo-refractory metastastic, liver dominant colorectal cancer patients: outcome assessment applying a predictive scoring system.

BACKGROUND: In treatment-refractory liver dominant metastatic colorectal cancer, the role of liver directed therapies still is unclear. We sought to determine a prognostic score for Y90 radioembolization in these patients. METHODS: We analyzed 106 patients with refractory liver dominant mCRC who had undergone a total of 178 Y90 radioembolizations with resin microspheres was collected. Potential factors influencing survival were analyzed using a Cox regression. The Log rank test served to establish prognostic factors and to form a clinical score for outcome prediction after Y90 radioembolization. RESULTS: Median survival of all patients was 6.7 months. Neither age nor prior surgical or systemic therapy nor metastatic spread had an effect on survival. In contrast, hepatic tumor load, Karnofsky index as well as CEA and CA19-9 serums level had a significant influence (p < 0.001, p = 0.037, p = 0.023 and p < 0.001, respectively). These three factors formed a score with 1 point each for tumor load >20 %, CEA >130 ng/ml or CA19-9 > 200U/ml and Karnofsky index <80 %. Patients with a score of 0 and 1 displayed a median OS of 10.4 months. Patients with a score of 2 and 3 demonstrated a median OS of 5.1 months only (p < 0.001). CONCLUSION: Overaggressive patient selection for Y90 radioembolization of liver dominant chemorefractory mCRC is of questionable benefit. A scoring system comprising hepatic tumor load, CEA and CA19-9 serum levels and Karnofsky index (TuCK-score) may support an improved patient selection. In our cohort of liver only versus liver dominant disease, extrahepatic lung or lymphatic metastases did not significantly alter the prognosis.

Adjuvant treatment for resected rectal cancer: impact of standard and intensified postoperative chemotherapy on disease-free survival in patients undergoing preoperative chemoradiation-a propensity score-matched analysis of an observational database.

AIMS: Adjuvant chemotherapy for resected rectal cancer is widely used. However, studies on adjuvant treatment following neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME) have yielded conflicting results. Recent studies have focused on adding oxaliplatin to both preoperative and postoperative therapy, making it difficult to assess the impact of adjuvant oxaliplatin alone. This study was aimed at determining the impact of (i) any adjuvant treatment and (ii) oxaliplatin-containing adjuvant treatment on disease-free survival in CRT-pretreated, R0-resected rectal cancer patients. METHOD: Patients undergoing R0 TME following 5-fluorouracil (5FU)-only-based CRT between January 1, 2008, and December 31, 2010, were selected from a nationwide registry. After propensity score matching (PSM), comparison of disease-free survival (DFS) using Kaplan-Meier analysis and log-rank test was performed in (i) patients receiving no vs. any adjuvant treatment and (ii) patients treated with adjuvant 5FU/capecitabine without vs. with oxaliplatin. RESULTS: Out of 1497 patients, 520 matched pairs were generated for analysis of no vs. any adjuvant treatment. Mean DFS was significantly prolonged with adjuvant treatment (81.8 ± 2.06 vs. 70.1 ± 3.02 months, p < 0.001). One hundred forty-eight matched pairs were available for analysis of adjuvant therapy with or without oxaliplatin, showing no improvement in DFS in patients receiving oxaliplatin (76.9 ± 4.12 vs. 79.3 ± 4.44 months, p = 0.254). Local recurrence rate was not significantly different between groups in either analysis. CONCLUSION: In this cohort of rectal cancer patients treated with neoadjuvant CRT and TME surgery under routine conditions, adjuvant chemotherapy significantly improved DFS. No benefit was observed for the addition of oxaliplatin to adjuvant chemotherapy in this setting.

Left-liver hypertrophy after therapeutic right-liver radioembolization is substantial but less than after portal vein embolization.

UNLABELLED: In patients with liver malignancies potentially amenable to curative extended right hepatectomy but insufficient size of the future liver remnant (FLR), portal vein embolization (PVE) of the tumor-bearing liver is used to induce contralateral liver hypertrophy but leaves the tumor untreated. Radioembolization (RE) treats the tumor in the embolized lobe along with contralateral hypertrophy induction. We performed a matched-pair analysis to compare the capacity for hypertrophy induction of these two modalities. Patients with right-hepatic secondary liver malignancies with no or negligible left-hepatic tumor involvement who were treated by right-lobar PVE (n = 141) or RE (n = 35) at two centers were matched for criteria known to influence liver regeneration following PVE: 1) baseline FLR/Total liver volume ratio (<25 versus ≥ 25%); 2) prior platinum-containing systemic chemotherapy; 3) embolization of segments 5-8 versus 4-8; and 4) baseline platelet count (<200 versus ≥ 200 Gpt/L).The primary endpoint was relative change in FLR volume from baseline to follow-up. Twenty-six matched pairs were identified. FLR volume increase from baseline to follow-up (median 33 [24-56] days after PVE or 46 [27-79] days after RE) was significant in both groups but PVE produced significantly more FLR hypertrophy than RE (61.5 versus 29%, P < 0.001). Time between treatment and follow-up was not correlated with the degree of contralateral hypertrophy achieved in both groups. Although group differences in patient history and treatment setting were present and some bias cannot be excluded, this was minimized by the matched-pair design, as remaining group differences after matching were found to have no significant influence on contralateral hypertrophy development. CONCLUSION: PVE induces significantly more contralateral hypertrophy than RE with therapeutic (nonlobectomy) doses. However, contralateral hypertrophy induced by RE is substantial and RE minimizes the risk of tumor progression in the treated lobe, possibly making it a suitable modality for selected patients.

Locally ablative treatment of breast cancer liver metastases: identification of factors influencing survival (the Mammary Cancer Microtherapy and Interventional Approaches (MAMMA MIA) study).

BACKGROUND: Liver metastases from breast cancer (LMBC) are typically considered to indicate systemic disease spread and patients are most often offered systemic palliative treatment only. However, retrospective studies suggest that some patients may have improved survival with local treatment of their liver metastases compared to systemic therapy alone. In the absence of randomized trials, it is important to identify patient characteristics indicating that benefit from local treatment can be expected. METHODS: 59 patients undergoing radiofrequency ablation (RFA), interstitial brachytherapy (BT), or radioembolization (RE) of LMBC as a salvage treatment were studied. Potential factors influencing survival were analyzed in a multivariate Cox model. For factors identified to have an independent survival impact, Kaplan-Meier analysis and comparison of overall survival (OS) using the log-rank test was performed. RESULTS: Median OS following local interventional treatment was 21.9 months. Considering only factors evaluable at treatment initiation, maximum diameter of liver metastases (≥3.9 cm; HR: 3.1), liver volume (≥ 1376 mL; HR: 2.3), and history of prior chemotherapy (≥ 3 lines of treatment; HR: 2.5-2.6) showed an independent survival impact. When follow-up data were included in the analysis, significant factors were maximum diameter of liver metastases (≥ 3.9 cm; HR: 3.1), control of LMBC during follow-up (HR: 0.29), and objective response as best overall response (HR: 0.21). Neither the presence of any extrahepatic metastases nor presence of bone metastases only had a significant survival impact. Median OS was 38.7 vs. 16.1 months in patients with metastases < vs. ≥ 3.9 cm, 36.6 vs. 10.2 months for patients having objective response vs. stable/progressive disease, and 38.5 vs. 14.2 months for patients having controlled vs. non-controlled disease at follow-up. CONCLUSION: Local control of LMBC confers a survival benefit and local interventional treatment for LMBC should be studied in a randomized trial. Patients with small metastases and limited history of systemic LMBC treatment are most likely to benefit from local approaches. Limited extrahepatic disease should not lead to exclusion from a randomized study and should not be a contraindication for local LMBC treatment as long as no randomized data are available.

Assessing regional hepatic function changes after hypertrophy induction by radioembolisation: comparison of gadoxetic acid-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy.

BACKGROUND: To compare Gd-ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and 99mTc-labelled mebrofenin hepatobiliary scintigraphy (HBS) as imaging-based liver function tests after unilateral radioembolisation (RE) in patients with primary or secondary liver malignancies. METHODS: Twenty-three patients with primary or secondary liver malignancies who underwent Gd-EOB-DTPA-enhanced MRI within a prospective study (REVoluTion) were evaluated. REVoluTion was a prospective open-label, non-randomised, therapy-optimising study of patients undergoing right-sided or sequential RE for contralateral liver hypertrophy at a single centre in Germany. MRI and hepatobiliary scintigraphy were performed before RE (baseline) and 6 weeks after (follow-up). This exploratory subanalysis compared liver enhancement on hepatobiliary phase MRI normalised to the spleen (liver-to-spleen ratio (LSR)) and the muscle (liver-to-muscle ratio (LMR)) with mebrofenin uptake on HBS for the total liver (TL) and separately for the right (RLL) and left liver lobe (LLL). RESULTS: Mebrofenin uptake at baseline and follow-up each correlated significantly with LSR and LMR on MRI for TL (≤ 0.013) and RLL (≤ 0.049). Regarding the LLL, mebrofenin uptake correlated significantly with LMR (baseline, p = 0.013; follow-up, p = 0.004), whereas with LSR, a borderline significant correlation was only seen at follow-up (p = 0.051; p = 0.046). CONCLUSION: LSRs and LMR correlate with mebrofenin uptake in HBS. This study indicates that Gd-EOB-DTPA-enhanced MRI and 99mTc-labelled mebrofenin HBS may equally be used to assess an increase in contralateral liver lobe function after right-sided RE. RELEVANCE STATEMENT: MRI may be a convenient and reliable method for assessing the future liver remnant facilitating treatment planning and monitoring of patients after RE-induced hypertrophy induction. KEY POINTS: • Both MRI and HBS can assess liver function after RE. • Liver enhancement on MRI correlates with mebrofenin uptake on HBS. • MRI might be a convenient alternative for estimating future liver remnants after hypertrophy induction.

Multimodal Treatment of cT3 Rectal Cancer in a Prospective Multi-Center Observational Study: Can Neoadjuvant Chemoradiation Be Omitted in Patients with an MRI-Assessed, Negative Circumferential Resection Margin?

BACKGROUND/AIM: Neoadjuvant chemoradiation (nCRT) in rectal cancer is associated with significant long-term morbidity. It is unclear whether nCRT in resectable mesorectal fascia circumferential resection margin (mrCRM)-negative rectal cancer treated by adequate total mesorectal excision (TME) is beneficial. The aim was to determine if nCRT can be omitted in patients with MRI-assessed cT3 rectal cancer and a negative mrCRM undergoing good-quality TME. METHODS: By means of a prospective nationwide registry (n = 43.147; prospective multi-center observational study), patients with cT3 rectal cancer <12 cm from the anal verge with a negative (>1 mm) MRI-assessed CRM undergoing radical resection from 2006 to 2008 were selected. Overall, 87 patients were available for the final analysis (TME-alone, n = 25; nCRT+TME, n = 62). Groups were balanced for age, sex, and ASA score, with a nonsignificant predominance of males in the nCRT+TME group. As main outcome measures, local and distant recurrence rates were compared between patients undergoing primary surgery (TME-alone) vs. neoadjuvant chemoradiation + surgery (nCRT+TME). RESULTS: In the TME-alone group, tumors were located closer to the anal verge (p = 0.018) and demonstrated a smaller minimal circumferential distance from the resection margin (p = 0.036). TME quality was comparable, as was median follow-up (48.9 vs. 44.9 months; p = 0.268). Local recurrences occurred at a similar rate in the TME-alone (n = 1; 5.3%) and nCRT+TME groups (n = 3; 5.5%) (p = 0.994) and were diagnosed at 10 months (TME-alone) and at 8, 13, and 18 months (nCRT+TME). Distant recurrences occurred in 28.9 and 17.4% of the cases, respectively (p = 0.626). The analysis was limited to cT3 cancers with a negative mrCRM. In addition, caution is required when appraising these results because of the limited number of evaluable subjects (especially in the TME-alone group), which adds some uncertainty to the statistical analysis. CONCLUSIONS: In this cohort of patients with rectal cancer located <12 cm from the anal verge and a negative mrCRM undergoing adequate TME, omission of nCRT had no impact onto the local recurrence rate.

The Impact of Unilateral 90Y-radioembolization on Functional Changes in the Contralateral Hepatic Lobe: The Prospective, Open-label RadioEmbolization, Volumetry, and Liver FuncTion Measurements (REVoluTion) Study.

Objectives: To investigate how metabolic function of the contralateral liver lobe is affected by unilateral radioembolization (RE), and to compare the changes in volume and metabolic function. Background: Unilateral RE induces contralateral liver hypertrophy, but it is unknown if metabolic liver function improves in line with volume increases. Methods: This prospective open-label, nonrandomized, therapy-optimizing study included all consecutive patients undergoing right-sided or sequential 90Y-RE for liver malignancies without underlying liver disease or biliary obstruction at a single center in Germany. Magnetic resonance imaging volumetry and hepatobiliary scintigraphy were performed immediately before RE and approximately 6 weeks after RE. Results: Twenty-three patients were evaluated (11 metastatic colorectal cancer, 4 cholangiocellular carcinoma, 3 metastatic breast cancer, 1 each of metastatic neuroendocrine tumor, hepatocellular carcinoma, renal cell carcinoma, oesophageal cancer, pancreatic ductal adenocarcinoma). In the untreated contralateral left liver lobe, mean (SD) metabolic function significantly increased from 1.34 (0.76) %/min/m2 at baseline to 1.56 (0.75) %/min/m2 6 weeks after RE (P = 0.024). The mean (SD) functional volume (liver volume minus tumor volume) of the left liver lobe significantly increased from baseline (407.3 [170.3] mL) to follow-up (499.1 [209.8] mL; P < 0.01), with an equivalent magnitude to the metabolic function increase. There were no reports of grade ≥3 adverse events. Conclusion: This study indicates that unilobar RE produces a significant increase in the metabolic function, and equivalent volume increase, of the contralateral lobe. RE may be a useful option to induce hypertrophy of the future liver remnant before surgical resection of primary or secondary liver malignancies.

Neoadjuvant chemoradiotherapy for rectal carcinoma: effects on anastomotic leak rate and postoperative bladder dysfunction after non-emergency sphincter-preserving anterior rectal resection. Results of the Quality Assurance in Rectal Cancer Surgery multicenter observational trial.

INTRODUCTION: Randomized trials have demonstrated a reduction in local recurrence rate in rectal cancer patients treated with preoperative chemoradiotherapy and total mesorectal excision (TME) compared to patients undergoing TME alone. Accordingly, preoperative chemoradiotherapy in all UICC stages II and III rectal cancers has been recommended in the German treatment guidelines as of 2004. However, this policy has been questioned in recent years, partly due to concern regarding an increase in postoperative complications through preoperative therapy. Studies on this issue are sparse; most have been conducted in specialized centers, included relatively few patients, and yielded partly contradicting results. It was the aim of our analysis to investigate the influence of preoperative chemoradiotherapy on anastomotic leak rate and postoperative bladder dysfunction in rectal cancer patients using a representative data set from the Quality Assurance in Rectal Cancer Surgery multicenter observational trial. METHOD: This is a retrospective analysis of data from the Quality Assurance in Rectal Cancer Surgery prospective multicenter observational trial. Data of all patients undergoing curatively intended sphincter-preserving resection for UICC stage I through III rectal carcinoma between 01 Jan 2005 and 31 Dec 2007 with or without preoperative chemoradiotherapy (groups A and B, respectively) were included. Multivariate statistical analysis using propensity score analysis was carried out regarding outcome parameters total anastomotic leak rate, rate of anastomotic leaks requiring reoperation, and postoperative bladder dysfunction. RESULTS: A total of 2,085 patients were included (group A, n = 676, group B, n = 1,409). Significant differences were present between groups regarding age, sex, distance of the tumor from the anal verge, pT-stage, UICC stage, hepatic risk factors, and use of protective enterostomy by univariate analysis. Multivariate logistic regression including these parameters was used to calculate the propensity score (likelihood to be assigned to group A or B as a consequence of the individual profile of these factors) for each patient. When outcome parameters were compared between groups A and B after stratification for propensity score, no significant differences regarding postoperative bladder dysfunction (p = 0.12), total anastomotic leak rate (p = 0.56), and anastomotic leaks requiring reoperation (p = 0.56) could be demonstrated. CONCLUSION: Neoadjuvant chemoradiotherapy for rectal carcinoma does not increase the risk for anastomotic leakage or postoperative bladder dysfunction after curatively intended sphincter-preserving rectal resection.

Cytokines and 90Y-Radioembolization: Relation to Liver Function and Overall Survival.

BACKGROUND: To evaluate the course of pro- and anti-inflammatory cytokines after 90Y-radioembolization (RE) of liver malignancies and to identify prognosticators for liver-related adverse events and survival. METHODS: In 34 consecutive patients with secondary or primary liver tumors scheduled for RE, the following cytokines were measured prior to and 2 h, 3 days, and 6 weeks after RE: interleukin (IL) -1, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), and interferon-γ. Liver function impairment was defined as an elevation of liver-related laboratory values as graded by CTCAE ≥ 2 and/or serum bilirubin ≥30 µmol/l and/or development of ascites at 6-week follow-up. RESULTS: Significant changes over time were seen in IL-1 (increase from 0.4 pg/ml (±0.7) at baseline to 1.1 pg/ml (±1.4) 3 days after RE (p = 0.02)), and in IL-6 (increase from 16.8 pg/ml (±21.8) at baseline to 54.6 pg/ml (±78.2) 3 days after RE (p = 0.003)). Baseline values of IL-6 and IL-8 were independently associated with liver function impairment at follow-up as well as decreased survival with an optimal cutoff at 6.53 and 60.8 pg/ml, respectively. CONCLUSION: Expected changes in pro- and anti-inflammatory cytokines after RE were shown. Furthermore, baseline values of IL-6 and IL-8 were associated with later liver dysfunction and survival. We hypothesize that these biomarkers are potential prognosticators and might help in patient selection for RE.

Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model.

PURPOSE: We aimed to assess the feasibility, efficacy and safety of a local application of sorafenib within a conventional transarterial chemoembolization in the VX-2 tumor-bearing rabbit model. METHODS: VX-2 tumors were induced in the left liver lobe of 10 New Zealand White rabbits. After two weeks, growth was verified by contrast-enhanced computed tomography (CT). Five rabbits were treated by transarterial chemoembolization using an emulsion of sorafenib and ethiodized oil (referred to as SORATACE; n=5). Rabbits receiving oral sorafenib for two weeks (n=2) and untreated rabbits (n=3) served as controls. After two weeks, contrast-enhanced CT was performed, followed by animal necropsy. RESULTS: The change in tumor diameter between baseline and follow-up was significantly different in the SORATACE group compared with the other groups; tumor shrinkage was observed in the SORATACE group only (P = 0.016). In both control groups, preserved hypervascularity was seen in the follow-up CT in all but one tumor. All tumors in the SORATACE group were devascularized in the follow-up CT. Importantly, substantial parenchymal damage in nontargeted areas of the tumor-bearing liver lobe was seen in rabbits treated with SORATACE. CONCLUSION: SORATACE demonstrated high efficacy in the treatment of experimental VX-2 liver tumors but was also associated with substantial liver parenchymal toxicity.

Radiation-induced liver damage: correlation of histopathology with hepatobiliary magnetic resonance imaging, a feasibility study.

PURPOSE: Radiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA). METHODS: Patients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluable liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined. RESULTS: Fourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition. CONCLUSIONS: Absence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.

Epidemiology, surgical management and early postoperative outcome in a cohort of gastric cancer patients of a tertiary referral center in relation to multi-center quality assurance studies.

UNLABELLED: The aim of the study was to analyze epidemiologic parameters, treatment-related data and prognostic factors in the management of gastric cancer patients of a university surgical center under conditions of routine clinical care before the onset of the era of multimodal therapies. By analyzing our data in relation with multi-center quality assurance trials [German Gastric Cancer Study - GGCS (1992) and East German Gastric Cancer Study - EGGCS (2004)] we aimed at providing an instrument of internal quality control at our institution as well as a base for comparison with future analyses taking into account the implementation of evolving (multimodal) therapies and their influence on treatment results. MATERIAL AND METHODS: Retrospective analysis of prospectively gathered data of gastric cancer patients treated at a single institution during a defined 10-year time period with multivariate analysis of risk factors for early postoperative outcome. RESULTS: From 04/01/1993 through 03/31/2003, a total of 328 gastric cancer patients were treated. In comparison with the EGGCS cohort there was a larger proportion of patients with locally advanced and proximally located tumors. 272 patients (82.9%) underwent surgery with curative intent; in 88.4% of these an R0 resection was achieved (EGGCS/GGCS: 82.5%/71.5%). 68.2% of patients underwent preoperative endoluminal ultrasound (EUS) (EGGCS: 27.4%); the proportion of patients undergoing EUS increased over the study period. Diagnostic accuracy of EUS for T stage was 50.6% (EGGCS: 42.6%). 77.2% of operated patients with curative intent underwent gastrectomy (EGGCS/GGCS: 79.8%/71.1%). Anastomotic leaks at the esophagojejunostomy occurred slightly more frequently (8.8%) than in the EGGCS (5.9%) and GGCS (7.2%); however, postoperative morbidity (36.1%) and early postoperative mortality (5.3%) were not increased compared to the multi-center quality assurance study results (EGGCS morbidity, 45%); EGGCS/GGCS mortality, 8%/8.9%). D2 lymphadenectomy was performed in 72.6% of cases (EGGCS: 70.9%). Multivariate analysis revealed splenectomy as an independent risk factor for postoperative morbidity and ASA status 3 or 4 as an independent risk factor for early postoperative mortality. The rate of splenectomies performed during gastric cancer surgery decreased substantially during the study period. CONCLUSIONS: Preoperative diagnostics were able to accurately predict resectability in almost 90% of patients which is substantially more than the corresponding results of both the EGGCS and the GGCS. In the future, more wide-spread use of EUS will play an increasing role as stage-dependent differentiation of therapeutic concepts gains acceptance. However, diagnostic accuracy of EUS needs to be improved. Our early postoperative outcome data demonstrate that the quality standard of gastric cancer care established by the EGGCS is being fulfilled at our institution in spite of distinct characteristics placing our patients at higher surgical risk. Besides being a valuable instrument of internal quality control, our study provides a good base for comparison with ongoing analyses on future developments in gastric cancer therapy.

Conversion in laparoscopic colorectal cancer surgery: impact on short- and long-term outcome.

INTRODUCTION: Despite the well-documented safety and effectiveness of laparoscopic colorectal surgery in curative intention, the role of conversion and its impact on short- and long-term outcome after resection of a carcinoma are unclear and continue to give rise to controversial discussion. METHODS: Within the framework of a prospective, multicenter observational study (Laparoscopic Colorectal Surgery Study Group), into which a total of 5,863 patients from 69 hospitals were recruited over a period of 10 years, a subgroup of all patients who had undergone curative resection was analyzed with regard to the effects of conversion. RESULTS: Of the 1409 patients who had undergone curative resection for colorectal carcinoma, conversion had to be performed in 80 (5.7%) cases for the most diverse reasons. The duration of surgery (median: 183 vs. 241 minutes; P<.001) was significantly longer in the conversion group. Perioperatively, significant disadvantages were noted in converted patients in terms of intraoperative blood loss (median: 243 vs. 573 mL, P<.001), need for perioperative blood transfusion (10.8% vs. 33.8%; P<.001), and resumption of bowel movement (median: after 3 vs. 4 days; P<.001). With regard to postoperative morbidity, significant disadvantages were observed in converted patients, in particular in terms of specific surgical complications, including a higher rate of anastomotic insufficiency (5.0% vs. 13.8%; P=.003) and a higher reoperation rate (4.9% vs. 15.0%; P=.001). In the long term, conversion was associated with lower overall survival, but not with poorer disease-free survival. CONCLUSION: Significantly higher postoperative morbidity was observed in patients after conversion, in particular in terms of specific surgical complications. In addition, conversion is associated with overall lower survival but not with poorer disease-free survival.