Perioperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer: Long-Term Follow-Up of the ASSO-LM1 Trial.

In 2007, the ASSO-LM1 trial, a multicenter prospective study, was initiated to investigate the resectability (R0) rate following preoperative combination therapy with XELOX and bevacizumab in patients with potentially resectable colorectal liver metastases. Six cycles of systemic therapy were administered preoperatively, although the sixth cycle did not include bevacizumab, resulting in 5 weeks between the last bevacizumab dose and surgery. Treatment with bevacizumab plus XELOX was restarted for another six cycles postoperatively. In total, 43 patients were enrolled in the ASSO-LM1 trial. Eight patients were ineligible for resection due to protocol violation and progression in two patients. The resectability of operated patients was 97% with 34 R0 resections and one R1 resection. Postoperative morbidity occurred in 22% of patients, of which three operative revisions were related to the primary tumor resection. Efficacy results for response in 38 eligible patients confirmed an ORR of 66%, 31% SD and 3% PD according to RECIST. Preoperative grade 3/4 adverse events were 17% diarrhea, 5% HFS and 5% thromboembolic events. Overall survival significantly differed depending upon the fulfillment of adjuvant treatment in curative resected patients (59.1 mo vs. 30.8 mo). In conclusion, the ASSO-LM1 trial is a hypothesis-generating study confirming the prognostic benefits of perioperative therapy with XELOX and bevacizumab in patients with metastatic colorectal cancer confined to the liver.

Glucagon-like peptide-1 and glucagon-like peptide-2 regulation during human liver regeneration.

Accumulating evidence suggests that metabolic demands of the regenerating liver are met via lipid metabolism and critical regulators of this process. As such, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) critically affect hepatic regeneration in rodent models. The present study aimed to evaluate potential alterations and dynamics of circulating GLP-1 and GLP-2 in patients undergoing liver resections, focusing on post-hepatectomy liver failure (PHLF). GLP-1, GLP-2, Interleukin-6 (IL-6) and parameters of lipid metabolism were determined perioperatively in fasting plasma of 46 patients, who underwent liver resection. GLP-1 and GLP-2 demonstrated a rapid and consistently inverse time course during hepatic regeneration with a significant decrease of GLP-1 and increase of GLP-2 on POD1. Importantly, these postoperative dynamics were significantly more pronounced when PHLF occurred. Of note, the extent of resection or development of complications were not associated with these alterations. IL-6 mirrored the time course of GLP-2. Assessing the main degradation protein dipeptidyl peptidase 4 (DPP4) no significant association with either GLP-1 or -2 could be found. Additionally, in PHLF distinct postoperative declines in plasma lipid parameters were present and correlated with GLP-2 dynamics. Our data suggest dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, rather caused by an increase in expression/release than by changes in degradation capacity and might be associated with inflammatory responses. Their close association with circulating markers of lipid metabolism and insufficient hepatic regeneration after liver surgery suggest a critical involvement during these processes in humans.

Comparison of nab-paclitaxel plus gemcitabine in elderly versus younger patients with metastatic pancreatic cancer: Analysis of a multicentre, prospective, non-interventional study.

BACKGROUND: Pancreatic cancer (PC) ranks among the deadliest malignancies worldwide. In the MPACT study, first-line nab-paclitaxel plus gemcitabine (nab-P/G) demonstrated activity (median overall survival [OS], 8.7 months) and tolerability in patients with metastatic PC (mPC). However, the clinical evidence of nab-P/G in the elderly (>70 years), who account for the majority of patients with mPC, is limited. This is the first prospective, multicentre, non-interventional study evaluating the tolerability and effectiveness of nab-P/G in younger (≤70 years) versus elderly (>70 years) patients with mPC in the daily clinical routine. METHODS: Eligible patients with mPC were treated with nab-P/G and observed until disease progression or unacceptable toxicity. The primary objectives were safety and tolerability of nab-P/G, and the secondary objectives were efficacy and real-life dosing. RESULTS: A total of 317 patients with mPC (median age, 70 years) were recruited, of which 299, aged ≤70 (n = 162) and >70 (n = 137) years, were eligible for analysis. Baseline characteristics and the safety profile were comparable between the groups. However, fatigue (22.8% versus 13.0%) and decreased appetite (8.8% versus 1.2%) were more frequent in elderly patients. Younger versus elderly patients equally benefited in terms of objective response rate (36% versus 48%), median progression-free survival (5.6 versus 5.5 months; hazard ratio [HR] = 1.03; p = 0.81) and OS (10.6 versus 10.2 months; HR = 0.89; p = 0.4). In addition, the median treatment duration (5 versus 4 cycles), relative dose intensity (70% versus 74%) or reasons for treatment discontinuation were similar. Most patients (56.2% versus 47.4%) benefited from a second-line therapy. CONCLUSION: This prospective real-world analysis confirms the feasibility and tolerability of nab-P/G treatment and reveals OS data similar for younger patients and elderly patients aged >70 years. CLINICALTRIALS. GOV REGISTRATION: NCT02555813. AUSTRIAN NIS REGISTRY: NIS005071.

The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: post hoc analysis of an Austrian multicenter, noninterventional study.

BACKGROUND: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. METHODS: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. RESULTS: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94, p = 0.020). CONCLUSIONS: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Limited value of CA 19-9 in predicting early treatment failure in patients with advanced pancreatic cancer.

OBJECTIVE: The role of CA 19-9 in monitoring treatment response in advanced pancreatic cancer remains uncertain. We assessed its value in predicting early failure of first-line chemotherapy. METHODS: Data of 84 patients with advanced pancreatic cancer who had received first-line chemotherapy were analyzed with regard to changes in CA 19-9 during the first 2 months of treatment. RESULTS: Median time to progression and overall survival in patients with a transient increase in CA 19-9 during month 1 (n = 15; 5.5 and 13 months) and in those with no increase during the 2 months (n = 52; 6.5 and 12 months) were comparable and slightly above the median values of the entire study population. The hazard ratios for disease progression for a 20% increase in CA 19-9 during the first and second month of therapy were 1.065 and 1.339 in the univariate- and 1.092 and 1.298 in the multiple Cox regression model, respectively. CA 19-9 did not influence survival. CONCLUSION: Our results suggest that early CA 19-9 measurements are weakly associated with disease progression rather than survival in patients with advanced pancreatic cancer receiving palliative chemotherapy. In view of a possible tumor marker flare, values after the first month of therapy must be interpreted with caution.

The 3-60 criteria challenge established predictors of postoperative mortality and enable timely therapeutic intervention after liver resection.

BACKGROUND: To date, definitions of liver dysfunction (LD) after hepatic resection rely on late postoperative time points. Further, the used parameters are markedly influenced by perioperative management. Thus, we aimed to establish a very early postoperative score to predict postoperative mortality. METHODS: Liver related parameters were evaluated after liver resection in a retrospective evaluation cohort of 228 colorectal cancer patients with liver metastasis (mCRC) and subsequent validation in a prospective set of 482 consecutive patients from 4 independent institutions undergoing hepatic resection was performed. RESULTS: C-reactive protein (CRP, AUC =0.739, P<0.001) and antithrombinIII-activity (ATIII, AUC =0.844, P<0.001) on the first postoperative day (POD) were found to be elevated in patients with LD. Cut-off values for CRP at 3 mg/dL and for ATIII at 60% significantly identified high-risk patients for postoperative LD and mortality (P<0.001) and thus defined the 3-60 criteria on POD1. The 3-60 criteria showed superior sensitivity and specificity compared to established criteria for LD [3-60 criteria: total positive patients: 26 patients (70% mortality detected), odds ratio (OR): 48.8; International Study Group for Liver Surgery: total positive patients: 43 (70% mortality detected), OR: 23.3; Peak7: total positive patients: 9 (30% mortality detected), OR: 27.8; 50-50: total positive patients: 9 (30% mortality detected), OR: 27.8]. These results could be validated in a multi-center analysis and ultimately the 3-60 criteria remained an independent predictor of postoperative mortality upon multivariable analysis. CONCLUSIONS: The 3-60 criteria on POD1 predict postoperative LD and mortality early after liver resection with a comparable or better accuracy than established criteria, allowing for immediate identification of high-risk patients.

Phase II trial of capecitabine plus nab-paclitaxel in patients with metastatic pancreatic adenocarcinoma.

BACKGROUND: Combination chemotherapy regimens including fluoropyrimidines as well as albumin-bound paclitaxel have shown promising results in patients with metastatic pancreatic adenocarcinoma (mPC). Based on the recently described excellent therapeutic index of capecitabine plus nab-paclitaxel in metastatic breast cancer, the present phase II trial was initiated. METHODS: Patients with previously untreated mPC were treated with capecitabine (825 mg/m(2) orally bid on days 1-15) and nab-paclitaxel (125 mg/m(2) intravenously on days 1 and 8) every 3 weeks. In patients without clinically relevant adverse reactions after the 1st treatment course (≤ grade 2 toxicities according to NCI-CTC vs. 4.0, exuding alopecia and fatigue of any degree) and adequate bone marrow function, the nab-paclitaxel dose was escalated to 100 mg/m(2) on days 1, 8 and 15 of each cycle; this intra-individual dose escalation was maintained during subsequent treatment courses if tolerated. The primary endpoint was objective response rate (ORR) according to RECIST criteria, assessed by an independent radiological review committee with evaluation performed every 2 months. RESULTS: Between 12/2013 and 01/2015, 30 patients were entered in this monocentric academic phase II trial. All patients had an ECOG performance status of 0-1, 80% had liver metastases and 23% had biliary stents in place at time of study initiation. Median CA19-9 was 1,004 U/mL (0.9-100.000 U/mL). In all patients except 2, a dose escalation of nab-paclitaxel after the 1st treatment course could be accomplished. The most common grade 3 adverse events (AEs) included transient sensory neuropathy (23%), (afebrile) neutropenia (17%), hand-foot-syndrome (13%) and phototoxic skin reaction (10%). Among 29 RECIST-response assessable patients, the ORR was 41.4% and stable disease (SD) was noted in 34.5%, resulting in a disease control rate (DCR) of 76%. After a median follow-up duration of 10.3 months (range, 1.9-19.0 months), 13/30 patients (43.3%) are presently being alive. CONCLUSIONS: The combination of capecitabine + nab-paclitaxel at these doses and scheduling was well tolerated and showed substantial antitumor efficacy.

Prognostic scoring in colorectal cancer liver metastases: development and validation.

HYPOTHESIS: A prognostic scoring system for colorectal cancer liver metastases that is derived from unselected patients referred for hepatic resection would improve the applicability and increase the accuracy of prognostication. DESIGN: Retrospective analysis of prospectively documented data; validation against an unrelated cohort from another institution. The median follow-up was 16.4 months (95% confidence interval, 15.0-17.8 months) (original cohort). SETTING: Two tertiary referral centers at unrelated university hospitals. PATIENTS: Independent prognosticators of survival were derived from 337 patients with colorectal cancer liver metastases referred for consideration of liver resection, and prognostic scores were calculated in 269 patients (79.8%) (original cohort). Calculation of prognostic scores was also applied to 193 patients referred and treated in an unrelated institution (validation cohort). MAIN OUTCOME MEASURES: Kaplan-Meier survival curve analysis (log-rank test) between different prognostic groups in the original and the validation cohorts. RESULTS: Independent prognosticators of survival were Dukes stage, number of metastases, and serum concentrations of carcinoembryonic antigen, alkaline phosphatase, and albumin. Significant differences were found in cumulative overall survival between patients assigned to good, moderate, and poor prognoses in the original and validation cohorts (P<.05). Liver resection improved survival in all prognostic groups. However, no patient with poor prognosis and only 19.7% (13 of 66) of patients with moderate prognosis survived 5 years, compared with 62.5% (10 of 16) of patients with good prognosis (P<.001). CONCLUSIONS: This prognostic scoring system is derived from and can be applied to patients with colorectal cancer liver metastases at the time of referral for consideration of surgery. Patients with poor prognosis have no long-term benefit from curative liver resection and should therefore be considered for combined multimodal treatment.

Intraoperative ultrasonography in patients who undergo liver resection or transplantation for hepatocellular carcinoma.

Careful staging of hepatic tumors forms the basis of appropriate selection of, and is a precondition for, customized treatment. Advances in radiodiagnostic technology have increased the sensitivity of noninvasive liver staging by means of magnetic resonance imaging (MRI), computed tomography (CT), and helical CT (HCT). Nevertheless, surgical exploration and intraoperative ultrasonography (IOUS) are considered the "gold standard." The value of HCT and IOUS was investigated in patients who underwent orthotopic liver transplantation (OLT) (group A; n=23) or hepatic resection for hepatocellular carcinoma (HCC) (group B; n=52). In group A, the results of liver imaging (HCT performed immediately before OLT, IOUS) were compared with histopathological results after 3-mm slicing of the explanted liver. In group B, patients were evaluated by CT (n=8), HCT (n=43), MRI (n=18), or both, as indicated by the respective surgeon. The results were compared with those of surgical exploration and IOUS (n=52), as well as with the pathological examination of the resected liver specimen. In group A, 52 malignant lesions were detected by histopathology. By each of the preoperative examinations (IOUS, HCT), 54 lesions were suspected of being malignant. Thirteen HCCs were missed by HCT (for IOUS: n=4) and 15 lesions were false-positive (for IOUS: n=6). Thirty-nine of 52 lesions were verified to be true-positive by HCT in contrast to 48/52 by IOUS, which resulted in sensitivities of 75% (HCT) and 92% (IOUS, P=0.017), respectively. In group B, the sensitivity of CT was 77%, HCT 90%, MR 93%, and IOUS 99% (P<0.01). In 10%, the strategy of surgical treatment was changed because of IOUS findings. IOUS offered relevant additional information in 6%. Even after sufficient preoperative evaluation, IOUS can provide additional information that frequently has a remarkable impact on surgical decision-making. Identification of HCC is commonly hampered by coexistent cirrhosis. Identification of lesions and orientation of borders to non-tumorous tissue are assessed reliably by IOUS. Thus, IOUS remains a mandatory tool in patients treated by locoregional surgical modalities such as resection, cryotherapy, and intraoperative ethanol instillation for HCC even after refinement of radiological technologies.

Surgery for gastrointestinal stromal tumors of the stomach.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the main mesenchymal neoplasms in the gastrointestinal tract. Tumor size, mitotic rate, and location correlate with potential malignancy and recurrence rate. Results of surgical treatment of gastric GIST are analyzed with emphasis on recurrence of disease after intermediate follow-up. METHODS: From 1998 to 2006, a total of 63 patients (median age 62.1 +/- 14.1) underwent gastric resection for GIST. Fifty-five patients (93.6%) returned for follow-up investigations, which included computed tomography in 45, gastroscopy in 32, and endosonography in 29. Positron emission tomography was done in five patients. RESULTS: Mean tumor size was 5.3 +/- 3.8 cm. Open atypical gastric resection was done in 32, distal gastric resection in five, and remnant gastrectomy in four patients. Laparoscopic gastric resection was initiated in 22 patients; the conversion rate was four of 22 (18.2%). Overall, R0 resection was reached in 61/63 patients (96.8%). According to the Fletcher criteria, 33 tumors (52.4%) were classified as intermediate or high risk GIST. Six patients (9.5%) died of unrelated causes before follow-up. After a median follow-up of 2.5 years, overall recurrence rate was 7.0% after R0 resection. CONCLUSION: Histologically proven complete resection is an effective treatment for gastric GIST. Laparoscopic procedures were carried out successfully in selected patients.

Resection of hilar cholangiocarcinomas: pivotal prognostic factors and impact of tumor sclerosis.

The well-known poor prognosis of proximal bile duct cancer is due to its unfortunate anatomical location and its late diagnosis. Successful tumor resection, which is considered to be optimal treatment, depends on many factors. Eighty-eight patients suffering from proximal bile duct cancer underwent surgical exploration at our institution between 1977 and 1998. In 37 patients the tumor was resectable; in the remaining 51 patients exploratory laparotomy or a palliative operation was performed. The median survival after tumor resection was 18.6 months, but median survival after a palliative procedure or an exploratory laparotomy was only 3.4 months (p < 0.001). A curative R0 resection was possible in 11 patients, an R1 resection was performed in 22 patients, and 4 patients had an R2 resection. The median survival rate after R0 resection was 83.6 months, 12.3 months after R1 resection, and 2.7 months after R2 resection (p < 0.001). Survival after resection in patients with negative lymph nodes (n = 30) was significantly longer than in those with positive lymph nodes (n = 7) (p = 0.022). Grade of tumor sclerosis tended to have an influence on resectability rate (p = 0.076). The pattern of tumor growth was without statistical influence. Multivariate analysis revealed resection (p < 0.001) as the only significant prognostic marker for patient survival. Radical resection is the only therapy that provides a chance for long-term survival, with sclerosis of the cancer tending to have an influence on univariate analysis.

Atypical focal nodular hyperplasia of the liver: imaging features of nonspecific and liver-specific MR contrast agents.

OBJECTIVE: The objective of our study was to describe the functional and differential uptake features of atypical focal nodular hyperplasia using different MR contrast agents and to evaluate their potential role in the diagnosis and characterization of focal nodular hyperplasia. MATERIALS AND METHODS: Contrast-enhanced MR images of 45 patients with 85 focal nodular hyperplasia lesions were retrospectively reviewed. In these patients, sonographic findings were nonspecific (n = 37), or CT features were inconclusive (n = 8). Non-liver specific gadolinium chelates were used in 18 patients (48 lesions) suspected of having either focal nodular hyperplasia or hemangioma. The following liver-specific agents were used in patients with suspected focal nodular hyperplasia or metastases: mangafodipir trisodium, 30 patients (55 lesions); ferumoxides, six patients (16 lesions); and SHU 555 A, six patients (six lesions). Individual lesions were quantified by signal intensity and assessed qualitatively by homogeneity, contrast enhancement, and presence of a central scar. RESULTS: At unenhanced MR imaging, the triad of homogeneity, isointensity, and central scar was found in 22% of the focal nodular hyperplasia lesions. On mangafodipir trisodium-enhanced T1-weighted images, all focal nodular hyperplasia lesions showed contrast uptake: in 64% of the lesions, uptake was equal to parenchyma; 25%, greater than the parenchyma; and 11%, less than the parenchyma. On iron oxide-enhanced T2-weighted images, all focal nodular hyperplasia lesions showed uptake of the contrast agent, but contrast uptake in the lesions was less than in the surrounding parenchyma. Dynamic gadolinium chelate-enhanced MR imaging showed early and vigorous enhancement of focal nodular hyperplasia lesions with rapid washout in 88%. Atypical imaging features of the lesions included hyperintensity on T1-weighted images, necrosis and hemorrhage, and inhomogeneous or only minimal contrast uptake. CONCLUSION: For patients in whom the diagnosis of focal nodular hyperplasia cannot be established on unenhanced or gadolinium-enhanced MR imaging, homogeneous uptake of liver-specific contrast agent with better delineation of central scar may help to make a confident diagnosis of focal nodular hyperplasia.