Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with primary liver cancer: a phase II-study (NCT00356161).

BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers. METHODS: 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5-Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration. RESULTS: Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed. CONCLUSIONS: HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated.

Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with colorectal liver metastases: a Phase II-study and historical comparison with the surgical approach.

BACKGROUND: The high complication rates of surgically implanted port catheter systems (SIPCS) represents a major drawback in the treatment of isolated liver neoplasms by hepatic arterial infusion (HAI) of chemotherapy. Interventionally implanted port catheter systems (IIPCS) have evolved into a promising alternative that enable initiation of HAI without laparatomy, but prospective data on this approach are still sparse. Aim of this study was to evaluate the most important technical endpoints associated with the use of IIPCS for the delivery of 5-fluorouracil-based HAI in patients with colorectal liver metastases in a phase 2-study, and to perform a non-randomised comparison with a historical group of patients in which HAI was administered via SIPCS. METHODS: 41 patients with isolated liver metastases of colorectal cancer were enrolled into a phase II-study and provided with IIPCS between 2001 and 2004 (group A). The primary objective of the trial was defined as evaluation of device-related complications and port duration. Results were compared with those observed in a pre-defined historical collective of 40 patients treated with HAI via SIPCS at our institution between 1996 and 2000 (group B). RESULTS: Baseline characteristics were balanced between both groups, except for higher proportions of previous palliative pre-treatment and elevated serum alkaline phosphatase in patients of group A. Implantation of port catheters was successful in all patients of group A, whereas two primary failures were observed in group B. The frequency of device-related complications was similar between both groups, but the secondary failure rate was significantly higher with the use of surgical approach (17% vs. 50%, p < 0.01). Mean port duration was significantly longer in the interventional group (19 vs. 14 months, p = 0.01), with 77 vs. 50% of devices functioning at 12 months (p < 0.01). No unexpected complications were observed in both groups. CONCLUSION: HAI via interventionally implanted port catheters can be safely provided to a collective of patients with colorectal liver metastases, including a relevant proportion of preatreated individuals. It appears to offer technical advantages over the surgical approach.

Cetuximab: appraisal of a novel drug against colorectal cancer.

Cetuximab (C225, Erbitux, Merck, Darmstadt, Germany) is a human-mouse chimeric therapeutic monoclonal antibody (mAb) that competitively binds to the extracellular domain of the human epidermal growth-factor receptor (EGFR). It has been developed out of the murine antibody M225 "from bench to bedside" in less than two decades, and is the anti-EGFR mAb furthest ahead in clinical evaluation. In Europe, cetuximab is approved for the treatment of patients with EGFR-expressing, metastatic colorectal cancer after failure of treatment with irinotecan since 2004, and for the treatment of patients with locally advanced squamous cell cancer of the head and neck concomitant to radiotherapy since 2006. We here summarize the current role of cetuximab in the treatment of colorectal cancer, give an overview on the ongoing studies, address the most important controversies, and point out the chances and challenges for the future use of cetuximab in colorectal cancer and other human malignancies.

Detection of circulating tumor-associated antigen depends on the domains recognized by the monoclonal antibodies used: N-terminal trimmed EpCAM-levels are much higher than untrimmed forms.

The measurement of tumor-associated proteins is of high diagnostic value in the follow-up of cancer patients. Most tests ignore that various forms of the protein can exist; especially in epithelial cancers and the soluble receptors they produce. We choose EpCAM as model-antigen to analyze whether tests recognizing different domains of the protein give different results in patients' sera. EpCAM-reactive autoantibodies are present in the sera of patients with colorectal carcinoma, however little is known about the existence and possible relevance of circulating soluble EpCAM protein. Most monoclonal EpCAM-antibodies recognize the first EGF-like repeat and fail to detect N-terminal trimmed protein. We developed a novel ELISA to determine the concentration of serum EpCAM with mAbs recognizing the second EGF-like repeat. In 59 healthy controls, EpCAM concentrations ranged from 232 to 8893ng/ml (mean 1525ng/ml). Levels of EpCAM in 412 patients with adenocarcinoma were somewhat higher with concentrations ranging from 176 to 36,259ng/ml (mean 1971ng/ml). In direct comparison, the untrimmed protein specific ELISA detected lower levels and frequencies as compared to the EGFII-specific ELISA. Only sera with less than 1µg/ml circulating EGFII-EpCAM (66% of the sera) contained EpCAM-specific IgG antibodies. The absence of IgG antibodies in the sera with more than 1µg/ml circulating EpCAM was not due to immune complex formation. Anti-EpCAM IgA and IgM antibodies did not show such a correlation. It will be important to assess whether the presence of high levels of circulating EGFII-EpCAM is associated with side effects in patients given immunotherapy.

Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era.

BACKGROUND: A growing number of patients with hepatocellular carcinoma undergo liver transplantation, but there is little data on recurrence and its treatment in the posttransplant setting. METHODS: This article presents a retrospective analysis of adult hepatocellular carcinoma patients. The aim of the study was to characterize the clinical pattern of posttransplant hepatocellular carcinoma recurrence, treatment options in recurrence and overall survival after liver transplantation and after recurrence. RESULTS: A total of 139 patients with histological proven hepatocellular carcinoma was included in the study. The median follow-up after liver transplantation was 37.2 months. Twenty-four of 139 patients experienced a recurrence. In 72.7% of the cases, the hepatocellular carcinoma recurred outside the transplant. Median overall survival after recurrence was 23.1 months. A total of 68.2% of patients received a mean of 2.2 treatments for posttransplant hepatocellular carcinoma recurrence. While on treatment with sorafenib, the use of mTOR inhibitors and radiotherapy had no statistically significant effect on overall survival, complete surgical resection of metastatic lesions significantly improved overall survival. Non-resectable patients with isolated hepatic relapse also benefited from local control strategies. CONCLUSIONS: Posttransplant hepatocellular carcinoma recurrence frequently is located outside the transplant, and despite the proven efficacy of sorafenib, complete surgical resection of metastatic lesions remains the hallmark of treatment.

Phase II feasibility study on the combination of two different regional treatment approaches in patients with colorectal "liver-only" metastases: hepatic interstitial brachytherapy plus regional chemotherapy.

The aim of this study was to evaluate the feasibility, safety, and efficacy of combined treatment with hepatic interstitial brachytherapy (HIB) and hepatic arterial infusion (HAI) of chemotherapy after interventional implantation of port catheter systems. Thirty-three patients with unresectable "liver-only" metastases of colorectal cancer were treated with both HIB and HAI during the course of their disease. All 33 patients had recurrent disease and 27 had received previous chemotherapy. Of these, 15 received HAI first and were then consolidated with HIB, 9 started with HIB and were continued with HAI, and 9 received first HIB and subsequently HAI after hepatic disease progression. Patients were evaluated for treatment characteristics, side effects, and efficacy. Comparisons between treatment groups were also performed. The median tumor diameter of metastases treated with brachytherapy was 4.6 cm (range: 1-12 cm). The median minimal irradiation dose inside the tumor margin was 18 Gy administered to a mean of two metastases in 69 interventions. Minor (n = 4) and major (n = 3) complications occurred in 10% of interventions. WHO grade III adverse events of the regional chemotherapy were observed in seven patients; grade IV, in one patient. At a median follow-up of 28 months (range: 7-74 months), the median time to disease progression after first treatment was 10.5 months (range: 1-35 months). Of 138 metastases treated by brachytherapy, 16 local recurrences were seen (mean, 12.3 months; range, 3-45 months). No signs of hepatic failure were observed in any of our patients. In conclusion, combinations of two minimally invasive therapeutic methods are feasible, with acceptable complication rates, and provide promising results in colorectal cancer patients with unresectable hepatic metastases.

Multislice computed tomographic angiography for preinterventional planning of port placement for intra-arterial hepatic infusion chemotherapy.

PURPOSE: To determine the impact of preinterventional multislice computed tomographic angiography (MSCTA) on the interventional management of patients scheduled for hepatic port placement. METHODS: A total of 21 patients with metastatic colorectal cancer confined to the liver were referred for interventional placement of an intra-arterial hepatic port system and underwent triphasic MSCT of the abdomen. The arterial phase images were processed to reveal the arterial anatomy, to identify anomalies, and to prospectively plan the interventional management. Ten anatomical characteristics of the liver blood supply, which were considered to be crucial for the interventional procedure, were analyzed per patient (presence, origin, and configuration of liver arteries, angles, and distances to connected vessels). Based on these data, 6 predictions on the interventional procedure were made, including final catheter position, catheter type, the necessity for guiding catheter, expenditure of time, and the need for changing the standard implantation procedure. All findings were correlated with catheter angiography during the port placement. RESULTS: Normal vascular anatomy of the hepatic arteries was seen in 43% of the patients. As vascular variants, most frequently, we found an accessory right artery (19%), a replaced right artery arising from the superior mesenteric artery (14%), or a left hepatic artery, fed by the left gastric artery, in combination with a middle hepatic artery arising from the right hepatic artery (10%). The correct detailed anatomical description compared with angiographic findings was provided by an MSCTA image analysis in 20 of 21 patients (sensitivity = 0.98, specificity = 0.99; chi2 = 1.024, P = 0.311; 95% confidence interval (CI) = 95.24; 76.18-99.88). The prospective planning of the angiographic management, including the appropriate choice of the port catheter based on MSCTA, was correct in 17 of 21 patients (sensitivity = 0.71, specificity = 0.76; chi2 = 2.487, P = 0.115; 95% CI = 80.95; 58.09-94.55). CONCLUSIONS: The MSCTA is effective for planning interventional port implantation in patients considered for hepatic arterial infusion chemotherapy.

Adjuvant chemotherapy with folinic acid and 5-fluorouracil in patients with locally advanced rectal cancer previously treated by preoperative radiochemotherapy and curative tumor resection.

BACKGROUND AND AIMS: The role of postoperative adjuvant chemotherapy in patients with rectal cancer pretreated by preoperative radiochemotherapy (RCT) and curative surgery is still poorly investigated. PATIENTS AND METHODS: We pooled data from both arms of a phase III trial in which patients with locally advanced (T3/4) rectal cancer were randomized to preoperative RCT alone or combined with pelvic radio-frequency hyperthermia. After surgery, R0-resected patients were scheduled to adjuvant chemotherapy with four monthly courses of 50 mg folinic acid (FA) and gradually escalated 5-fluorouracil (5-FU, 350-500 mg/m2, days 1-5). Reasons preventing initiation of chemotherapy and treatment-related toxicities were evaluated. Patients' characteristics and survival parameters were compared between the treated and untreated patient groups. RESULTS: Out of 93 patients, 73 (79%) started adjuvant chemotherapy, whereas 19 (21%) did not, mostly due to perioperative complications and refusal. Chemotherapy-related toxicities were mild to moderate in most cases, but--together with protracted postoperative complications--prevented the intended dose escalation of 5-FU in 71% of patients. Distant-failure-free (p=0.03) and overall survival (p=0.03) were improved in the chemotherapy group, although there was a negative selection of patients with unfavourable characteristics into the untreated patient group. INTERPRETATION/CONCLUSION: Adjuvant chemotherapy using FA and 5-FU can be safely applied to the majority of patients with rectal cancer pretreated by RCT and surgery. Survival data are not suitable to allow far-reaching conclusions, but are in line with suggestions of a favourable effect of adjuvant chemotherapy in these patients.

Fusion imaging using a hybrid SPECT-CT camera improves port perfusion scintigraphy for control of hepatic arterial infusion of chemotherapy in colorectal cancer patients.

PURPOSE: Exclusive and homogeneous perfusion of the liver is considered essential for the efficacy of hepatic arterial infusion of chemotherapy (HAI). The aim of this study was to evaluate port perfusion scintigraphy in colorectal cancer patients using a hybrid SPECT-CT system for control of minimally invasive intra-arterial port systems within the scope of a phase II trial. METHODS: In 24 consecutive patients, the perfusion territories of intra-arterial hepatic port systems were assessed by port scintigraphy with( 99m)Tc-labelled macroaggregated albumin employing planar imaging, SPECT and SPECT-CT (acquired with a hybrid SPECT-CT camera). The results of blinded reading of the scintigraphic modalities concerning the intra- and extrahepatic perfusion pattern were compared with combined image analysis (angiography and contrast-enhanced dedicated CT) and patient history for validation. RESULTS: Extrahepatic perfusion was correctly seen in three patients, while suspected extrahepatic perfusion could be excluded in one. In 46 liver lobes, perfusion patterns were correctly visualised by SPECT-CT in 100% of cases (planar, 67%; SPECT, 86%). Assessing the perfusion pattern inside the liver on a segmental basis (segments, n=138), SPECT-CT revealed correct segmental assignment of tracer distribution in 100% and was significantly superior to SPECT alone (accuracy, 84%; p<0.001). The scintigraphic findings resulted in changes in therapeutic management in 8/24 patients (33%); in two of these the relevant findings were visualised only by SPECT-CT. CONCLUSION: In patients receiving HAI, port perfusion scintigraphy by fusion imaging with a hybrid SPECT-CT system provides important information for therapy optimisation and appears to be superior to SPECT alone.

[Standards and perspectives in locoregional hyperthermia]. / Lokoregionäre Hyperthermie: Standards und neue Entwicklungen.

The term "hyperthermia" summarises different procedures of raising the temperature of a tumour-loaded tissue to a temperature of 40-43 degrees C. In this context, locoregional procedures (radiative/capacitive local, interstitial and regional hyperthermia; endoluminal hyperthermia), hyperthermic perfusion techniques (hyperthermic peritoneal and isolated limb perfusion), and whole-body hyperthermia differ with regard to their indication, expenditure of application, and evidence of efficacy. All hyperthermia techniques have in common that they have no sufficient antineoplastic activity alone in the temperature range below 43-45 degrees C, but act in a synergistic way with radiotherapy and certain cytotoxic drugs. 14 out of 18 published randomised trials on hyperthermia as an adjunct to standard radio- or chemotherapy refer to locoregional approaches. Particular progress has been made in regional radiofrequency hyperthermia, where novel multiantenna-applicators and their integration into MR-applicators ("hybrid-systems") have recently been introduced into clinical practice. In addition, combinations of hyperthermia with novel technologies (magnetic fluid hyperthermia, thermosensitive liposomes, immunotherapy, gene targeting) are imminent. We here give a critical update on the proven indications of the different locoregional hyperthermia approaches and on the current clinical and technological progress in this field.

Hepatic arterial port systems for treatment of liver metastases: factors affecting patency and adverse events.

PURPOSE: To assess the outcome of interventional hepatic arterial port placement in a prospective phase II trial. MATERIALS AND METHODS: One-hundred five consecutive patients were included in this study. Primary endpoint was port patency; secondary endpoints were complications, toxicity, response, and progression free and overall survival. Seventy-eight patients presented with liver metastasis only, 6 patients had additional minor extrahepatic disease, and 21 patients had no evidence of disease after liver resection, laser-induced thermotherapy, or computed tomography (CT)-guided interstitial brachytherapy of liver metastasis. Exclusive access route was the femoral artery. Subgroup analysis compared either 4-F catheters (n = 58) to 2.2-F (n = 33) and 2.7-F (n = 20) microcatheters or different strategies in anatomic variants of the celiac branch: neglect (n = 10) or embolization of minor hepatic feeders (n = 11), splenic arterial port (n = 8), double port (n = 7). RESULTS: Technical success was 99%. Assisted port patency after 6 months was 93%. Complications demanding port revisions were significantly lower in patients receiving 4-F versus 2.2-F and 2.7-F systems (P <.001), with disconnection as the major problem with use of microcatheters. Hepatic artery thrombosis occurred in 10 patients (9%), with successful lysis in two patients. With use of 4-F and 2.2-F catheters, there was no difference with respect to catheter occlusion or hepatic thrombosis. No differences were noted in complications or outcome applying four different strategies in celiac branch variants. In a subgroup of patients receiving folinic acid/5-fluorouracil (170 mg/600 mg; 10% dose escalation per cycle) for 5 days every 4 weeks only 15% experienced Grade 3 toxicity. Patients with liver metastasis and salvage therapy demonstrated progression-free survival of 63% after 6 months and a median survival of 16 months. CONCLUSION: Interventional placement of hepatic arterial port systems may overcome frequent hepatic arterial chemotherapy failures as encountered in all published major trials on hepatic arterial infusion.