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Background: Patients with chronic limb threatening ischemia have a risk of undergoing a major amputation within 1 year of nearly 30% with a substantial risk of re-amputation since wound healing is often impaired. Quantitative assessment of regional tissue viability following amputation surgery can identify patients at risk for impaired wound healing. In quantification of regional tissue perfusion, near-infrared (NIR) fluorescence imaging using Indocyanine Green (ICG) seems promising. Methods: This pilot study included adult patients undergoing lower extremity amputation surgery due to peripheral artery disease or diabetes mellitus. ICG NIR fluorescence imaging was performed within 5 days following amputation surgery using the Quest Spectrum Platform (R). Following intravenous administration of ICG, the NIR fluorescence intensity of the amputation wound was recorded for 10 minutes. The NIR fluorescence intensity videos were analyzed and if a fluorescence deficit was observed, this region was marked as "low fluorescence." All other regions were marked as "normal fluorescence." Results: Successful ICG NIR fluorescence imaging was performed in 10 patients undergoing a total of 15 amputations. No "low fluorescence" regions were observed in 11 out of 15 amputation wounds. In 10 out of these 11 amputations, no wound healing problems occurred during followup. Regions with "low fluorescence" were observed in 4 amputation wounds. Impaired wound healing corresponding to these regions was observed in all wounds and a re-amputation was necessary in 3 out of 4. When observing time-related parameters, regions with low fluorescence had a significantly longer time to maximum intensity (113 seconds vs. 32 seconds, P = 0.003) and a significantly lesser decline in outflow after five minutes (80.3% vs. 57.0%, P = 0.003). Conclusions: ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Quantitative assessment of regional perfusion remains challenging due to influencing factors on the NIR fluorescence intensity signal, including camera angle, camera distance and ICG dosage. This was also observed in this study, contributing to a large variety in fluorescence intensity parameters among patients. To provide surgeons with reliable NIR fluorescence cut-off values for prediction of wound healing, prospective studies on the intraoperative use of this technique are required. The potential prediction of wound healing using ICG NIR fluorescence imaging will have a huge impact on patient mortality, morbidity as well as the burden of amputation surgery on health care.

Objectives Current diagnostic modalities for patients with peripheral artery disease (PAD) mainly focus on the macrovascular level. For assessment of tissue perfusion, near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) seems promising. In this prospective cohort study, ICG NIR fluorescence imaging was performed pre- and post-revascularization to assess changes in foot perfusion. Methods ICG NIR fluorescence imaging was performed in 36 patients with PAD pre- and post-intervention. After intravenous bolus injection of 0.1 mg/kg ICG, the camera registered the NIR fluorescence intensity over time on the dorsum of the feet for 15 min using the Quest Spectrum Platform®. Time-intensity curves were plotted for three regions of interest (ROI): (1) the dorsum of the foot, (2) the forefoot, and (3) the hallux. Time-intensity curves were normalized for maximum fluorescence intensity. Extracted parameters were the maximum slope, area under the curve (AUC) for the ingress, and the AUC for the egress. The non-treated contralateral leg was used as a control group. Results Successful revascularization was performed in 32 patients. There was a significant increase for the maximum slope and AUC egress in all three ROIs. The most significant difference was seen for the maximum slope in ROI 3 (3.7%/s to 6.6%/s, p < 0.001). In the control group, no significant differences were seen for the maximum slope and AUC egress in all ROIs. Conclusions This study shows the potential of ICG NIR fluorescence imaging in assessing the effect of revascularization procedures on foot perfusion. Future studies should focus on the use of this technique in predicting favorable outcome of revascularization procedures.

Highlights • Near-infrared fluorescence imaging should be considered as an additional imaging technique to intraoperative ultrasound during surgery for hepatic metastasis. • Near-infrared fluorescence imaging can aid surgeons in the identification of preoperatively identified liver metastases from primary GIST. • For the detection of additional superficially located liver metastases from primary GIST near-infrared fluorescence imaging can be used. • Real-time evaluation of resection margins with NIRF imaging may lead to a lower number of R1 resections., Introduction and importance Gastrointestinal stromal tumors are the most prevalent mesenchymal tumors of the gastrointestinal tract. Distant metastases are most often found in the liver or peritoneum with surgery being the preferred treatment option. In our center, fluorescence-guided surgery with indocyanine green is used as standard-of-care for hepatic metastases in colorectal cancer. This case report describes fluorescence-guided metastasectomy for a hepatic gastrointestinal stromal tumor in two patients undergoing open liver resection and radiofrequency ablation. Case presentation A 69-year old women was seen during follow-up after laparoscopic resection of a GIST in the lesser curvature of the stomach. Contrast-enhanced computed tomography imaging showed two suspicious lesions in liver segment VI and VIII. Intraoperative near-infrared fluorescence imaging of the liver clearly revealed the lesion in segment VIII, and an additional lesion in segment V – which was not seen on preoperative CT-imaging, neither on intraoperative ultrasonography. The lesion in segment VI was not seen with NIRF imaging due to its deeper location in the liver parenchyma. The second case is an 82-year old man who was also diagnosed with liver metastases from a GIST in the stomach and was scheduled for near-infrared fluorescence-guided liver resection and radio frequency ablation. Clinical discussion In this case report we demonstrated the feasibility of fluorescence-guided surgery in detection of liver metastases and treatment planning of two patients with hepatic GIST metastases using indocyanine green. Conclusion NIRF-imaging with ICG is useful for identification of preoperatively discovered lesions, surgical resection planning and margin evaluation, and for detection of additional hepatic GIST metastases.

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin αvβ6, carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5), mesothelin, prostate-specific membrane antigen (PSMA), urokinase-type plasminogen activator receptor, fibroblast activating receptor, integrin α5 subunit and epidermal growth factor receptor was evaluated using immunohistochemistry. Immunoreactivity was determined using the semiquantitative H-score. Resection specimens from patients after neoadjuvant FOLFIRINOX treatment containing PDAC (n = 32), tumor associated pancreatitis (TAP) and TIF (n = 15), normal pancreas parenchyma (NPP) (n = 32) and tumor positive (n = 24) and negative (n = 56) lymph nodes were included. Integrin αvβ6, CEACAM5, mesothelin and PSMA stainings showed significantly higher expression in PDAC compared to TAP and NPP. No expression of αvβ6, CEACAM5 and mesothelin was observed in TIF. Integrin αvβ6 and CEACAM5 allow for accurate metastatic lymph node detection. Targeting integrin αvβ6, CEA, mesothelin and PSMA has the potential to distinguish vital PDAC from fibrotic tissue after neoadjuvant FOLFIRINOX treatment. Integrin αvβ6 and CEACAM5 detect primary tumors and tumor positive lymph nodes.

Introduction The field of tumor-specific fluorescence-guided surgery has seen a significant increase in the development of novel tumor-targeted imaging agents. Studying patient benefit using intraoperative fluorescence-guided imaging for cancer surgery is the final step needed for implementation in standard treatment protocols. Translation into phase III clinical trials can be challenging and time consuming. Recent studies have helped to identify certain waypoints in this transition phase between studying imaging agent efficacy (phase I–II) and proving patient benefit (phase III). Trial initiation Performing these trials outside centers of expertise, thus involving motivated clinicians, training them, and providing feedback on data quality, increases the translatability of imaging agents and the surgical technique. Furthermore, timely formation of a trial team which oversees the translational process is vital. They are responsible for establishing an imaging framework (camera system, imaging protocol, surgical workflow) and clinical framework (disease stage, procedure type, clinical research question) in which the trial is executed. Providing participating clinicians with well-defined protocols with the aim to answer clinically relevant research questions within the context of care is the pinnacle in gathering reliable trial data. Outlook If all these aspects are taken into consideration, tumor-specific fluorescence-guided surgery is expected be of significant value when integrated into the diagnostic work-up, surgical procedure, and follow-up of cancer patients. It is only by involving and collaborating with all stakeholders involved in this process that successful clinical translation can occur. Aim Here, we discuss the challenges faced during this important translational phase and present potential solutions to enable final clinical translation and implementation of imaging agents for image-guided cancer surgery.

Background: Approximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin alpha(nu)beta 6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin alpha(nu)beta 6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry.Materials & methods: Three tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin anb6 and quantified using the H-score.Results: Immunohistochemical staining for integrin alpha(nu)beta 6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 +/- 71, compared to a mean H-score of 126 +/- 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin anb6 expression. The mean H-score across ten ICC was 33 +/- 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062).Conclusion: Integrin anb6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging. (C) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/

Introduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC.Methods. Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and Ill) in vivo application.Results. In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A.Discussion. This overview identified 7 potential biomarkers that can be used in the development of VSCCspecific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions. (C) 2019 Published by Elsevier Inc.

Background Several studies demonstrated that intraoperative near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) identifies (sub)capsular colorectal liver metastases (CRLM) missed by other techniques. It is unclear if this results in any survival benefit. This study evaluates long-term follow-up after NIRF-guided resection of CRLM using ICG. Methods First, patients undergoing resection of CRLM with or without NIRF imaging were analyzed retrospectively. Perioperative details, liver-specific recurrence-free interval and overall survival were compared. Second, the prognosis of patients in whom additional metastases were identified solely by NIRF was studied. Results Eighty-six patients underwent resection with NIRF imaging and 87 without. In significantly more patients of the NIRF imaging cohort additional metastases were identified during surgery (25% vs. 13%, p = 0.04). Tumors identified solely by NIRF imaging were significantly smaller compared to additional metastases identified also by inspection, palpation or intraoperative ultrasound (3.2 ± 1.8 mm vs. 7.4 ± 2.6 mm, p < 0.001). Liver-specific recurrence-free survival at 4 years was 47% with NIRF imaging and 39% without (hazard ratio at multivariate analysis 0.73, 95% CI 0.42–1.28, p = 0.28). Overall survival at 4 years was 62% and 59%, respectively (p = 0.79). No liver recurrences occurred within 3 years follow-up in 52% of patients in whom additional metastases were resected based on only NIRF imaging. Conclusions This study suggests that NIRF imaging identifies significantly more and smaller tumors during resection of CRLM, preventing recurrences in a subset of patients. Given its safety profile and low expense, routine use can be considered until tumor targeting fluorescent tracers are clinically available.

Background: Pre- and intraoperative visualization of cancer cells using monoclonal antibody-based multimodal tracers can demarcate tumor margins in breast-conserving surgery. We focused on trastuzumab (Tmab) to develop a tracer for HER2-positive breast cancer by conjugation with a fluorescent dye. However, whether Tmab can be used as an imaging tracer for patients who receive Tmab as neoadjuvant therapy (NAD) is unclear, because tumor-cell HER2 could be bound by NAD Tmab at the time of surgery. This study evaluated immunohistochemical (IHC) staining and in vitro experiments with Tmab and pertuzumab (Pmab) as primary antibodies to find a suitable tracer. Pmab has a different antigen epitope than Tmab. Methods: We included 43 patients with HER2-positive breast cancer, who were treated between 2010 and 2016. The NAD cohort (n=10, with 26 lesions) received chemotherapy and Tmab before surgery. The Tmab-naïve cohort (n=33, with 95 lesions) did not receive chemotherapy or Tmab before surgery. We excluded NAD patients with pathological complete responses. We evaluated the lesions, using IHC with Tmab and Pmab. We also performed flow cytometry and fluorescent microscopic analysis (FMA) using Tmab and Pmab conjugated with a fluorescent agent for the HER2-negative MCF7 and HER2-positive HCC1954 cell lines, which were pre-treated with Tmab to model NAD conditions. Results: IHC with anti-HER2 antibody showed positive staining in all patients. Tmab staining was less intense, but positive Tmab IHC reactions were detected on tumor cell membranes in 77.8% of lesions in the naïve cohort and 70.8% in the NAD cohort. Pmab staining was seen in 46.3% of naïve cohort lesions and 22.2% of NAD lesions. Notably, we observed cytoplasmic staining in 87.8% of Pmab-negative cases in the NAD cohort. Flow cytometry showed less Tmab binding than Pmab binding in HCC1954 cells. After 24 hours' pretreatment incubation with Tmab, FMA showed a clear decrease in Tmab binding from 73.3% (without pretreatment) to 5.7%(after pretreatment), and a smaller decrease in Pmab binding from 72.7% (without pretreatment) to 66.4% (after pretreatment) in HCC1954 cells. Conclusions:Pmab might be a suitable tracer for image-guided surgery after NAD, but identifying a suitable tracer for HER2-positive breast cancer will require further study. Citation Format: Otsubo R, Kuppen PJ, Bhairosingh S, Vahrmeijer AL, Smit VT, Nagayasu T, van de Velde CJ, Sier CF. Immunohistochemical staining and in vitro analysis of HER2-positive breast cancer using trastuzumab and pertuzumab to develop an appropriate tracer in image-guided surgery [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-01-01.

Purpose Near-infrared (NIR) fluorescence imaging can provide the surgeon with real-time visualization of, e.g., tumor margins and lymph nodes. We describe and evaluate the Artemis, a novel, handheld NIR fluorescence camera. Procedures We evaluated minimal detectable cell numbers (FaDu-luc2, 7D12-IRDye 800CW), preclinical intraoperative detection of sentinel lymph nodes (SLN) using indocyanine green (ICG), and of orthotopic tongue tumors using 7D12-800CW. Results were compared with the Pearl imager. Clinically, three patients with liver metastases were imaged using ICG. Results Minimum detectable cell counts for Artemis and Pearl were 2 × 105 and 4 × 104 cells, respectively. In vivo, seven SLNs were detected in four mice with both cameras. Orthotopic OSC-19-luc2-cGFP tongue tumors were clearly identifiable, and a minimum FaDu-luc2 tumor size of 1 mm3 could be identified. Six human malignant lesions were identified during three liver surgery procedures. Conclusions Based on this study, the Artemis system has demonstrated its utility in fluorescence-guided cancer surgery. Electronic supplementary material The online version of this article (doi:10.1007/s11307-014-0799-z) contains supplementary material, which is available to authorized users.

Background: Tumour aggressiveness might be related to the degree of main cancer hallmark acquirement of tumour cells, reflected by expression levels of specific biomarkers. We investigated the expression of Aldh1, Survivin, and EpCAM, together reflecting main cancer hallmarks, in relation to clinical outcome of colorectal cancer (CRC) patients. Methods: Immunohistochemistry was performed using a tumour tissue microarray of TNM (Tumour, Node, Metastasis)-stage I–IV CRC tissues. Single-marker expression or their combination was assessed for associations with the clinical outcome of CRC patients (N=309). Results: Increased expression of Aldh1 or Survivin, or decreased expression of EpCAM was each associated with poor clinical outcome, and was therefore identified as clinically unfavourable expression. Analyses of the combination of all three markers showed worse clinical outcome, specifically in colon cancer patients, with an increasing number of markers showing unfavourable expression. Hazard ratios ranged up to 8.3 for overall survival (P

Bacteriochlorin a (BCA) is a second-generation photosensitizer that is effective in tumour destruction upon illumination with light of a wavelength of 760 nm. Tissue penetration by light at this wavelength is greater compared with wavelengths at which commonly used photosensitizers are illuminated, making it possible to treat larger tumours. In a model of experimental liver metastases in rats, we measured lesion sizes after interstitial illumination of tumours at different times after intravenous administration of BCA (10 mg kg(-1) bodyweight), as well as BCA concentrations in liver and tumour tissue. In both, BCA concentrations showed a rapid decline within the first 4 h, followed by a slow decrease over the next 20 h, suggesting biphasic pharmacokinetics. No selective uptake in tumour tissue was observed. A near-linear relationship was found between lesion sizes and liver and tumour BCA concentrations, suggesting that optimal results with photodynamic therapy (PDT) could be obtained by illumination within a short time interval after administration, when tissue concentrations are highest. No severe liver toxicity was observed as indicated by serum ALAT levels. However, in all tumours evaluated, islands of vital-looking cells were present leading to tumour regrowth within 35 days. In view of the obtained lesion diameters of approximately 13 mm after BCA-PDT and the rapid clearance rate of BCA, the concept of a near-infrared absorbing photosensitizer for PDT of liver tumours is a potential interesting strategy. Images Figure 2

In this study we determined the level of tumour necrosis factor alpha (TNF-alpha) in liver and tumour tissue samples obtained from patients with colorectal metastases confined to the liver, who were treated with isolated liver perfusion with TNF-alpha and melphalan. We adapted a standard enzyme-linked immunosorbent assay kit for the quantification of TNF-alpha in serum to measure the amount of this cytokine in solid tissue. For this purpose, we developed a buffer that lysed the tissues without affecting the TNF-alpha present. The minimum detection level was about 2 pg of TNF-alpha per mg tissue. Using this technique, we found a significant increase in the TNF-alpha level after perfusion in the liver tissue of all evaluable patients, which may explain the transient liver toxicity we observed in all patients. In tumour tissue, a significant TNF-alpha increase was observed in one out of five patients. The level of TNF-alpha in all liver tissue samples and some of the tumours after treatment by isolated liver perfusion was much higher than the peak serum concentrations obtained after systemic administration of the maximum tolerated dose of TNF-alpha. Furthermore, we demonstrated that the level of TNF-alpha in the liver tissue samples was about seven to eight times higher than in tumour tissue. We concluded that regional liver treatment resulted in a relatively high local level of TNF-alpha, but also that this cytokine did not preferentially accumulate in tumour tissue.

De uitgebreidheid van lymfeklierresecties bij de behandeling van blaaskanker is onderwerp van discussie, waarbij ook de waarde van de schildwachtklierprocedure is onderzocht. Nabij-infrarode (NIR) fluorescente beeldvorming is een innovatieve techniek voor de peroperatieve visualisatie van lymfebanen en lymfeklieren.

AIM: Near-infrared (NIR) fluorescence optical imaging is a promising technique to assess the extent of colorectal metastases during curative-intended surgery. However, NIR fluorescence imaging of liver metastases is highly challenging due to hepatic uptake and clearance of many fluorescent dyes. In the current study, the biodistribution and the ability to demarcate liver and peritoneal metastases were assessed during surgery in a syngeneic rat model of colorectal cancer using an integrin α(v)β(3)-directed NIR fluorescence probe. METHODS: Liver tumors and peritoneal metastases were induced in 7 male WAG/Rij rats by subcapsular inoculation of 0.5 × 10(6) CC531 colorectal cancer rat cells into three distinct liver lobes. Intraoperative and ex vivo fluorescence measurements were performed 24 (N = 3 rats, 7 tumors) and 48 h (N = 4 rats, 9 tumors) after intravenous administration of the integrin α(v)β(3)-directed NIR fluorescence probe. RESULTS: Colorectal metastases had a minimal two-fold higher NIR fluorescence signal than healthy liver tissue and other abdominal organs (p < 0.001). The tumor-to-background ratio was independent of time of imaging (24 h vs. 48 h post-injection; p = 0.31), which facilitates flexible operation planning in future clinical applications. Total fluorescence intensity was significantly correlated with the size of metastases (R(2) = 0.92 for the 24 h group, R(2) = 0.96 for the 48 h group). CONCLUSION: These results demonstrate that colorectal intra-abdominal metastases can be clearly demarcated during surgery using an integrin α(v)β(3) targeting NIR fluorescence probe. Translating these findings to the clinic will have an excellent potential to substantially improve the quality of cancer surgery.

110. Percutaneous hepatic perfusion with melphalan in treating unresectable liver metastases of colorectal cancer and uveal melanoma: A phase I/II trial E.M. De Leede, M.C. Burgmans, C.H. Martini, H.W. Kapiteijn, J.Vuyk, F.G.J. Tyl, A.R.VanErkel,C.Verhoef,C.J.H.VandeVelde, A.L. Vahrmeijer 1 Leiden University Medical Center, Surgery, Leiden, Netherlands 2 Leiden University Medical Center, Radiology, Leiden, Netherlands 3 Leiden University Medical Center, Anesthesiology, Leiden, Netherlands 4 Leiden University Medical Center, Medical Oncology, Leiden, Netherlands 5 Leiden University Medical Center, Extra Corporeal Circulation, Leiden, Netherlands 6 Erasmus Medical Centre, Surgery, Leiden, Netherlands

In an attempt to improve tumor response and survival among patients with colorectal cancer metastases confined to the liver, we developed an experimental (rats and pigs) and clinical isolated hepatic perfusion (IHP) technique to exploit maximally the steep dose-response relation of many anticancer drugs. In this overview we present our experimental and clinical results with mitomycin C (MMC) and melphalan (L-PAM). In rats, treatment with a four times higher maximally tolerated dose (MTD) of MMC during IHP compared to hepatic artery infusion (HAI) resulted in higher, more effective intratumoral concentrations of MMC. As a result, only in the IHP-treated rats were complete remissions observed and long-term survival achieved. Hepatotoxic side effects were minimal and transient in all animals. In the clinical phase I/II study with MMC 30 mg/m2 administrated as a bolus in the isolated circuit, two of nine patients had a complete remission, with a median survival of 17 months. Four patients developed venoocclusive disease (VOD) of the liver, and as a result one patient died. Therefore we consider MMC unsuitable for further IHP studies. Meanwhile experiments in rats showed that IHP with the L-PAM MTD of 12 mg/kg was even more effective than MMC and did not cause hepatotoxic side effects. In the phase I/II dose-finding study with L-PAM in IHP, the MTD in humans was approximately 3.0 mg/kg. As in the rats, systemic toxicity was dose-limiting. The median survival of the whole group was 18 months. We have started a phase II study of L-PAM in IHP with a fixed dose of 200 mg L-PAM to determine if IHP can significantly increase the median survival and complete remission rate compared to other treatment modalities. Results from this study are expected by the end of 1997.

We report our experience with isolated hepatic perfusion (IHP) with tumor necrosis factor (TNF) and melphalan in an experimental pig study and of a phase I study in humans. IHP was performed with inflow catheters in the hepatic artery and portal vein and an outflow catheter in the caval vein. An extracorporeal venovenous bypass was used. IHP consisted of a 60-min perfusion with hyperthermia (> 41 °C). For the pig protocol rhTNFα 50 μg/kg alone (n = 5) or rhTNFα 50 μg/kg plus melphalan 1 mg/kg (n = 3) were added. In two control pigs no drugs were added. In the phase I study, patients received melphalan 1 mg/kg with 0.4 mg rhTNFα (n = 8) or 0.8 mg rhTNFα (n = 1). After the perfusion the liver was washed with Macrodex before vascular continuity was restored. All pigs but one survived the procedure. Systemic leakage was less than 0.02%. Transient, mild liver toxicity was seen in all pigs, including controls, as demonstrated by liver enzyme assays and histology. There was no significant hemodynamic, cardiopulmonary hemotological, or renal toxicity. In the phase I clinical study there was leakage in one patient (cumulative leakage 20%). There were three perioperative deaths (one possibly drug-related). All patients demonstrated significant hepatotoxicity. Survival ranged from 6 to 26 months (median 10.3 months). All patients demonstrated a tumor response (partial response 5/6, 1/6 stable disease) with a median duration of 18 weeks. In contrast to our pig program, many problems were encountered in the phase I study. By using both the hepatic artery and portal vein for IHP we encountered more toxicity than expected based on data from the pig program, resulting in fatal coagulative disturbances in one patient who received the second rhTNFα dose. Furthermore, local control after one IHP with TNFα and melphalan is only temporary.

Hepatic metastases are a major cause of death in patients with disseminated colorectal cancer. The prognosis of patients with hepatic metastases is very poor and mainly determined by the extent of hepatic disease at presentation. In these patients, the goal of any treatment is to obtain a complete tumour remission in the liver; this is the only way to obtain a significant survival benefit. In this overview, we summarise data from (i) studies comparing survival of patients after primary resection of liver metastases with survival after repeat liver resections, (ii) studies comparing hepatic arterial infusion of fluoropyrimidines with systemic delivery of these anticancer drugs, and (iii) phase I/II studies on isolated liver perfusion (ILP) with alkylating compounds. Furthermore, we discuss alternative strategies to combat liver metastases, including those taking advantage of an ILP setting.