Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Appearance of Focal Nodular Hyperplasia after Chemotherapy in Two Patients during Follow-Up of Colon Carcinoma.

Surgical liver resection is a treatment option in patients with resectable colorectal liver metastases. We present two cases of focal nodular hyperplasia (FNH) development after treatment with oxaliplatin during follow-up of colon carcinoma. The first case was a 40-year-old male patient who developed multiple liver lesions suspect for metastatic disease four years after he had undergone laparoscopic right-sided hemicolectomy and adjuvant chemotherapy (capecitabine and oxaliplatin). He underwent a metastasectomy of segments three and four and microwave ablation (MWA) of the lesion in segment one. Pathological analysis demonstrated FNH. The second patient was a 21-year-old woman who presented with multiple liver lesions during follow-up for colon carcinoma. She underwent a laparoscopic right-sided hemicolectomy and was adjuvantly treated with capecitabine and oxaliplatin three years ago. Magnetic resonance imaging (MRI) was performed, and the lesions showed no signs of metastatic disease but were classified as FNH. Therefore, the decision was made to follow up the patient. In conclusion, the development of benign liver lesions could occur during follow-up of colon carcinoma and might be caused by oxaliplatin-induced changes to the liver parenchyma. Hence, it is important to distinguish these from metastatic liver disease.

An economic evaluation of eribulin for advanced breast cancer treatment based on the Southeast Netherlands advanced breast cancer registry.

Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data.Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated.Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (€15,321) compared with non-eribulin chemotherapy. This resulted in an ICER of €220,608. At a €80,000 per QALY threshold, the risk of reimbursing eribulin was €9,791 per patient (EVPI €13, eML €9,778). Scaled up to the Dutch population, the estimated annual budget impact was €1.9 million and the annual risk of reimbursing eribulin was €2.7 million.Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.

Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients: a study of the Southeast Netherlands Breast Cancer Consortium.

INTRODUCTION: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. CONCLUSION: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

BACKGROUND: We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients. METHODS: Consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy. RESULTS: Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49-2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy. CONCLUSION: Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.

Self-replenishing ability of cross-linked low surface energy polymer films investigated by a complementary experimental-simulation approach.

Nowadays, many self-healing strategies are available for recovering mechanical damage of bulk polymeric materials. The recovery of surface-dependent functionalities on polymer films is, however, equally important and has been less investigated. In this work we study the ability of low surface energy cross-linked poly(ester urethane) networks containing perfluorinated dangling chains to self-replenish their surface, after being submitted to repeated surface damage. For this purpose we used a combined experimental-simulation approach. Experimentally, the cross-linked films were intentionally damaged by cryo-microtoming to remove top layers and create new surfaces which were characterized by water Contact Angle measurements and X-Ray Photoelectron Spectroscopy. The same systems were simultaneously represented by a Dissipative Particles Dynamics simulation method, where the damage was modeled by removing the top film layers in the simulation box and replacing it by new "air" beads. The influence of different experimental parameters, such as the concentration of the low surface energy component and the molecular mobility span of the dangling chains, on the surface recovery is discussed. The combined approach reveals important details of the self-replenishing ability of damaged polymer films such as the occurrence of multiple-healing events, the self-replenishing efficiency, and the minimum "healing agent" concentration for a maximum recovery.

A phase I and pharmacokinetic study of gemcitabine given by 24-h hepatic arterial infusion.

PURPOSE: This study was performed to assess the toxicities, the maximum-tolerated dose (MTD), the pharmacokinetics and the anti-tumour activity of gemcitabine given by 24-h hepatic arterial infusion (HAI). PATIENTS AND METHODS: Patients with liver malignancies received gemcitabine by 24-h HAI, weekly x 3, every 4 weeks. On day 1 or day 8 of the first cycle, patients received one administration by 24-h intravenous infusion for pharmacokinetic comparison and to determine hepatic extraction. RESULTS: Thirteen patients received gemcitabine at the dose levels of 75, 135 and 180 mg/m(2). The MTD was 180 mg/m(2) with thrombocytopaenia as the dose-limiting toxicity. Pharmacokinetic analysis showed a significantly lower maximum gemcitabine plasma concentration (C(max): HAI, 26, 80 and 128 nM, respectively; IV, 229, 264 and 293 nM, respectively) and area under the plasma-concentration-versus-time curve (AUC(0-24h): HAI, 386, 1247 and 2033 nmol x h/L, respectively; IV, 3526, 4818 and 5363 nmol x h/L, respectively) during HAI, compared with intravenous infusion (both P<0.001). Additionally, the mean hepatic extraction ratios of gemcitabine at the 75, 135 and 180 mg/m(2) dose level were 0.89, 0.75 and 0.55, respectively. Hepatic extraction decreased linearly with increasing dose. The C(max) and AUC(0-24h) of 2',2'-difluoro-2'-deoxyuridine, the deaminated product of gemcitabine, were similar for HAI and intravenous infusion. Seven patients had stable disease for a median duration of 9 months (range: 2-11 months). CONCLUSIONS: Gemcitabine given by 24-h HAI was well tolerated and resulted in significantly lower systemic gemcitabine plasma concentrations than intravenous infusion due to a relatively high hepatic extraction.

Continuous infusion of hepatic arterial irinotecan in pretreated patients with colorectal cancer metastatic to the liver.

BACKGROUND: Irinotecan is an active drug in colorectal cancer. In patients with liver metastases, hepatic arterial infusion of irinotecan could theoretically result in higher exposure to the drug. In order to determine the efficacy of hepatic arterial irinotecan we conducted a phase II study in pretreated patients with liver metastases of colorectal cancer. PATIENTS AND METHODS: Patients with measurable liver metastases of colorectal cancer with World Health Organization performance status (WHO PS) <2 were treated with a 5-day continuous infusion of hepatic arterial irinotecan every 3 weeks at a dose of 20 mg/m(2)/day. RESULTS: Of the 25 patients included, 22 were evaluable for response. Three of 22 patients (13.6%) had a partial response, nine (40.9%) had stable disease and 10 (45.4%) had progressive disease. No complete responses were observed. Median time to progression was 2.8 (range 1.2-23.8) months. Major toxicities were vomiting and diarrhea. There was no major hematological toxicity. CONCLUSIONS: Five-day continuous hepatic arterial infusion of irinotecan 20 mg/m(2)/day has low activity in patients with liver metastases of colorectal cancer previously treated by chemotherapy.

Metastasectomy and active specific immunotherapy for a large single melanoma metastasis.

A patient with a large duodenal melanoma metastasis, involving adjacent jejunum and colon, is presented. Treatment consisted of a combination of radical surgery and active specific immunotherapy by means of an autologous tumor cell vaccine and BCG after which a recurrence-free survival of now more than 10 years has been observed. The role of surgery and immunotherapy in the treatment of metastatic melanoma are discussed.

Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer.

A feasibility study was performed to assess the toxicity and efficacy of a combination of gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer (LAPC). 24 patients (15 females and 9 males) with measurable LAPC were included; the median age of the patients was 63 years (range 39-74 years). The performance status ranged from 0 to 2. Gemcitabine was administered at a dose of 300 mg/m(2), concurrent with radiotherapy, three fractions of 8 Gy, on days 1, 8 and 15. When compliance allowed, gemcitabine alone was continued thereafter, at 1000 mg/m(2), weekly times 3, every 4 weeks, depending on the response and toxicity. All patients were evaluable for toxicity and response. The objective response rate was 29.2% (1 complete remission+6 partial remissions); 12 patients had stable disease. However, 2 of the radiological partial remissions were shown to be complete remissions by pathology assessment. Median duration of response was 3 months (range 1-35+months). Median time to progression was 7 months (range 2-37+months). Median survival was 10 months (range 3-37+months). Dose reduction or omission of gemcitabine was necessary in 10 patients. Non-haematological toxicity consisted of 87.5% nausea and vomiting grade I-II, diarrhoea 54%, ulceration in stomach and duodenum 37.5% (20.8% ulceration with bleeding); 1 patient developed a fistula between the duodenum and aorta, 5 months after treatment. Anaemia grade III-IV was observed in 8.3% of the patients. Neutropenia grade III-IV was observed in 8.3%, thrombocytopenia grades III-IV in 16.7%. In 1 patient who underwent resection postchemoradiation, no viable tumour cells were found. In addition, in the patient who suddenly died of a fistula between the duodenum and aorta, no viable tumour cells were detectable at autopsy. Although the toxicity of this treatment was occasionally severe, the response and survival are encouraging and warrant further studies of this combination.

Rb, mcl-1 and p53 expression correlate with clinical outcome in patients with liver metastases from colorectal cancer.

BACKGROUND: Thymidylate synthase (TS) has been associated with clinical outcome in disseminated colorectal cancer. However, many patients with low TS expression still fail to respond to treatment. Therefore, we studied the cell cycle proteins, Rb, E2F2, Ki67, p21 and p53 and the apoptotic proteins, mcl-1, hax, bcl-xl, bcl-2, Fas receptor, Fas ligand, caspase-3, M30 and PARP as potential predictive factors. PATIENTS AND METHODS: In biopsy specimens of liver metastases from 31 colorectal cancer patients, protein expression was retrospectively determined by immunohistochemistry and related to response to hepatic arterial or intravenous (i.v.) 5-fluorouracil (5-FU) treatment, time to tumour progression (TTP) and overall survival. RESULTS: Expression of both p53 and Rb correlated with survival benefit after 5-FU treatment. A median survival time of 79 weeks was found in patients with high levels of p53 or Rb compared to 36 and 44 weeks for patients expressing low levels of p53 (P = 0.027) or Rb (P = 0.030), respectively. Multivariate analysis showed that p53 was the best predictor of survival independent of sex, age or prior treatment. Following 5-FU hepatic arterial infusion, patients with a high TS expression had a shorter survival time than those with a low expression (P = 0.025). The anti-apoptotic protein mcl-1 was the only factor, which correlated with response to 5-FU treatment. Thirty-five percent of patients with a diffuse mcl-1 expression responded whereas ninety percent of patients with a peri-nuclear expression responded (P = 0.041). CONCLUSIONS: These results indicate that besides TS, also Rb, p53 and mcl-1 are correlated with clinical outcome in patients with liver metastases from colorectal cancer.

5-Fluorouracil induced Fas upregulation associated with apoptosis in liver metastases of colorectal cancer patients.

BACKGROUND: In vitro, thymidylate synthase (TS) inhibition by 5-fluorouracil (5-FU) induces thymineless apoptosis possibly via Fas receptor Fas ligand interactions and cell-cycle arrest. In colorectal cancer patients we evaluated whether 5-FU administration also resulted in apoptosis and cell-cycle arrest and which proteins might be involved. PATIENTS AND METHODS: Biopsy specimens were taken from 36 patients 2, 22 or 46 hours after administration of 500 mg/m2 5-FU, and from 12 control patients who did not receive 5-FU. In frozen tissue-sections from liver metastases immunohistochemistry was performed with antibodies directed against p53, p21, E2F2, Rb, Ki67 and TS (cell-cycle related) and bax, BCL-2, BCL-x, mcl-1, PARP, caspase-3, Fas receptor and Fas ligand (apoptosis related). Apoptosis was determined by M30 immunostaining, which recognises a cleavage product of cytokeratin 18. RESULTS: Fas receptor expression was 50% higher (P = 0.036) 46 hours after 5-FU administration compared to the control group. This was associated with a 12% increase (P < 0.02) in M30 positive tumour cells and with elevation of caspase-3 and PARP expression. The expression of Ki67 and E2F2 was 30% lower after 46 hours compared to the control group, whereas TS was 56% lower after 2 hours and 32% higher again after 46 hours. No differences in the expression of the other proteins were found. CONCLUSIONS: These results suggest that 5-FU decreases proliferation status and induces apoptosis possibly via the Fas pathway. Since Fas mediated cell killing is important for cytotoxic T cells this indicates that clinical studies combining immunotherapy for activation of T cells and chemotherapy using 5-FU might be very effective.

Hepatic arterial chemotherapy for colorectal cancer metastatic to the liver.

In advanced colorectal cancer, liver metastases are a major problem. In patients with liver metastases as the major site of disease hepatic arterial chemotherapy is a valid alternative to systemic treatment. In this review about hepatic arterial chemotherapy we will discuss the theoretical and practical aspects, the results and complications, the selection of patients for hepatic arterial chemotherapy, and its future developments.

Palliative chemotherapy in advanced gastrointestinal cancer.

In this review, the role of chemotherapy in the palliative treatment of advanced gastrointestinal cancer is discussed. Emphasis is placed on chemotherapy-related problems, current chemo-therapy options, and new developments.

Hepatic arterial 5-fluorouracil in patients with liver metastases of colorectal cancer: single-centre experience in 145 patients.

BACKGROUND: Hepatic arterial chemotherapy for liver metastases of colorectal cancer is still under discussion. Mainly because of the technical complications of this mode of treatment and the lack of a survival benefit in randomized studies. We performed an analysis of hepatic arterial 5-fluorouracil (5-FU) chemotherapy in 145 consecutive patients treated at a single institution. PATIENTS AND METHODS: One hundred forty-five patients with inoperable liver metastases from colorectal cancer were included. 5-FU, 1000 mg/m2/day continuous infusion for five days every three weeks, was delivered in the hepatic artery by percutaneous catheter or arterial access device. RESULTS: The response rate was 34% for all patients, 40% in patients with extrahepatic disease, and 15% in patients with i.v. 5-FU-based pretreatment. TTP and OS for all patients were 7.5 and 14.3 months, respectively. In patients with extrahepatic disease or i.v. 5-FU-based pretreatment, OS was significantly shorter compared to patients without extrahepatic disease or 5-FU-based pretreatment (9.7 vs. 19.3 months and 10.1 vs. 17.4 months, respectively), forty-seven percent of patients stopped treatment because of a complication. Complications most often seen in patients with arterial ports were hepatic artery thrombosis (48%) and dislocation of the catheter (22%). CONCLUSIONS: The results of our analysis are in line with previous phase III studies. Extrahepatic disease and i.v. 5-FU-based pretreatment were prognostic for reduced OS. The complication rate of hepatic arterial delivery was worrisome. although, no negative impact on survival could be established. There is a strong need for improvement of hepatic arterial delivery methods before further evaluation of hepatic arterial

Current chemotherapeutic possibilities in pancreaticobiliary cancer.

At time of presentation the majority of patients with pancreaticobiliary cancer have locally advanced or metastatic disease which makes them unamenable for curative surgery. In these patients chemotherapy is an option which has gained more support over the past few years. Special problems faced in chemotherapeutic treatment are the patient's poor condition and the difficulties faced in evaluating response. 5-FU has been the only drug with some efficacy for a long time, but more recently gemcitabine appeared to be more efficient. In locally advanced pancreatic cancer the combination of chemotherapy with radiotherapy has not gained much support. However, studies are implicating better local control with combined treatment and recurrences appear more often at distant sides. In some cases irresectable tumors became resectable. Because of the poor survival after surgery with curative intent, adjuvant and neoadjuvant therapy are becoming important issues. Although studies of adjuvant therapy suggest benefit, research is seriously hampered by poor patient accrual due to the morbidity of pancreaticoduodenectomy. Neoadjuvant treatment may overcome this problem. Until now there has been only modest improvement in the treatment of pancreatic cancer. Hopefully, new treatment modalities such as immunotherapy, gene therapy and antiangiogenic therapy will alter this dismal picture. In biliary cancer the role of chemotherapy is less well defined, since only few studies with low patients numbers have been performed.

Pancreaticobiliary cancer: the future aspects of medical oncology.

Pancreatic cancer is one of the most common and most lethal cancers in the Western world with a median survival of approximately 3 months. Thus far, the results of anti-cancer treatment have been dismal, with a median survival of only 20 months in resectable pancreatic cancer, and 6 months in advanced disease. Although combined chemoradiation results in improved local control, it has only a modest impact on survival due to the development of distal metastases. In this review we will discuss the progress made in the treatment of pancreatic cancer over the past few years and discuss future therapies such as: immunoradiotherapy, matrix metalloproteinase inhibitors, anti-angiogenesis therapies, gene therapy, immunotherapy, ONYX-015, and farnesylation inhibitors.

Peripheral neuropathy due to biweekly paclitaxel, epirubicin and cisplatin in patients with advanced ovarian cancer.

We assessed the peripheral neuropathic changes induced by biweekly combination chemotherapy including paclitaxel 100-165 mg/m2 (in a 3-h infusion), epirubicin 75 mg/m2 and cisplatin 50 mg/m2 (TEC) in patients with advanced ovarian cancer. Neurologic evaluation, including a standardized questionnaire, bed-side neurological examination, and quantitative determination of vibratory perception thresholds (VPT) and grip strength took place before therapy, after 3 and 6 cycles, and thereafter whenever possible. During chemotherapy all patients received granulocyte colony-stimulating factor from days 2 to 12. Pretreated patients received amifostine two times, before epirubicin and before cisplatin administration. Neuropathic symptoms developed in 11/13 non-pretreated patients and in 7/9 chemotherapy-pretreated patients. Neuropathic signs developed in all patients. Neuropathic symptoms and signs were predominantly sensory in character. VPT changes developed primarily in the feet. According to National Cancer Institute of Canada Common Toxicity Criteria, grade 3 peripheral neuropathy after 6 cycles developed in 1/6 and 2/4 non-pretreated patients who received TEC containing paclitaxel 150 and 165 mg/m2, respectively. We conclude that peripheral neuropathy is dose-limiting in chemonaïve patients treated with biweekly TEC combination chemotherapy, at paclitaxel dose level 165 mg/m2 in a 3-h intravenous administration.

[Ischemic hepatitis]. / Ischemische hepatitis.

Triggered by a case of ischaemic hepatitis (shock liver) in a patient with severe respiratory insufficiency, we tried to gather information about clinical characteristics and incidence. To our surprise, this information could be found neither in major critical care, medical or gastroenterology textbooks nor in textbook indices or works on differential diagnosis. From Sept. 1989 to May 1990 we studied all possible cases of ischaemic hepatitis in a 390 bed general hospital, to establish incidence. Using computerised data from the clinical chemistry laboratory, all patients with grossly abnormal liver function tests were identified. In this nine-month period 27 adult patients had a peak ALAT level of > 500 U/l: 8 of these suffered from ischaemic hepatitis, using the criteria described by Gibson et al. In another 5 this diagnosis was suspected but could not be ascertained before death (30% and 18% of all cases). In all these cases ASAT, ALAT, LDH levels were 8-100 times normal, but bilirubin, alkaline phosphatase, gamma-glutamyl transferase and prothrombin time were only slightly abnormal. With correction of the underlying disorder enzyme levels returned to normal very rapidly, in 5-10 days. Ischaemic hepatitis could easily be distinguished from other causes such as alcoholic, viral or drug-induced hepatitis. Ischaemic hepatitis was the most frequent cause of severely elevated ASAT, ALAT and LDH in hospitalised patients. The diagnosis can easily be made on clinical characteristics and the typical biochemical pattern. An elaborate work-up or invasive procedure is redundant. Prognosis per se is excellent but depends on the underlying disorder.