Endocrine treatment of hepatocellular carcinoma. Any evidence of benefit?
Pignata S. Daniele B. Gallo C. De Vivo R. Monfardini S. Perrone F.
Istituto Nazionale dei Tumori, Napoli, Italy.
In the past 20 years, a number of studies have investigated the relationship between sex hormones and liver cancer. Experimental studies indicate that a dynamic process, with sequential modifications in the pattern of sex hormones in the serum and of sex hormone receptors in the liver, occurs progressively during hepatocarcinogenesis. Overall, it seems that both androgens and oestrogens may enhance liver carcinogenesis, while androgens may also support the growth of established liver tumours. Unfortunately, clinical studies of endocrine treatment of hepatocellular carcinoma (HCC) have not adequately tested the suggestions from biological studies. So far, no clinical trial has been performed to test the efficacy of endocrine manipulation for the chemoprevention of HCC in cirrhotic patients nor in preventing relapse after radical resection of primary HCC. Anti-oestrogens have been the most studied agents for the endocrine treatment of established HCC, although the rationale that supports their use is weaker than for anti-androgens. Studies with anti-androgens have produced prevalently negative results, due to either a lack of activity or excessive toxicity. The use of chemical castration, which theoretically could enhance the activity of antihormonal compounds, yielded no benefit at all. In summary, there is, as yet, no definitive evidence that endocrine treatment favourably affects the outcome of patients with HCC.
Pharmacokinetics of anticancer agents in patients with impaired liver function.
Donelli MG. Zucchetti M. Munzone E. D'Incalci M. Crosignani A.
Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
This report reviews published information on the clinical pharmacokinetics of antitumour agents in patients with liver dysfunction, associated with primary liver disease or liver metastases. Information was available for anthracyclines and their related compounds, antimetabolites, cyclophosphamide, vinca alkaloids, taxanes and epipodophyllotoxins. Changes in the pharmacokinetic profile or metabolism in patients with mild or severe hepatobiliary dysfunction are described and the relationships between serum levels, parameters employed for measuring hepatic function and toxic or therapeutic effects are examined. Current knowledge of the pharmacokinetics of antineoplastic agents in liver disease is far from complete, mostly obtained in small numbers of non-homogeneous patients often presenting only moderate liver dysfunction, and empirical guidelines for dose assessment are still largely applied in clinical practice. Because of the complex pathophysiological mechanisms of liver insufficiency in cancer patients, there is still doubt whether endogenous markers are useful. Although caution in treating cancer patients with liver insufficiency is compulsory, for most compounds there seems no need to recommend dose reductions for moderate impairment. However, for the tubulin acting agents, vincristine, vinblastine and possibly for paclitaxel and docetaxel, there is strong evidence that dose adjustment is mandatory in order to avoid excessive neutropenia and neurotoxicity.
Expression of the multidrug resistance protein (MRP) in squamous cell carcinoma of the oesophagus and response to pre-operative chemotherapy.
Nooter K. Kok T. Bosman FT. van Wingerden KE. Stoter G.
Department of Medical Oncology, University Hospital Rotterdam, The Netherlands.
One of the major problems in the treatment of squamous cell carcinoma of the oesophagus (ESCC) is the unresponsiveness to cytotoxic drugs. So far, the mechanisms underlying the intrinsic drug resistance of ESCC remain unclear. The aim of this study was to determine the role of the newly recognised drug resistance protein, the multidrug resistance protein (MRP), in ESCC drug resistance. Tumour biopsies from ESCCs were analysed by RNase protection assay (RPA) as well as by immunohistochemistry (IHC) for the presence of MRP mRNA or protein, respectively. The ESCC samples were obtained from patients participating in a prospective randomised clinical phase III trial, evaluating pre-operative chemotherapy (cisplatin and etoposide) followed by surgery versus surgery alone in patients with operable ESCC. For most patients, tumour biopsies taken at diagnosis by endoscopy as well as surgically resected primary tumours were available. Of 58 ESCC patients enrolled, 28 received chemotherapy before surgical resection of their tumours, and 30 were treated with surgery alone. 12 patients (3 complete and 9 partial responses; 43%) showed a major response after chemotherapy, 10 patients (36%) had stable disease (SD), and 6 (21%) progressive disease (PD). On 14 surgically resected, untreated, primary ESCCs, the IHC scores correlated with the MRP mRNA levels, quantitated by RPA (multiple testing, P < 0.01). MRP expression was detected by IHC in the vast majority (52/58; 90%) of the diagnostic biopsies. MRP expression did not differ significantly between CR + PR, and patients with SD or PD. In addition, multivariate analysis by logistic regression did not show any effect of tumour cell differentiation or UICC tumour stage on the outcome of pre-operative chemotherapy in relation to MRP expression. However, a difference became apparent (Sign-test, P < 0.05) for higher MRP expression in tumours from patients with PR or SD, when comparing MRP levels in paired tumour samples before and after chemotherapy, suggesting that chemotherapy selected for drug-resistant cell clones.
Phase I pharmacological study of intra-arterially infused fotemustine for colorectal liver metastases.
Hartmann JT. Schmoll E. Bokemeyer C. Fety R. Lucas C. Giroux B. Schmoll HJ.
Department of Haematology/Oncology/Immunology, Eberhard-Karls-University Medical Centre, Tubingen, Germany.
Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 +/- 11.5 min) and a high body clearance (CL = 2193 +/- 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1-3.
Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis.
Etienne MC. Chatelut E. Pivot X. Lavit M. Pujol A. Canal P. Milano G.
Oncopharmacology Laboratory, Centre Antoine Lacassagne, Toulouse, France.
The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.
Cancer mortality in Europe: effects of age, cohort of birth and period of death.
La Vecchia C. Negri E. Levi F. Decarli A. Boyle P.
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Death certification data for 19 cancers or groups of cancers, plus total cancer mortality, in 16 major European countries were analysed using a log-linear Poisson model with arbitrary constraints on the parameters to disentangle the effects of age, birth cohort and period of death. Three major patterns emerged including: first, the prominent role of cohort of birth in defining trends in mortality from most cancer sites (except testis or Hodgkin's disease, where newer treatments had a major period of death effect); and second, the major role of lung and other tobacco-related neoplasm epidemics in determining the diverging pattern of cancer mortality, for each sex and in various European countries and geographic areas. In most countries, the peak male cohort values were reached for generations born between 1900 and 1930. This was observed in women only for Denmark and the U.K., i.e. the two countries where lung and other tobacco-related neoplasm epidemics had already reached appreciable levels. This confirms the importance of cigarette smoking in subsequent generations as a major cause of cancer deaths in Europe. Further, there is a persistent rise in several cancer rates, again chiefly on a cohort basis, in Eastern Europe, which calls for urgent intervention to control the cancer burden in these countries.
The DNA content of chromosome division figures and interphase nuclei classifies ulcerative colitis.
Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden.
Long-standing ulcerative colitis is considered to be a precancerous condition. Therefore, a practical and reliable method is required for monitoring the progress of the disease. Liberation of the S-phase from karyokinesis occurs in DNA amplification and endoreplication, producing nuclei with more than 4 c DNA. The amount of Feulgen DNA was quantified with an image microphotometer in 8 microns sections for interphase nuclei and in 15 microns sections for chromosome division figures (CDFs). Development of ulcerative colitis was investigated in low grade dysplasia (n = 93 cases; score 3-7) and high grade dysplasia (n = 22; score 8-10). Bacterial colitis (n = 34) and invasive adenocarcinoma (n = 26) provided a basis for data interpretation in dysplasia. Lymphocyte nuclei served as an internal DNA standard. CDFs represent a novel type of aberrant 'mitoses'; they are different from and much more frequent than figures with multipolar spindles. Endoreplication began with low grade dysplasia in interphase nuclei as well as with CDFs; it was fully established in high grade dysplasia and carcinoma. Endoreplicated interphase nuclei and CDFs represent an early morphological mosaic of genomic instability. Both characteristics support a reproducible two-level classification of low and high grade dysplasia in ulcerative colitis.
A clinically applicable assay for tumoral thymidylate synthase combining reverse transcriptase-PCR and high-performance liquid chromatography.
Leccia JR. Milano G. Formento P. Francoual M. Formento JL. Pierrefite V.
Oncopharmacology Department, Centre Antoine Lacassagne, Nice, France.
The main clinically relevant cellular target of 5-fluorouracil (5-FU) is the enzyme thymidylate synthase (TS). Both preclinical data and clinical data in digestive tract cancer indicate that an increased amount of TS in tumours can predict for 5-FU resistance. We developed an automated method combining the principle of RT-PCR coupled with HPLC separation and quantification. The RT-PCR HPLC method was applied to TS determination in tumoral biopsies from patients with colorectal cancer. The PCR samples were separated and quantified using a polystyrene divinylbenzene C 18 column. Within 22 min, it was possible to elute 18 peaks representing DNA sizes ranging from 34 to 622 bp. Both separation and quantification of beta 2 microglobulin (beta 2m, internal standard) and TS PCR products were achieved in approximately 10 min per sample. Validation of the RT-PCR HPLC method was established by comparing RT-PCR quantification of TS after electrophoresis and HPLC and by comparing the RT-PCR quantification of TS after HPLC with the classical biochemical method. The proposed HPLC method offers a 10-50 fold sensitivity advantage over electrophoresis. In addition, this RT-PCR HPLC procedure allows not only the quantification of TS expression but also the direct collection of unaltered amplified DNA sequence which could be useful for sequencing analysis, since TS mutations have been described. The present RT-PCR HPLC method for determining TS expression in tumoral biopsies is a valuable analytical approach as it is specific, sensitive and clinically applicable.
Growth inhibitory effect of lithium gammalinolenate on pancreatic cancer cell lines: the influence of albumin and iron.
Ravichandran D. Cooper A. Johnson CD.
University Surgical Unit, Southampton General Hospital, UK.
Essential fatty acids, especially gamma linolenic (GLA) and eicosapentaenoic acids, have been proposed as potential anticancer drugs. Our aim was to study the effect of the lithium salt of gamma linolenic acid (LiGLA) on the growth of two human pancreatic cancer cell lines (MIA PaCa2 and Panc 1) and primary human fibroblasts (HFF 5) in vitro. Cell growth was assessed by a microculture tetrazolium (MTT) assay. LiGLA had a selective growth inhibitory effect on pancreatic cancer cell lines with 50% growth inhibition (IC50) at approximately 6-16 mumol/l compared with approximately 111 mumol/l for the fibroblasts. The degree of growth inhibition increased with the time of exposure to LiGLA. Special attention was paid to the influence of albumin and iron on LiGLA-mediated growth inhibition. Albumin incorporated into essentially serum-free culture medium inhibited the effect of LiGLA in a dose-dependent manner, associated with reduced GLA uptake by cancer cells. Ferric ions were confirmed as potentiators of the growth inhibitory effect of LiGLA but more physiologically relevant transferrin-bound iron was ineffective. With further improvements in the fatty acid delivery mechanism, LiGLA may become a useful adjunct in the management of pancreatic cancer patients.
Randomised double-blind study comparing tropisetron alone and in combination with dexamethasone in the prevention of acute and delayed cisplatin-induced emesis.
Garcia-del-Muro X. Vadell C. Perez Manga G. Bover I. Rifa J. Beltran M. Barros MM. Germa JR. Fabregat X. Moreno V. Salvador A. Viladiu P.
Institut Catala d'Oncologia, Hospital Duran i Reynals, Dept. of Medical Oncology, Barcelona, Spain.
In a randomised, double-blind and parallel-design multicentre study, 282 chemotherapy-naive cancer patients received tropisetron 5 mg intravenously (i.v.) before high-dose cisplatin on day 1, and oral tropisetron 5 mg daily on days 2-6, in combination with either placebo (n = 143) or dexamethasone (n = 135), given i.v. on day 1 and orally on days 2-6. Complete protection from acute vomiting/nausea was achieved in 76.3%/79.3% of patients receiving the combination and in 55.2%/61.5% of those receiving tropisetron alone. Complete protection on days 2-6 from delayed vomiting/nausea was obtained in 60%/60% and 39.2%/40.6%, respectively. Tropisetron in combination with dexamethasone is safe and more effective than tropisetron alone in the prevention of both acute and delayed cisplatin-induced emesis.
Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy.
Janes RJ. Muhonen T. Karjalainen UP. Wiklund T.
Department of Oncology, Helsinki University Hospital, Finland.
Highly emetogenic drugs such as cisplatin induce an increase in the urinary 5-hydroxyindoleacetic acid (5-HIAA) level, the main metabolite of serotonin (5-HT), within the first 24 h following a single infusion, thus providing a possible cause for acute emesis and an explanation for the action of 5-HT3 antagonists. No further excretion peaks have been observed, suggesting that additional or serotonin-independent mechanisms cause delayed emesis. Our aim was to study the mechanisms behind emesis seen during a highly emetogenic chemotherapy regimen given as a continuous infusion over several days. Seven women treated with a 4-day high-dose chemotherapy (HDCT) regimen for breast cancer entered the study. Pooled urine samples were collected prior to and during chemotherapy for determining 5-HIAA excretion. An excretion peak in the urinary 5-HIAA level was observed within the first 24 h with no further peaks thereafter. Thus, the mechanisms behind the emesis experienced during this highly emetogenic multiple-day chemotherapy regimen from days 2-3 onwards would appear to be at least partially serotonin independent and would not be expected to be completely relieved by 5-HT3 antagonists alone.