We present a retrospective analysis of Hickman line use and associated complications in patients with solid tumours undergoing treatment with infusional chemotherapy. One hundred and ten lines were inserted in 94 patients (55 females and 39 males, median age 51), of whom 107 were placed under radiological screening, the remainder by a surgical approach. Catheters were in situ for a total of 9670 days (median 101 days, range 1-278). Fifty-five complications occurred during the lifespan of 39 catheters (35.5%), giving an overall complication rate of 4.03/1000 catheter days. Early complications included pneumothorax (4%), arterial puncture (1%) and failure of placement (1%). Late complications included sepsis (superficial and systemic) (24.5%), venous thrombosis (9%), line displacement (10%) and catheter blockage (1%). Fifteen episodes of systemic sepsis occurred in 12 patients, giving an overall sepsis rate of 1.55/1000 catheter days, while complications requiring catheter removal occurred in 20 cases (18% of insertions, 2.07/1000 catheter days). We conclude that the use of Hickman catheters as a means of long-term venous access in infusional chemotherapy patients is generally safe, but is associated with significant morbidity.

Background A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. Methods Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). Results 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m 2 . MTD was 10 mg/m 2 ; DLTs at 12 (2/4 patients) and 10 mg/m 2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and C max from 1–10 mg/m 2 . Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. Conclusions TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage. Trial registration EU-CTR2006-001345-33

521 Background: Use of PMT as pre-operative therapy for large primary, or locally advanced inoperable, breast cancer (BC)is increasing. Such regimens usually contain A,in combination with C (AC). D is among the most active single agents in metastatic BC and is increasingly used with A in advanced BC. Methods: Patients suitable for PMT (n=363) were randomised to receive up to 6 cycles of either (a) A (50mg/m2) and D (75mg/m2) i/v every 3 weeks, or (b) A (60mg/m2) and C (600mg/m2) i/v every 3 weeks. Patients with operable disease after completing chemotherapy had surgery followed by radiotherapy if indicated, and tamoxifen if ER+. We compared the response rates (clinical and pathological), relapse-free survival (RFS) after subsequent surgery, and overall survival (OS) of patients treated with AC and AD as PMT. Results: Patients with locally advanced inoperable (8%), inflammatory (15%) or large, operable (77%) primary BC, and with no evidence of metastatic disease, were randomised to AC (n=180) or AD (n=183). Clinical response rates (CR+PR) were 61% and 71% for AC and AD respectively (p=0.06). 7 patients treated with AC (4%) and 8 with AD (4%) received less than the planned 6 cycles of chemotherapy due to disease progression, with 14 patients (AC=8, AD=6) withdrawn early due to toxicity despite dose modifications. Pathological involvement of axillary LNs was present at surgery in 61% treated with AC and 66% with AD (p=0.28). Pathological CR rates for AC and AD were 24% and 21% respectively (p=0.61). No significant difference exists yet between the 2 groups for number of relapses. The median RFS and OS have not yet been reached with a median follow-up of 32 months. Conclusions: Both AC and AD are tolerated as PMT in primary BC. There is a trend to a superior clinical response rate with AD compared to AC, which does not reach statistical significance. There is no evidence of differences in the pathological CR rates or axillary LN involvement. In contrast to the positive results reported for sequential D following AC as PMT, our data do not suggest a benefit for simultaneous AD over AC. Updated analyses will be presented at conference. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

PURPOSE:BMS-214662 is a potent and selective inhibitor of the farnesyl transferase enzyme with in vitro and in vivo antitumor activity. The aims of this study were to characterize the toxicities and to determine the pharmacokinetic profiles of BMS-214662 when administered in combination with cisplatin, and to determine the constitutive farnesyltransferase activity as a surrogate pharmacodynamic end point.EXPERIMENTAL DESIGN:Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological, renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after an interval of 30 min by 75 mg/m(2) cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic analyses were collected during the first cycle of treatment only.RESULTS:Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m(2) BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after 6 cycles of treatment.CONCLUSIONS:A dose of 200 mg/m(2) of BMS-214662 administered as a 1-h infusion with 75 mg/m(2) cisplatin over 4 h is the recommended dose for additional studies.

Amyloidosis is usually a systemic disorder. A localised form can involve the breast and may mimic breast cancer. We report a case of primary amyloid deposit confirmed by immunohistochemistry, occurring in a patient with early breast cancer and review other cases of breast involvement with various types of amyloid.

Neutropenia is frequently observed in the practice of oncology, usually resulting from the use of cytotoxic drugs. Less frequently, neutropenia is due to infiltration of the bone marrow by malignant disease. Both of these usually cause some depletion of all haematopoietic linages. True isolated neutropenia is, in contrast, a less frequent phenomenon. We report a case of auto-immune neutropenia occurring in a patient with metastatic melanoma, and discuss the differential diagnosis and implications for patient management.

OBJECTIVES:This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity.PATIENTS AND METHODS:Twenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m2 twice daily, days 1-14) in combination with oxaliplatin (130 mg/m2, 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle, and safety and efficacy were evaluated throughout treatment.RESULTS:The recommended dosing schedule is oral capecitabine 1000 mg/m2 twice daily (days 1-14) with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan.CONCLUSIONS:Oral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing, phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study.

BACKGROUND The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated. PATIENTS AND METHODS Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m(2) i.v., 3-weekly), cisplatin (60 mg/m(2) i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m(2) bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1. RESULTS Thirty-two patients, median age 63 years (range 32-76 years), ECOG performance status < or =2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m(2) bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses [24% response rate [95% confidence interval (CI) 10% to 44%]], a median PFS of 22 weeks (95% CI 17-27 weeks) and median overall survival of 34 weeks (95% CI 19-49 weeks). Capecitabine was rapidly absorbed after oral administration, with a t(max) of 1-2 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The C(max) and AUC(0-)( infinity ) for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food. CONCLUSION A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.

The past 25 years have seen unparalleled advances in our understanding of the molecular basis of cancer. As a result, novel molecular targets have been identified that provide great potential for the development of new cancer diagnostics and therapies. Four key features of cancer cells distinguish them from their normal counterparts: loss of cell‐cycle regulation, loss of control over invasion and metastasis, failure of apoptotic mechanisms, and bypass of senescence. This review examines our understanding of the bypass of senescence and the process of immortalization during carcinogenesis. In addition, the realistic opportunities for telomerase in cancer diagnostics and the challenges faced in clinical trial design for telomerase therapeutics are discussed. Copyright © 2001 John Wiley & Sons, Ltd.

Background: The aim of this study was to evaluate the efficacy of the combination of epirubicin, cisplatin and ralitrexed (Tomudex), ECT, in patients with advanced oesophageal or gastric adenocarcinoma. Efficacy was assessed primarily as response rate and secondarily in terms of toxicity, time to progression and survival.Patients and methods: Twenty-one patients with histologically and/or cytologically proven unresectable (7) or metastatic (14) gastro-oesophageal adenocarcinoma, who had bi-dimensionally measurable disease, with ECOG performance status less than or equal to2, with adequate haematological, hepatic and renal function received first-line chemotherapy with epirubicin (50 mg/m(2)), cisplatin (60 mg/m(2)) and Tomudex (2.5 mg/m(2)), ECT, at three-weekly intervals. Treatment consisted of three cycles of chemotherapy, with a further three cycles if there was disease response or stabilisation.Results: ECT is an active regimen in the treatment of advanced gastro-oesophageal adenocarcinoma with an overall intention-to-treat response rate of 29% (95% confidence intervals (CI): 11%-52%). In addition, 4 (19%) patients had stable disease. Median time to progression was 19 weeks (95% CI: 7-31 weeks). Median overall survival was 18 weeks (95% CI: 11-24 weeks). Seventeen patients failed to complete the six cycles of treatment due to disease progression (5), toxicity (3), non-toxic death (1 pulmonary embolism, 1 cardiac), severe allergy to epirubicin (1), patient decision (1) and five patients after the study was discontinued early due to toxicity. There were three toxic deaths: two due to sepsis complicating neutropaenia and one due to cardiorespiratory failure following drug induced enteritis. Nine patients experienced grade 3 or 4 neutropaenia, two patients experienced grade 3 or 4 nausea and vomiting and one patient had grade 4 diarrhoea.Conclusions: The combination of epirubicin, cisplatin and tomudex is active against advanced gastro-oesophageal adenocarcinoma but the toxicity suggests that further evaluation in a randomised comparison to ECF is not appropriate.

ONO-4007 is a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide, which exhibits antitumor activity by the induction of intratumoral tumor necrosis factor alpha, the potentiation of tumor-infiltrating macrophages, and the inhibition of angiogenesis. Interleukin (IL)-1 alpha, IL-6, and IL-12 induction by ONO-4007 activates cytotoxic natural killer cells to up-regulate IFN-gamma and nitric oxide synthase activity. ONO-4007 was given to 24 patients (13 males and 11 females; median age, 53 years) as a 30-min i.v. infusion on day 1, followed on day 15 by a first treatment cycle consisting of three weekly infusions at the same dose, followed by a rest period of 1 week. Cohorts of six patients received up to a maximum of four treatment cycles at increasing dose levels (75, 100, and 125 mg). The maximum tolerated dose was 125 mg, with grade 3 National Cancer Institute Common Toxicity Criteria toxicity (rigors with cyanosis) occurring in two of six patients at this dose level. An additional six patients were treated at 100 mg, the dose below the maximum tolerated dose. Other toxicities included grade 2 National Cancer Institute Common Toxicity Criteria myalgia, nausea, and hypotension. The pharmacokinetics of ONO-4007 appeared to be independent of dose and showed linearity with respect to time. ONO-4007 has a low systemic clearance (approximately 1.3 ml/min) and a small volume of distribution (5-8 liters) with a long t1/2 of 74-95 h. The administration of ONO-4007 was shown to result in a significant increase in circulating levels of tumor necrosis factor alpha and IL-6. No objective antitumor responses were observed. Seven patients maintained stable disease for at least two cycles, whereas five patients maintained stable disease for the full four-cycle duration of the study. Additional studies are required to determine the antitumor activity of ONO-4007.

Paraneoplastic syndromes (PNS) involving the central nervous system are a rare manifestation of malignant disease. As they commonly precede the diagnosis of malignancy their acute manifestations do not often present themselves to oncologists in the first instance. It is currently believed that most, if not all, neurological PNS are autoimmune in nature. Proteins expressed ectopically on the surface of tumour cells generate an immune response which cross-reacts with the same, or similar, proteins in the nervous system resulting in damage. This can involve a single cell type of the nervous system whilst in other cases the impairment is more widespread. The following report is of a case of chronic inflammatory demyelinating polyneuropathy (CIDP) occurring in metastatic malignant melanoma, following treatment with interferon-alpha. We review the current literature on this rare association and speculate on its pathogenesis, and the implications for future therapeutic strategies in melanoma targeting tumour antigens.

Tumour imaging is an essential part of the practice of oncology, with a crucial role in screening programmes and in diagnosis and staging of established disease. Furthermore, the assessment of tumour size by imaging, usually with computer tomography (CT) scanning, is a key component in determining the tumour response to therapy both in clinical trials and in daily oncology practice. Techniques such as CT, ultrasound (US) and magnetic resonance imaging (MRI) provide high resolution anatomical images with detailed structural information. However, these imaging modalities yield limited functional information on the tumour tissues and often cannot distinguish residual disease from non-viable or necrotic tumour masses, nor can they detect minimal residual disease. In contrast, radiopharmaceutical imaging and, in particular, positron emission tomography (PET) can give some functional information about the underlying tissues. The possibility of refining these techniques and also the emergence of newer imaging modalities that can detect changes in cancers at the physiological, cellular or molecular levels, gives rise to the notion that these methods will have implications for drug development strategies and also future clinical management. In this review, we briefly discuss the current role of imaging in clinical practice, describe some of the advances in imaging modalities currently undergoing evaluation, and speculate on the future role of these techniques in developmental therapeutics programmes.

In the 1890s, William B. Coley started to treat cancer patients with inoculations of bacterial extracts (Coley's toxins) to activate general systemic immunity, some of which might be directed against the tumour.1,,2 Subsequent efforts to enhance our understanding of the molecular basis of immune recognition and immune regulation of cancer cells have led to the identification of potential new targets on tumour cells, and the potential to create potent, specific cancer vaccines. In this review, we discuss the principles of tumour immunity, the tumour antigens that can be recognized by the immune system, the different types of vaccines that have been evaluated, and the potential clinical applications of these approaches. Unlike most vaccines for infectious agents, the goal of cancer vaccination is therapeutic and this can be achieved by activating immune responses against tumour antigens. The immune response can be crudely divided into either antibody responses or T-cell responses. Antibodies recognize and bind to conformational determinants on cell surface proteins, and can kill the cell by either antibody-dependent cellular cytotoxicity or complement-mediated cell lysis. Conversely, T cells recognize small proteins presented on the cell surface on major histocompatibility (MHC) antigens, and T-cell activation requires a co-stimulatory signal which is usually present on the cell surface of antigen-presenting cells. However, attempts to exploit the immune system as a therapeutic strategy in cancer treatment have to overcome the host's inability to develop effective endogenous immunity against cancer. Several mechanisms have been proposed to explain this phenomenon, including generation of tumour variants lacking certain tumour antigens,3–,5 loss of MHC expression,6–,9 downregulation of the antigen processing mechanism10 and also expression of inhibitory molecules which may promote escape from immune surveillance including TGF β 11 and Fas ligand.12 A further significant contributor to escape … Dr T.R.J. Evans, CRC Department of Medical Oncology, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD. e-mail: trjelv{at}udcf.gla.ac.uk

Three ongoing, dose-escalation, phase I studies are evaluating the combination of raltitrexed with oxaliplatin or anthracyclines (with and without cisplatin). In study 1, patients with advanced solid tumours received 2.0-3.75 mg/m2 raltitrexed, followed 45 min later by 85-130 mg/m2 oxaliplatin (2-h infusion) every 3 weeks. In study 2, patients with advanced oesophageal or gastric adenocarcinoma received 2.0-3.0 mg/m2 raltitrexed with 50 mg/m2 intravenous (i.v.) epirubicin and 60 mg/m2 i.v. cisplatin every 3 weeks. In study 3, patients with advanced or metastatic gastric cancer received 2.5-3.5 mg/m2 raltitrexed followed by 30-60 mg/m2 i.v. doxorubicin every 3 weeks. In all studies, raltitrexed was given as a 15-min infusion. All the combinations evaluated were administered in convenient 3-weekly schedules and were generally well tolerated. Recommended doses for raltitrexed and oxaliplatin are the same in combination as for single-agent use, i.e. 3.0 mg/m2 raltitrexed and 130 mg/m2 oxaliplatin. The recommended dose of raltitrexed in combination with cisplatin and epirubicin is 2.5 mg/m2. No dose-limiting toxicities were observed during co-administration of the full single-agent doses of raltitrexed and doxorubicin (3.0 mg/m2 and 60 mg/m2, respectively); dose escalation is continuing. Preliminary efficacy results were encouraging, particularly for the combination of raltitrexed and oxaliplatin in patients with mesothelioma and advanced colorectal cancer. Preliminary data from these phase I studies suggest that the combination of raltitrexed with platinum-based agents and/or anthracyclines may represent useful regimens for the treatment of patients with advanced cancer. Further studies are required to identify the most effective combinations of raltitrexed with both established and new anticancer agents.

Vitamin A and its biologically active derivatives, retinal and retinoic acid (RA), together with a large repertoire of synthetic analogues are collectively referred to as retinoids. Naturally occurring retinoids regulate the growth and differentiation of a wide variety of cell types and play a crucial role in the physiology of vision and as morphogenic agents during embryonic development. Retinoids and their analogues have been evaluated as chemoprevention agents, and also in the management of acute promyelocytic leukaemia. Retinoids exert most of their effects by binding to specific receptors and modulating gene expression. The development of new active retinoids and the identification of two distinct families of retinoid receptors has led to an increased understanding of the cellular effects of activation of these receptors. In this article we review the use of retinoids in chemoprevention strategies, discuss the cellular consequences of activated retinoid receptors, and speculate on how our increasing understanding of retinoid-induced signalling pathways may contribute to future therapeutic strategies in the management of malignant disease.