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Background: As androgen deprivation therapy (ADT) is increasingly being used in men with localised prostate cancer, our goal was to examine the association between ADT and the risk of cardiovascular disease (CVD). Methods: We conducted a prospective cohort study using records of a large health-care system in California. The study included men with newly diagnosed localised prostate cancer (1998–2008) who initially underwent active surveillance (N=7637) and were followed through 2010. We examined 10 individual CVD outcomes. Cox proportional hazard models incorporated time-varying treatment variables and controlled for race/ethnicity, age, and tumour characteristics, recurrence risk, CVD medication use, and CVD risk factors. Results: Of the 7637 subjects, nearly 30% were exposed to ADT. In the multivariable analyses, ADT was associated with an increased risk of heart failure (adjusted HR=1.81, 95% CI 1.40–2.32) in men without preexisting CVD. Elevated risks of arrhythmia (adjusted HR=1.44, 95% CI 1.02–2.01), and conduction disorder (adjusted HR=3.11, 95% CI 1.22, 7.91) were only observed among patients with preexisting CVD. Conclusions: In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.

Background: Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor. This phase 1 trial assessed the safety and tolerability of escalating doses of rIL-21 in combination with cetuximab in chemo-naïve patients with stage IV colorectal cancer. Patients and methods: Sequential cohorts of PS 0–1, asymptomatic patients, were treated weekly with cetuximab 250 mg m−2 intravenously (i.v.) plus escalating i.v. doses of rIL-21 following an initial loading dose of cetuximab 400 mg m−2. Initial treatment period was 8 weeks, with extension permitted in patients without disease progression. Results: In all, 15 patients were included in this study. Adverse events related to rIL-21 or rIL-21 plus cetuximab included lethargy, nausea/vomiting, stomatitis, lymphopenia and pyrexia and were mainly ⩽ grade 2. One dose limiting toxicity occurred (grade 3 diarrhoea). Maximum tolerated dose was not determined because of the premature study closure. Maximum administered dose was 100 μg kg−1 rIL-21 weekly. In all, 60% of the patients had stable disease. Immune activation was confirmed by various T- and NK-cell activation biomarkers, including dose-dependent increases in serum sCD25. Conclusion: rIL-21 weekly combined with cetuximab is well tolerated at doses up to 100 μg kg−1 and results in activation of immune response biomarkers.

Background: We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer. Methods: NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed. Results: The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85–1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83–1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4. Conclusion: Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.

Background: Complete resection of metastases can result in cure for selected patients with metastatic colorectal cancer. Methods: First BEAT evaluated the safety of bevacizumab with first-line chemotherapy in 1914 patients. Prospectively collected data from 225 patients who underwent curative-intent surgery were analysed, including an exploratory comparison of resection rate in patients treated with different regimens. NO16966 compared efficacy of oxaliplatin-based chemotherapy plus bevacizumab or placebo in 1400 patients. A retrospective analysis of resection rate was undertaken. Results: In First BEAT, 225 out of 1914 patients (11.8%) underwent curative-intent surgery at median 64 days (range 42–100) after the last dose of bevacizumab. R0 resection was achieved in 173 out of 225 patients (76.9%). There were no surgery-related deaths and serious post-operative complications were uncommon, with grade 3/4 bleeding and wound-healing events reported in 0.4% and 1.8%, respectively. Resection rates were highest in patients receiving oxaliplatin-based combination chemotherapy (P=0.002), possibly confounded by patient selection. In NO16966, 44 out of 699 patients treated with bevacizumab (6.3%) and 34 out of 701 patients treated with placebo (4.9%) underwent R0 metastasectomy (P=0.24). Conclusions: The rate of serious post-operative complications in First BEAT was comparable to historical controls without bevacizumab. In NO16966, there were no statistically significant differences in resection rates or overall survival in patients treated with bevacizumab vs placebo.

Using a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period. Data from 579 lung cancer cases and 1157 age- and sex-matched population-based controls were available for this analysis. Significant risk factors were fitted into multivariate conditional logistic regression models. The final multivariate model was combined with age-standardised lung cancer incidence data to calculate absolute risk estimates. Combinations of lifestyle risk factors were modelled to create risk profiles. For example, a 77-year-old male non-smoker, with a family history of lung cancer (early onset) and occupational exposure to asbestos has an absolute risk of 3.17% (95% CI, 1.67–5.95). Choosing a 2.5% cutoff to trigger increased surveillance, gave a sensitivity of 0.62 and specificity of 0.70, while a 6.0% cutoff gave a sensitivity of 0.34 and specificity of 0.90. A 10-fold cross validation produced an AUC statistic of 0.70, indicating good discrimination. If independent validation studies confirm these results, the LLP risk models' application as the first stage in an early detection strategy is a logical evolution in patient care.

Nuclear factor-kappa B (NF-kappaB) is a transcription factor with high transcriptional activity in cancer cells. In this study, we developed a novel enhancer-promoter system, kappaB4-CEA205, in which the basal carcinoembryonic antigen (CEA) promoter sequence (CEA205) was placed downstream of the four tandem-linked NF-kappaB DNA-binding sites (kappaB4). In combination with a kappaB4 enhancer, the transcriptional activity of the CEA promoter was significantly enhanced (three- to eight-fold) in cancer cell lines but not in normal cells. In cancer cell lines, the transcriptional activity of kappaB4-CEA205 was comparable with that of the SV40 promoter. We also constructed vectors in which the thymidine phosphorylase (TP) cDNA was under the control of CEA205, kappaB4, kappaB4-CEA205 and CMV promoters, respectively. TP protein and enzyme activity were detected at comparable levels in kappaB4-CEA205- and CMV-driven TP cDNA-transfected cancer cell lines (H630 and RKO). The kappaB4-TP and CEA205-TP-transfected cell lines, respectively, only demonstrated negligible and low levels of TP protein and enzyme activity. Both CMV- and kappaB4-CEA205-driven TP cDNA transiently transfected cells were 8- to 10-fold sensitised to 5-fluorouracil (5-FU) prodrug, 5'-deoxy-5-fluorouradine (5'-DFUR), in contrast to only 1.5- to 2-fold sensitised by the kappaB4- and CEA205-driven TP cDNA-transfected cells. The bystander killing effect of CMV- and kappaB4-CEA205-driven TP cDNA-transfected cells was comparable. This is the first report that indicates that the NF-kappaB DNA-binding site could be used as a novel cancer-specific enhancer to improve cancer-specific promoter activity in gene-directed enzyme prodrug therapy.

Oral capecitabine (Xeloda®) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.

Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a 'very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a 'very important' motivating factor were 'trust in the doctor' (66%), 'being treated by the latest treatment available' (66%), 'better standard of care and closer follow-up' (61%), and 'closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any 'reasonable' alternatives to the trial. In total, 71% strongly agreed that 'surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

Stage at diagnosis and survival from cancer vary according to where people live, suggesting some may have delays in diagnosis. The aim of this study was to determine if time from presentation to treatment was longer for colorectal and breast cancer patients living further from cancer centres, and identify other important factors in delay. Data were collected on 1097 patients with breast and 1223 with colorectal cancer in north and northeast Scotland. Women with breast cancer who lived further from cancer centres were treated more quickly than those living closer to cancer centres (P=0.011). Multilevel modelling found that this was largely due to them receiving earlier treatment at hospitals other than cancer centres. Breast lump, change in skin contour, lymphadenopathy, more symptoms and signs, and increasing age predicted faster treatment. Screen detected cancers and private referrals were treated more quickly. For colorectal cancer, time to treatment was similar for people in rural and urban areas. Quicker treatment was associated with palpable rectal or abdominal masses, tenesmus, abdominal pain, frequent GP consultations, age between 50 and 74 years, tumours of the transverse colon, and iron medication at presentation. Delay was associated with past anxiety or depression. There was variation between general practices and treatment appeared quicker at practices with more female general practitioners.

Although significant advances have been made in the treatment of advanced/metastatic colorectal cancer, 5-fluorouracil (5-FU) still forms the basis of chemotherapy. Recently, new 5-FU schedules and novel fluoropyrimidines have been developed, but there are no trials directly comparing these regimens. The current review describes the mechanisms of action, pre-clinical and phase I/II studies of two oral fluoropyrimidine therapies, capecitabine and uracil with tegafur plus leucovorin. It also compares the phase III studies of these agents with those of the two most popular infusional 5-FU-based regimens: de Gramont and German AIO (The Association of Medical Oncology (AIO) of the German Cancer Society). Both oral and infusional regimens demonstrated similar survival to the Mayo Clinic regimen, a standard treatment for colorectal cancer. Therefore, other endpoints must be examined to decide optimum therapy, including response rates, time to disease progression, tolerability and patients' convenience. All four new therapies demonstrated superior safety profiles compared with the Mayo Clinic regimen. However the uracil with tegafur plus leucovorin regimen was associated with severe diarrhoea and capecitabine with hand–foot syndrome. Patients will not sacrifice efficacy for the convenience of oral therapy alone, therefore the fact that capecitabine achieved superior response rates and equivalent time to disease progression compared with the Mayo Clinic regimen, while uracil with tegafur plus leucovorin produced lower response rates and significantly inferior time to disease progression, is highly relevant in choosing treatment. British Journal of Cancer (2002) 86, 1670–1676. doi:10.1038/sj.bjc.6600341 www.bjcancer.com © 2002 Cancer Research UK

We have investigated c-erbB-2 protein expression in a large cohort of well-characterized colorectal tumours, and in a subset of lymph node metastases. We have also evaluated a Val655Ile single nucleotide polymorphism, which is associated with an increased risk of breast cancer, in a subset of the colorectal cancer patients and in healthy control subjects. Immunohistochemical studies revealed that while 81.8% of tumours expressed c-erbB-2, in the majority of cases equivalent levels of c-erb-B2 were seen in adjacent normal mucosa. Colon tumours were significantly more likely to express c-erbB-2 than rectal tumours (P=0.015). Only 52.4% of the metastases displayed staining patterns concordant with their primary tumour, indicating that determination of c-erbB-2 protein in colorectal tumours cannot predict the status of lymph node metastases. PCR–RFLP analysis of the Val655Ile single nucleotide polymorphism demonstrated that allele frequencies were identical between colorectal cancer patients and a control group of Caucasian subjects (Ile=0.80 and Val=0.20 in each case), indicating that it is not related to the risk of developing colorectal cancer in this population. Furthermore, there was no relationship between c-erbB-2 protein expression and gene polymorphism (P=0.58). In terms of prognosis, no association was seen between either c-erbB-2 protein expression or the presence of the Val allele and patient survival (P>0.05 in each case), suggesting that c-erbB-2 is not a prognostic marker in colorectal cancer. British Journal of Cancer (2002) 86, 568–573. DOI: 10.1038/sj/bjc/6600127 www.bjcancer.com © 2002 Cancer Research UK

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0–20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.© 2001 Cancer Research Campaign http://www.bjcancer.com

There is evidence that patients living in outlying areas have poorer survival from cancer. This study set out to investigate whether they have more advanced disease at diagnosis. Case notes of 1323 patients in north and northeast Scotland who were diagnosed with lung or colorectal cancer in 1995 or 1996 were reviewed. Of patients with lung cancer, 42% (69/164) living 58 km or more from a cancer centre had disseminated disease at diagnosis compared to 33% (71/215) living within 5 km. For colorectal cancer the respective figures were 24% (38/161) and 16% (31/193). For both cancers combined, the adjusted odds ratio for disseminated disease at diagnosis in furthest group compared to the closest group was 1.59 (P = 0.037). Of 198 patients with non-small-cell lung cancer in the closest group, 56 (28%) had limited disease (stage I or II) at diagnosis compared to 23 of 165 (14%) of the furthest group (P = 0.002). The respective figures for Dukes A and B colorectal cancer were 101 of 196 (52%) and 67 of 172 (39%) (P = 0.025). These findings suggest that patients who live remote from cities and the associated cancer centres have poorer chances of survival from lung or colorectal cancer because of more advanced disease at diagnosis. This needs to be taken into account when planning investigation and treatment services. © 2001 Cancer Research Campaign http://www.bjcancer.com

The novel folate analogue AG2034, which was designed as an inhibitor of GARFT (glycinamide ribonucleotide formyltransferase), was evaluated in this phase I study under the auspices of The Cancer Research Campaign, UK. AG2034 blocks de novo purine synthesis through inhibition of GARFT. A total of 28 patients with histologically proven intractable cancers were enrolled. AG2034 was administered as a short intravenous infusion once every 3 weeks. 8 dose levels ranging from 1–11 mg/m2 were evaluated with patients receiving up to 6 cycles. Dose-limiting toxicities in the form of mucositis, diarrhoea and vomiting were observed at doses of 6 mg/m2 and above. Significant levels of thrombocytopenia, neutropenia and anaemia were also recorded. Other sporadic toxicities included fatigue and myalgia. The MTD with this schedule of AG2034 was 5 mg/m2. Most side effects occurred more frequently with cumulative dosing. In keeping with this, pharmacokinetic analysis revealed evidence of drug accumulation. The AG2034 AUC0–24 increased by a median of 184% (range 20–389%) from cycle 1 to 3 in all 10 patients examined. No objective antitumour responses were observed in the study. © 2001 Cancer Research Campaign http://www.bjcancer.com

In this survival study 63 976 patients diagnosed with one of six common cancers in Scotland were followed up. Increasing distance from a cancer centre was associated with less chance of diagnosis before death for stomach, breast and colorectal cancers and poorer survival after diagnosis for prostate and lung cancers. © 2000 Cancer Research Campaign

Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20–320 mg m−2 HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a ‘population approach’ was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 l h−1; central compartment volume (V1) 4.48 × (1+0.00074 × dose (mg)) l; peripheral compartment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h−1. Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 l h−1; apparent V1 (l) 1450 × (1+0.0013 × dose (mg)), apparent V2 (l) 21 300 × (1–0.0013 × dose (mg)) × (1+2.95 × height (m)) and apparent Q 6950 l h−1. Distribution and elimination half-lives were 0.13 h and 85 h respectively. © 1999 Cancer Research Campaign

In an attempt to ensure high quality cancer treatment for all patients in the UK, care is being centralized in specialist centres and units. For patients in outlying areas, however, access problems may adversely affect treatment. In an attempt to assess alternative methods of delivering cancer care, this paper reviews published evidence about programmes that have set out to provide oncology services in remote and rural areas in order to identify evidence of effectiveness and problems. Keyword and textword searches of on-line databases (MEDLINE, EMBASE, HEALTHSTAR and CINAHL) from 1978 to 1997 and manual searches of references were conducted. Fifteen papers reported evaluations of oncology outreach programmes, tele-oncology programmes and rural hospital initiatives. All studies were small and only two were controlled, so evidence was suggestive rather than conclusive. There were some indications that shared outreach care was safe and could make specialist care more accessible to outlying patients. Tele-oncology, by which some consultations are conducted using televideo, may be an acceptable adjunct. Larger and more methodologically robust studies are justified and should be conducted. © 1999 Cancer Research Campaign

Thirty-one patients with advanced renal carcinoma or malignant melanoma were treated in the first feasibility study of alpha-interferon (Roferon) and the new oral immunomodulating agent, Linomide. Linomide 5 mg or 10 mg p.o. daily was given for 2 weeks; alpha-interferon was then added at 3 MU s.c. three times weekly, escalating in each patient by 3 MU per week, if tolerable, up to 12 MJ. The combination was poorly tolerated with nausea, vomiting, somnolence and myalgia commonly reported. Adverse events accounted for treatment withdrawal in ten patients and contributed to withdrawal in four other patients. Treatment with Linomide alone in the first 2 weeks led to a significant increase in white blood cells, neutrophils and platelets. When alpha-interferon was added, the platelet count decreased significantly over the following 6 weeks. Nineteen patients had white cell phenotype and function measured. After 2 weeks of 5 mg Linomide, a transient but significant decrease in the absolute number of activated T-helper cells (CD4+DR+) was observed. No changes in natural killer (NK) cell number or activity were observed. Twenty-two patients were evaluable for response. One with metastatic renal cell carcinoma had a complete response and six had stable disease. This study does not support the use of the combination because significant toxicity was seen without the anticipated immunological benefits.

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.

Individuals with a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) may experience severe life-threatening toxicity when treated with 5-fluorouracil (5-FU). As routine measurement of enzyme activity is not practical in many clinical centres, we have investigated the use of DNA mutation analysis to identify cancer patients with low enzyme levels. We have identified two new mutations at codons 534 and 543 in the DPD cDNA of a patient with low enzyme activity and screened the DNA from 75 colorectal cancer patients for these mutations and the previously reported splice site mutation (Vreken et al, 1996; Wei et al, 1996). In all cases, DPD enzyme activity was also measured. The splice site mutation was detected in a patient (1 out of 72) with low enzyme activity whereas mutations at codons 534 (2 out of 75) and 543 (11 out of 23) were not associated with low enzyme activity. These studies highlight the need to combine DPD genotype and phenotype analysis to identify mutations that result in reduced enzyme activity. Images Figure 1 Figure 2 Figure 3

To investigate the little known risk of lung cancer at an early age when a first-degree relative has had such a diagnosis, 579 incident cases and 1157 population controls were studied in Liverpool between 1998 and 2004 using standardised questionnaires covering demography and lifestyle. A history of lung cancer in first-degree relatives was associated with a significantly increased risk in the proband where in both individuals the cancers were diagnosed before the age of 60 years (odds ratio (OR)=4.89; 95% confidence interval (CI): 1.47-16.25). A significantly elevated risk of lung cancer was also observed in association with a relative affected before the age of 60 years, regardless of age-at-onset of the disease (OR=2.08; 95% CI: 1.20-3.59). This finding is strongly consistent with a genetic component in early-onset lung cancer risk.

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.

Intakes of starch, non-starch polysaccharides (NSPs), protein and fat have been compared with colorectal cancer incidence in 12 populations worldwide. There were strong inverse associations between starch consumption and large bowel cancer incidence (large bowel r = -0.70, colon r = -0.76). There was no significant relation with NSPs, although the association with large bowel cancer incidence was still significant when NSP was combined with resistant starch (RS) to give an estimate of fermentable carbohydrate (large bowel r = -0.52, colon r = -0.60). The relationships between starch, RS and NSPs and cancer incidence remained statistically significant after adjusting for fat and protein intakes. The strong inverse associations found here suggest a potentially important role for starch in protection against colorectal cancer and correspond with the hypothesis that fermentation in the colon is the mechanism for preventing colorectal cancer. Measures of both starch and NSPs need to be included in future epidemiological studies of diet and bowel cancer.

Background: Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs). Methods: The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis. Results: Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 μ), the IC50 concentrations of DS in BC cell lines were 200–500 n. Disulfiram/copper significantly enhanced (3.7–15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1+VE and CD24Low/CD44High CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NFκB activity in BC cell lines was inhibited by DS/Cu. Conclusion: Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NFκB.

Background: Plasma biomarkers may be particularly useful as a predictor or early marker of clinical response to treatment in addition to radiological imaging. Cytokeratin 18 (CK18) is an epithelial-specific cytokeratin that undergoes cleavage by caspases during apoptosis. Measurement of caspase-cleaved (CK18–Asp396) or total cytokeratin 18 (CK18) from epithelial-derived tumours could be a simple, non-invasive way to monitor or predict responses to treatment. Methods: Soluble plasma CK18–Asp396 and CK18 were measured by ELISA from 73 patients with advanced gastrointestinal adenocarcinomas before treatment and during chemotherapy, as well as 100 healthy volunteers. Results: Both CK18–Asp396 and total CK18 plasma levels were significantly higher in patients compared with the healthy volunteers (P=0.015, P

Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39–73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2–5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.

In this study, the gene copy number, mRNA and protein expression levels and nuclear DNA-binding activity of nuclear factor kappa B (NF-kappa B) were compared in a panel of five pairs of thymidylate synthase (TS) inhibitor-resistant and wild-type parent cancer cell lines. High constitutive NF-kappa B DNA-binding activity was detected in all chemoresistant cell lines. The upregulated NF-kappa B activity was composed of NF-kappa B subunits p50 and p65. Four out of five resistant cell lines constitutively overexpressed NF-kappa B p50 and p65 mRNA and protein. One resistant cell line with the highest NF-kappa B DNA-binding activity showed normal p50 and p65 protein expression. No NF-kappa B gene amplification was detected in resistant cell lines. Transient exposure of wild-type RKO(WT) and H630(WT) cells to 5-FU induced NF-kappa B DNA-binding activity but had no effect on NF-kappa B protein expression in these cells. Our results indicate that high constitutive NF-kappa B activity caused by its gene overexpression is an intrinsic character of TS inhibitor-resistant cells. NF-kappa B can antagonise anticancer drug-induced apoptosis. High NF-kappa B expression and nuclear activity in TS inhibitor-resistant cancer cells may play an important role in the chemoresistance.

For common cancers, survival is poorer for deprived and outlying, rural patients. This study investigated whether there were differences in treatment of colorectal and lung cancer in these groups. Case notes of 1314 patients in north and northeast Scotland who were diagnosed with lung or colorectal cancer in 1995 or 1996 were reviewed. On univariate analysis, the proportions of patients receiving surgery, chemotherapy and radiotherapy appeared similar in all socio-economic and rural categories. Adjusting for disease stage, age and other factors, there was less chemotherapy among deprived patients with lung cancer (odds ratio 0.39; 95% confidence intervals 0.16 to 0.96) and less radiotherapy among outlying patients with colorectal cancer (0.39; 0.19 to 0.82). The time between first referral and treatment also appeared similar in all socio-economic and rural groups. Adjusting for disease stage and other variables, times to lung cancer treatment remained similar, but colorectal cancer treatment was quicker for outlying patients (adjusted hazard ratio 1.30; 95% confidence intervals 1.03 to 1.64). These findings suggest that socio-economic status and rurality may have a minor impact on modalities of treatment for colorectal and lung cancer, but do not lead to delays between referral and treatment. British Journal of Cancer (2002) 21, 585–590. doi:10.1038/sj.bjc.6600515 www.bjcancer.com © 2002 Cancer Research UK

In the last 2 years (1989-1990) we have treated a total of 53 patients with metastatic nonseminomatous germ cell tumours (teratoma). In ten cases surgery to remove residual abdominal masses was required on completion of chemotherapy and normalisation of tumour markers (HCG and AFP). In a further three patients with large intra-abdominal masses and little or no other sites of disease surgery was performed as a therapeutic intervention, in the context of plateauing or rising tumour markers despite intensive chemotherapy. In all three, this approach resulted in a rapid fall in tumour markers, and following further chemotherapy all three remain disease free at 7, 12 and 25 months. For this small sub-group of patient failing to respond to chemotherapy who have resectable lesions, interventional surgery should be considered as part of a combined approach to treatment.

We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for degradation of 5-fluorouracil (5-FU). DPD activity is highly variable in liver and peripheral mononuclear cells (PMNCs) and it has not been well studied in human tumours. Characterization of DPD in colorectal cancer is of clinical interest through its role in the regulation of 5-FU, the main chemotherapeutic agent used in this disease. Therefore, DPD activity was analysed in colorectal tumour and adjacent normal tissue from 63 patients, including three liver metastasis. DPD activity was highly variable in all tissues studied (coefficient of variation 43-61%) and was higher in normal tissue than in tumour. The tumour-normal activity ratio ranged from 0.19 to 3.32 (median 0.76). PMNC DPD activity was available for 57 patients and was correlated with tumour activity (r(s) = 0.29, P < 0.001). A higher correlation was observed between PMNCs and tumour samples that were both obtained in the morning (r(s) = 0.49), consistent with circadian variation in DPD activity. Normal tissue DPD activity was not correlated with either tumour (r(s) = 0.11) or PMNC activity (r(s) = -0.06). This study provides the first analysis of DPD activity in colorectal cancer and illustrates the large degree of variation in tumour activity. The tumour-normal activity ratio results suggest that elevated tumour DPD can play a role in 5-FU resistance through increased inactivation in tumour cells, but is an uncommon event in colorectal tumours. The results support the use of PMNCs for monitoring tumour DPD activity, particularly when circadian variation is taken into account. As a large degree of the variation in tumour DPD activity is not explained by PMNC activity, more accurate alternatives are needed before DPD activity can be used for targeting 5-FU therapy.

A total of 161 previously untreated patients with FIGO stage III or IV epithelial ovarian cancer were randomised after surgery to receive six courses of either carboplatin 400 mg m-2 alone (Arm A) or carboplatin 300 mg m-2 with chlorambucil 10 mg day-1 for 7 days (Arm B). The median progression free survival (PFS) was similar: arm A: 45 weeks; arm B: 61 weeks (P = 0.830). Multivariate Cox regression analysis showed that the extent of residual disease and performance status were the most important prognostic factors for PFS. Fifty-two per cent of patients received dose escalations based on nadir blood counts, and 89% of all dose adjustments were made according to protocol. Failure to achieve a significant degree of leucopenia was associated with worse progression free survival (P less than 0.001). A total of 29.4% of patients fall into this category. The median survival was similar in both arms, i.e. 75 weeks. It is unlikely that there is any major clinical advantage to adding chlorambucil to single agent carboplatin for the management of advanced ovarian cancer, but whether used in combination or a single agent, the dose of carboplatin should be sufficient to cause at least grade I leucopenia. This may best be achieved by determining the initial dose based on renal function, and then adjusting subsequent doses according to nadir blood counts.

The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.