Showing papers in "British Journal of Cancer in 2004"
TL;DR: The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer.
Abstract: The discovery of mutations in cancer genes has advanced our understanding of cancer. These results are dispersed across the scientific literature and with the availability of the human genome sequence will continue to accrue. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer. To populate this resource, data has currently been extracted from reports in the scientific literature for somatic mutations in four genes, BRAF, HRAS, KRAS2 and NRAS. At present, the database holds information on 66 634 samples and reports a total of 10 647 mutations. Through the web pages, these data can be queried, displayed as figures or tables and exported in a number of formats. COSMIC is an ongoing project that will continue to curate somatic mutation data and release it through the website.
1,163 citations
TL;DR: In this article, the authors assess a large representative sample of cancer patients on distress levels, common psychosocial problems, and awareness and use of psychOSocial support services, and conclude that distress is very common in cancer patients across diagnoses and across the disease trajectory.
Abstract: The purpose of the study was to assess a large representative sample of cancer patients on distress levels, common psychosocial problems, and awareness and use of psychosocial support services. A total of 3095 patients were assessed over a 4-week period with the Brief Symptom Inventory-18 (BSI-18), a common problems checklist, and on awareness and use of psychosocial resources. Full data was available on 2776 patients. On average, patients were 60 years old, Caucasian (78.3%), and middle class. Approximately, half were attending for follow-up care. Types of cancer varied, with the largest groups being breast (23.5%), prostate (16.9%), colorectal (7.5%), and lung (5.8%) cancer patients. Overall, 37.8% of all patients met criteria for general distress in the clinical range. A higher proportion of men met case criteria for somatisation, and more women for depression. There were no gender differences in anxiety or overall distress severity. Minority patients were more likely to be distressed, as were those with lower income, cancers other than prostate, and those currently on active treatment. Lung, pancreatic, head and neck, Hodgkin's disease, and brain cancer patients were the most distressed. Almost half of all patients who met distress criteria had not sought professional psychosocial support nor did they intend to in the future. In conclusion, distress is very common in cancer patients across diagnoses and across the disease trajectory. Many patients who report high levels of distress are not taking advantage of available supportive resources. Barriers to such use, and factors predicting distress and use of psychosocial care, require further exploration.
872 citations
TL;DR: Two published data sets are illustrated and the resulting estimates are compared with those obtained using the Kaplan–Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.
Abstract: Survival analysis encompasses investigation of time to event data. In most clinical studies, estimating the cumulative incidence function (or the probability of experiencing an event by a given time) is of primary interest. When the data consist of patients who experience an event and censored individuals, a nonparametric estimate of the cumulative incidence can be obtained using the Kaplan-Meier method. Under this approach, the censoring mechanism is assumed to be noninformative. In other words, the survival time of an individual (or the time at which a subject experiences an event) is assumed to be independent of a mechanism that would cause the patient to be censored. Often times, a patient may experience an event other than the one of interest which alters the probability of experiencing the event of interest. Such events are known as competing risk events. In this setting, it would often be of interest to calculate the cumulative incidence of a specific event of interest. Any subject who does not experience the event of interest can be treated as censored. However, a patient experiencing a competing risk event is censored in an informative manner. Hence, the Kaplan-Meier estimation procedure may not be directly applicable. The cumulative incidence function for an event of interest must be calculated by appropriately accounting for the presence of competing risk events. In this paper, we illustrate nonparametric estimation of the cumulative incidence function for an event of interest in the presence of competing risk events using two published data sets. We compare the resulting estimates with those obtained using the Kaplan-Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.
657 citations
TL;DR: The maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 were defined and a partial response was obtained in one patient with metastatic pancreatic cancer and its pharmacokinetic profile in man was well tolerated.
Abstract: NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.
579 citations
TL;DR: Antagonists of several integrins (α5β1, α vβ3 and αvβ5) are now under evaluation in clinical trials to determine their potential as therapeutics for cancer and other diseases.
Abstract: The integrin family of cell adhesion proteins promotes the attachment and migration of cells on the surrounding extracellular matrix (ECM). Through signals transduced upon integrin ligation by ECM proteins or immunoglobulin superfamily molecules, this family of proteins plays key roles in regulating tumour growth and metastasis as well as tumour angiogenesis. Several integrins play key roles in promoting tumour angiogenesis and tumour metastasis. Antagonists of several integrins (alpha5beta1, alphavbeta3 and alphavbeta5) are now under evaluation in clinical trials to determine their potential as therapeutics for cancer and other diseases.
578 citations
TL;DR: This model provides a rational basis for risk assessment in individuals with a FH of breast or ovarian cancer and is closer to the observed values than those obtained using the Claus model and BRCAPRO.
Abstract: Several genes conferring susceptibility to breast and ovarian cancer, notably BRCA1 and BRCA2, have been identified. The majority of the familial aggregation of breast cancer is, however, not explained by these genes. We have previously derived, using segregation analysis, a susceptibility model (BOADICEA, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) in which susceptibility to these genes is explained by mutations in BRCA1 and BRCA2 together with a polygenic component reflecting the joint multiplicative effect of multiple genes of small effect on breast cancer risk. Here, we consider the predictions made by this model. The overall familial risks of breast cancer predicted by this model are close to those observed in epidemiological studies. The predicted prevalences of BRCA1 and BRCA2 mutations among unselected cases of breast and ovarian cancer are also consistent with observations from population-based studies. These predictions are closer to the observed values than those obtained using the Claus model and BRCAPRO. The predicted mutation probabilities and cancer risks in individuals with a family history (FH) can differ markedly from those predicted by other models. We conclude that this model provides a rational basis for risk assessment in individuals with a FH of breast or ovarian cancer.
443 citations
TL;DR: The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.
Abstract: Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.
433 citations
TL;DR: Growing evidence supports a role for OPN as a potential prognostic factor for various human cancers, and aspects of OPN biology that can complicate interpretation of human studies are considered.
Abstract: Since its first identification as a transformation-associated protein, osteopontin (OPN) has been recognised as important in the processes of tumorigenicity and metastasis. Here, we review the evidence that OPN might be considered as a candidate prognostic marker in human cancer. In animal systems, evidence from cell injection experiments and genetically manipulated mice suggest an important but complex role for the protein in tumour progression. Moreover, studies in a variety of human cancers associate high levels of OPN expression in tumours or in blood with more advanced cancers. The mechanism of action of OPN in promoting cancer is still unclear, and we consider aspects of OPN biology that can complicate interpretation of human studies. Nevertheless, growing evidence supports a role for OPN as a potential prognostic factor for various human cancers.
419 citations
TL;DR: Weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival and an independent predictor of progression-free survival in patients with SCLC and NSCLC.
Abstract: To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994-2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival.
411 citations
TL;DR: In this article, the impact of early and intensive nutrition intervention (NI) on body weight, body composition, nutritional status, global quality of life (QoL) and physical function compared to usual practice in oncology outpatients receiving radiotherapy to the GI or head and neck area was determined.
Abstract: Malnutrition occurs frequently in patients with cancer of the gastrointestinal (GI) or head and neck area and can lead to negative outcomes. The aim of this study is to determine the impact of early and intensive nutrition intervention (NI) on body weight, body composition, nutritional status, global quality of life (QoL) and physical function compared to usual practice in oncology outpatients receiving radiotherapy to the GI or head and neck area. Outpatients commencing at least 20 fractions of radiotherapy to the GI or head and neck area were randomised to receive intensive, individualised nutrition counselling by a dietitian using a standard protocol and oral supplements if required, or the usual practice of the centre (general advice and nutrition booklet). Outcome parameters were measured at baseline and 4, 8 and 12 weeks after commencing radiotherapy using valid and reliable tools. A total of 60 patients (51M : 9F; mean age 61.9plusminus14.0 years) were randomised to receive either NI (n=29) or usual care (UC) (n=31). The NI group had statistically smaller deteriorations in weight (P<0.001), nutritional status (P=0.020) and global QoL (P=0.009) compared with those receiving UC. Clinically, but not statistically significant differences in fat-free mass were observed between the groups (P=0.195). Early and intensive NI appears beneficial in terms of minimising weight loss, deterioration in nutritional status, global QoL and physical function in oncology outpatients receiving radiotherapy to the GI or head and neck area. Weight maintenance in this population leads to beneficial outcomes and suggests that this, rather than weight gain, may be a more appropriate aim of NI.
402 citations
TL;DR: Patients with advanced pancreatic cancer were hypermetabolic, however, TEE was reduced and this was secondary to a reduction in physical activity, which may reflect improved quality of life.
Abstract: The aim of the study was to assess the total energy expenditure (TEE), resting energy expenditure (REE) and physical activity level (PAL) in home-living cachectic patients with advanced pancreatic cancer. The influence of an energy and protein dense oral supplement either enriched with or without the n-3 fatty acid eicosapentaenoic acid (EPA) and administered over an 8-week period was also determined. In total, 24 patients were studied at baseline. The total energy expenditure was measured using doubly labelled water and REE determined by indirect calorimetry. Patients were studied at baseline and then randomised to either oral nutritional supplement. Measurements were repeated at 8 weeks. At baseline, REE was increased compared with predicted values for healthy individuals (1387(42) vs 1268(32) kcal day(-1), P=0.001), but TEE (1732(82) vs 1903(48) kcal day(-1), P=0.023) and PAL (1.24(0.04) vs 1.50) were reduced. After 8 weeks, the REE, TEE and PAL of patients who received the control supplement did not change significantly. In contrast, although REE did not change, TEE and PAL increased significantly in those who received the n-3 (EPA) enriched supplement. In summary, patients with advanced pancreatic cancer were hypermetabolic. However, TEE was reduced and this was secondary to a reduction in physical activity. The control energy and protein dense oral supplement did not influence the physical activity component of TEE. In contrast, administration of the supplement enriched with EPA was associated with an increase in physical activity, which may reflect improved quality of life.
TL;DR: Repeated treatment of men with intact gonadal function with abiraterone acetate at a dose of 800 mg can successfully suppress testosterone levels to the castrate range, however, this level of suppression may not be sustained in all patients due to compensatory hypersecretion of LH.
Abstract: Hormonal impact of the 17 α -hydroxylase/C 17,20 -lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer
TL;DR: Serial analysis in 40 patients with recurrent prostate cancer showed that both cytokines became elevated at the point of prostate-specific antigen progression, suggesting that IL-6 and TNF-α correlate with the extent of disease in patients with prostate cancer and may be monitored in conjunction with other disease markers.
Abstract: Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) are important multifunctional cytokines involved in tumour growth and metastasis. In this study, we have measured serial levels of serum IL-6 and TNF-alpha in prostate cancer patients. A total of 80 patients with carcinoma of the prostate and 38 controls were studied. Three patient groups, with small bulk localised, large volume localised and metastatic prostate cancer, were assessed. Serum IL-6 and TNF-alpha levels were measured and correlated with clinicopathological variables and patient survival. Serial changes in these cytokines were also assessed and related to disease progression in 40 patients with recurrent prostate cancer. Serum IL-6 levels in patients with metastatic disease (9.3+/-7.8 pg x ml(-1)) were higher than those in patients with localised disease (1.3+/-0.8 pg x ml(-1), P<0.001). Significantly elevated levels of TNF-alpha were found in metastatic disease (6.3+/-3.6 pg x ml(-1)) compared with localised disease (1.1+/-0.5 pg x ml(-1), P<0.001). The levels of both cytokines were directly correlated with the extent of the disease. Serial analysis in 40 patients with recurrent tumours showed that both cytokines became elevated at the point of prostate-specific antigen progression. In conclusion, these results suggest that IL-6 and TNF-alpha correlate with the extent of disease in patients with prostate cancer and may be monitored in conjunction with other disease markers.
TL;DR: This review focuses on how aberrant covalent histone modifications may contribute to the development of a variety of human cancers, and discusses the recent findings with regard to potential therapies.
Abstract: Covalent modifications of histones, such as acetylation, methylation, and phosphorylation, and other epigenetic modulations of the chromatin, such as methylation of DNA and ATP-dependent chromatin reorganisation, can play a major part in the multistep process of carcinogenesis, with far-reaching implications for human biology and human health. This review focuses on how aberrant covalent histone modifications may contribute to the development of a variety of human cancers, and discusses the recent findings with regard to potential therapies.
Katholieke Universiteit Leuven1, University of Texas MD Anderson Cancer Center2, St Thomas' Hospital3, Cleveland Clinic4, The Royal Marsden NHS Foundation Trust5, Ruhr University Bochum6, Thomas Jefferson University7, Hospital General Universitario Gregorio Marañón8, University of Regensburg9, University of Chicago10
TL;DR: Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC, and is a suitable replacement for i.V.5-FU as the backbone of colorectal cancer therapy.
Abstract: This study evaluates the efficacy of capecitabine using data from a large, well-characterised population of patients with metastatic colorectal cancer (mCRC) treated in two identically designed phase III studies. A total of 1207 patients with previously untreated mCRC were randomised to either oral capecitabine (1250 mg m(-2) twice daily, days 1-14 every 21 days; n=603) or intravenous (i.v.) bolus 5-fluorouracil/leucovorin (5-FU/LV; Mayo Clinic regimen; n=604). Capecitabine demonstrated a statistically significant superior response rate compared with 5-FU/LV (26 vs 17%; P<0.0002). Subgroup analysis demonstrated that capecitabine consistently resulted in superior response rates (P<0.05), even in patient subgroups with poor prognostic indicators. The median time to response and duration of response were similar and time to progression (TTP) was equivalent in the two arms (hazard ratio (HR) 0.997, 95% confidence interval (CI) 0.885-1.123, P=0.95; median 4.6 vs 4.7 months with capecitabine and 5-FU/LV, respectively). Multivariate Cox regression analysis identified younger age, liver metastases, multiple metastases and poor Karnofsky Performance Status as independent prognostic indicators for poor TTP. Overall survival was equivalent in the two arms (HR 0.95, 95% CI 0.84-1.06, P=0.48; median 12.9 vs 12.8 months, respectively). Capecitabine results in superior response rate, equivalent TTP and overall survival, an improved safety profile and improved convenience compared with i.v. 5-FU/LV as first-line treatment for MCRC. For patients in whom fluoropyrimidine monotherapy is indicated, capecitabine should be strongly considered. Following encouraging results from phase I and II trials, randomised trials are evaluating capecitabine in combination with irinotecan, oxaliplatin and radiotherapy. Capecitabine is a suitable replacement for i.v. 5-FU as the backbone of colorectal cancer therapy.
TL;DR: A high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases, which indicates that HER-2-positive breast cancer may have a predilection for the brain, or trastzumab therapy may change the disease pattern by prolonging survival.
Abstract: Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.
TL;DR: Increases in cancer survival in England and Wales during the 1990s are shown to be significantly associated with a widening deprivation gap in survival, and appears likely to continue improving for most cancers in the near future.
Abstract: We examined national trends and socioeconomic inequalities in cancer survival in England and Wales during the 1990s, using population-based data on 2.2 million patients who were diagnosed with one of the 20 most common cancers between 1986 and 1999 and followed up to 2001. Patients were assigned to one of five deprivation categories (from ‘affluent’ to ‘deprived’) using characteristics of their electoral ward of residence at diagnosis. We estimated relative survival up to 5 years after diagnosis, adjusting separately in each deprivation category for background mortality by age, sex and calendar period. We estimated trends in survival and in the difference in survival between deprivation categories (‘deprivation gap’) over the periods 1986–90, 1991–95 and 1996–99. We used period analysis to examine likely survival rates in the near future. Survival improved for most cancers in both sexes during the 1990s, and appears likely to continue improving for most cancers in the near future. The deprivation gap in survival between rich and poor was wider for patients diagnosed in the late 1990s than in the late 1980s. Increases in cancer survival in England and Wales during the 1990s are shown to be significantly associated with a widening deprivation gap in survival.
TL;DR: The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3′UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy.
Abstract: In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.
TL;DR: The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin, and evidence of antitumour activity was seen in some patients with advanced resistant solid tumours.
Abstract: SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m−2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m−2. The maximum tolerated dose was 70 mg m−2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile.
TL;DR: An overview of the current understanding of ER signalling is provided and the unique mode of action of fulvestrant is illustrated, an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects.
Abstract: Due to their favourable tolerability profiles, endocrine therapies have long been considered the treatment of choice for hormone-sensitive metastatic breast cancer. However, the oestrogen agonist effects of the available selective oestrogen receptor modulators, such as tamoxifen, and the development of cross-resistance between endocrine therapies with similar modes of action have led to the need for new treatments that act through different mechanisms. Fulvestrant (‘Faslodex’) is the first of a new type of endocrine treatment – an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. This article provides an overview of the current understanding of ER signalling and illustrates the unique mode of action of fulvestrant. Preclinical and clinical study data are presented in support of the novel mechanism of action of this new type of ER antagonist.
TL;DR: Hypotheses regarding the aetiology of cancer-related fatigue are discussed, and clinical practice guidelines for the evaluation and management of oncology patients with fatigue are reviewed.
Abstract: Fatigue is the most prevalent cancer-related symptom and has a significant adverse impact on patients' functional ability and quality of life. Hypotheses regarding the aetiology of cancer-related fatigue are discussed, and clinical practice guidelines for the evaluation and management of oncology patients with fatigue are reviewed. Both nonpharmacologic and pharmacologic strategies for the management of fatigue are summarised.
TL;DR: Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease and has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer.
Abstract: Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.
TL;DR: The value of an inflammation-based prognostic score was compared with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer and only the GPS was a significant independent predictor of survival.
Abstract: The value of an inflammation-based prognostic score (GPS) was compared with performance status (ECOG) in patients (n=109) receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. On multivariate analysis with ECOG, white cell count and the GPS entered as covariates, only the GPS was a significant independent predictor of survival (HR 1.88, 95% CI 1.25–2.84, P=0.002).
TL;DR: Tumour size was a more valuable prognostic factor than tumour grade in this series of primary sarcomas of the breast and was significantly associated with OS and cause-specific survival.
Abstract: Primary sarcomas of the breast are extremely rare, with less than 0.1% of all malignant tumours of the breast. Mayo Clinic Surgical Pathology database was searched for all breast sarcoma from 1910 to 2000. Pathology reports and slides were reviewed and tumour types were determined. Metaplastic carcinomas and phyllodes tumours were excluded. There were 25 women ranging in age 24-81 years (mean 45 years). All but one patient presented with a palpable lump. Mastectomy was performed in 19 patients and lumpectomy in five patients. Histopathological diagnoses were fibrosarcoma (six), angiosarcoma (six), pleomorphic sarcoma (six), leiomyosarcoma (two), myxofibrosarcoma (three), hemangiopericytoma (one) and osteosarcoma (one). Tumour size ranged from 0.3 to 12 cm (mean 5.7). Low-grade lesions were observed in 10 cases and high-grade in 15. Overall, mean follow-up was 10.5 years. Local recurrence was observed in 11 patients and ranged from 2 to 36 months (mean 15 m), while distant metastasis was observed in 10 patients (40%) affecting lungs, bones, liver, spleen, and skin. Of the 25 patients, 12 have died of disease and six of other causes. Five-year overall (OS) and cause-specific survival (CSS) were 66 and 70%, respectively. OS and DFS at 5 years were 91% for tumours 5 cm. Tumour size was significantly associated with OS (risk ratio=1.3 per 1 cm increase; 95% CI, 1.02-1.7; P=0.036). There was no significant difference in OS or CSS between low- and high-grade lesions. In this series, tumour size was a more valuable prognostic factor than tumour grade.
TL;DR: The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses.
Abstract: SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1*28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1*28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1*28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1*28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.
TL;DR: The basic structure of the pathway was reviewed in this article, together with results of the clinical studies targeting mTOR for cancer therapy, and this group of drugs may have a place in Oncology for the treatment of cancers.
Abstract: mTOR is a downstream mediator in the PI3K/Akt signalling pathway, which plays a critical role in regulating basic cellular functions. These include cell proliferation, survival, mobility and angiogenesis. Rapamycin and its analogues (CCI-779, RAD001 and AP23573) have specific antagonistic action on the function of mTOR. This leads to inhibition of the downstream signalling elements and results in the cell cycle arrest in the G1 phase. This group of drugs may have a place in Oncology for the treatment of cancers, which occur as a result of increased activity of the PI3 kinase/Akt/m-TOR pathway. The basic structure of the pathway was reviewed in this article, together with results of the clinical studies targeting mTOR for cancer therapy. This is an exciting area for development and poses many challenges to researchers.
TL;DR: Multivariate analysis revealed pre-chemotherapy HBV DNA level, the use of steroids and a diagnosis of lymphoma or breast cancer to be significant factors for the development of HBV reactivation.
Abstract: For cancer patients with chronic hepatitis B virus (HBV) infection, who receive cytotoxic chemotherapy, HBV reactivation is a well-described complication, which may result in varying degrees of liver damage. Several clinical features and the pre-chemotherapy HBV viral load have been suggested to be associated with an increased risk of developing the condition: (1). to assess the clinical and virological factors in a comprehensive manner and thereby identify those that are associated with the development of HBV reactivation; (2). to develop a predictive model to quantify the risk of HBV reactivation. In all, 138 consecutive cancer patients who were HBV carriers and undergoing chemotherapy were studied, of which 128 patients had sera available for real-time PCR HBV DNA measurement. They were followed up throughout their course of chemotherapy and the HBV reactivation rate was determined. The clinical and virological features between those who did and did not develop viral reactivation were compared. These included age, sex, baseline liver function tests, HBeAg status and viral load (HBV DNA) prior to the chemotherapy, and the use of specific cytotoxic agents. In all, 36 (26%) developed HBV reactivation. Multivariate analysis revealed pre-chemotherapy HBV DNA level, the use of steroids and a diagnosis of lymphoma or breast cancer to be significant factors. Based on real-time HBV DNA PCR assay, detectable baseline HBV DNA prior to the administration of cytotoxic chemotherapy, the use of steroids and a diagnosis of lymphoma or breast cancer are predictive factors for the development of HBV reactivation. A predictive model was developed from the current data, based on a logistic regression method.
TL;DR: Although stratification by study area, with varied salt intake and gastric cancer incidence, attenuated the observed clear associations with salt and salting foods, the frequency categories of highly salted foods such as salted fish roe and saltedFish preserves were strongly associated with the risk in both sexes.
Abstract: Evidence on the association between salt intake and gastric cancer is sparse, especially in prospective studies. We conducted a population-based prospective study in Japan, where the majority of men has been infected with Helicobacter pylori. A total of 18 684 men and 20 381 women aged 40-59 years who reported their dietary habits and did not report any serious disease at baseline were followed from 1990 to 2001. A total of 486 cases, 358 men and 128 women, with histologically confirmed gastric cancer were documented among them. The quintile category of salt intake was dose-dependently associated with gastric cancer risk in men after adjusting for potential confounding factors (P for trend <0.001), while a trend was not clear in women (P for trend=0.48). Although stratification by study area, with varied salt intake and gastric cancer incidence, attenuated the observed clear associations with salt and salted foods, the frequency categories of highly salted foods such as salted fish roe and salted fish preserves were strongly associated with the risk in both sexes. Restriction of salt and salted food intake is a practical strategy to prevent gastric cancer in areas with high risk.
TL;DR: Snail or SIP1 expression may be induced during HCC progression, where Snail/SIP1 directly represses E-cad gene transcription and activates cancer invasion via the upregulation of the MMP gene family.
Abstract: Loss of E-cadherin (E-cad) triggers invasion, metastasis, and dedifferentiation in various epithelial carcinomas. Recently, it has been reported that two transcription factors, Snail and SIP1 (Smad interacting protein 1), directly repress transcription of the E-cad gene by binding E-box on E-cad promoter. Our aim is to solve the molecular mechanism of Snail and SIP1 in hepatocellular carcinoma (HCC). We first showed an inverse correlation between E-cad and Snail/SIP 1 expression among five HCC lines with different phenotypes. The result indicated that undifferentiated, but not differentiated type expressed Snail/SIP1. Then, we established transfectants stably expressing Snail and SIP1 in two differentiated cells with E-cad expression. Suppressed expression of E-cad, morphologic change into fibroblastoid feature, and remarkable acceleration of invasion activity were observed in the transfectants. In reverse transcription–polymerase chain reaction series of genes relating to motility and invasion, we demonstrated striking evidence that matrix metalloproteinase (MMP-1), MMP-2, MMP-7, and MT1-MMP expressions were strongly upregulated by Snail. On the other hand, MMP-1, MMP-2, and MT1-MMP expressions were enhanced by SIP1 transfection, however, the intensity was weaker than that in Snail transfection. In conclusion, Snail or SIP1 expression may be induced during HCC progression, where Snail/SIP1 directly represses E-cad gene transcription and activates cancer invasion via the upregulation of the MMP gene family.
TL;DR: This book provides a very comprehensive overview of in vitro and in vivo screening methodologies and toxicology, together with clinical trials design, and has the feel of a conference proceedings rather than a quality textbook or monograph.
Abstract: Part I. In Vitro Methods. High-Volume Screening, Michel Page. The NCI In Vitro Anticancer Drug Discovery Screen: Concept, Implementation, and Operation, 1985-1995, Michael R. Boyd. Human Tumor Screening, Axel-R. Hanauske, Susan G. Hilsenbeck, and Daniel D. Von Hoff. Part II. In Vivo Methods. Murine L1210 and P388 Leukemias, William R. Waud. In Vivo Methods for Screening and Preclinical Testing: Use of Rodent Solid Tumors for Drug Discovery, Thomas Corbett, Fred Valeriote, Patricia LoRusso, Lisa Polin, Chiab Panchapor, Susan Pugh, Kathryn White, Juiwanna Knight, Lisa Demchik, Julie Jones, Lynne Jones, and Loretta Lisow. Human Tumor Xenograft Models in NCI Drug Development, Jaqueline Plowman, Donald J. Dykes, Melinda Hollingshead, Linda Simpson-Herren, and Michael C. Alley. Fertile Seed and Rich Soil: The Development of Clinically Relevant Models of Human Cancer by Surgical Orthotopic Implantation of Intact Tissue, Robert M. Hoffman. Preclinical Models for High-Dose Therapy, Beverly A. Teicher. Models for Minimal Residual Tumor, Beverly A. Teicher. Spontaneously Occurring Tumors in Companion Animals as Models for Drug Development, David M. Vail and E. Gregory MacEwen. Part III. Clinical Testing. Working with the National Cancer Institute, Edward A. Sausville. Phase I Trial Design and Methodology, Deborah L. Toppmeyer. Phase II Clinical Trials in Oncology, Christine Khater, Paul Laub, James M. Gallo, Andre Rogatko, and Peter J. O'Dwyer. Drug Development in Europe, Thomas Anthony Connors and Herbert M. Pinedo. The Phase III Cancer Clinical Trial, Emil Frei III. FDA Role in Cancer Drug Development and Requirements for Approval, Robert L. Justice. Index