British Journal of Cancer

Published by Springer Nature

Online ISSN: 1532-1827


Print ISSN: 0007-0920


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April 1956


10 Reads



F. J. C. Roe

Sample size: How many patients are necessary?
The need for sample size calculations is briefly reviewed: many of the arguments against small trials are already well known, and we only cursorily repeat them in passing. Problems that arise in the estimation of sample size are then discussed, with particular reference to survival studies. However, most of the issues which we discuss are equally applicable to other types of study. Finally, prognostic factor analysis designs are discussed, since this is another area in which experience shows that far too many studies are of an inadequate size and yield misleading results.

Figure 2 Vasculature in the junctional region between tumour and underlying dermis showing; a, dense vascularity including many large calibre vessels and b, a tumour with relative sparse vascularity in this region. 
Figure 4 The length and surface density of vessels at the tumour base in relation to adjacent dermis. 0-dermis (n = 74); 0tumour base (n = 100). Regression line fitted to dermis data only. (S, = 0.0246 x L4 + 0.770). 
Figure 6 Clinical outcome in relation to tumour vascularity within a, the tumour base region (0-non-recurrence, n = 77;O}-recurrence, n = 20) and b, the tumour (0-non-recurrence, n 1= 70; *-recurrence, n= 17). 
Figure I Vasculature associated with primary cutaneous melan = number of 'hits' scored by the respective morphometric noma, visualised by endothelial staining using Ulex europaeus 
The vascularity of cutaneous melanoma: A quantitative histological study of lesions 0.85 - 1.25mm in thickness

August 1991


46 Reads

The vascularity of 107 primary cutaneous melanomas has been characterized by morphometric histological analysis. The lesions selected for study were of thickness 0.85-1.25 mm and the aim was to evaluate the prognostic significance of tumour vascularity. Two groups of patients were identified; 86 with no evidence of recurrence after a minimum follow-up period of 5 years and 21 with locoregional recurrence and/or metastasis. The lectin Ulex europaeus type I was used for endothelial cell staining of tissue sections and morphometric analysis was performed to derive the vascular length, surface and volume density from independent measurements of tumour, adjacent dermis and the junctional zone between tumour and underlying tissue. A wide range of values was obtained for each parameter with increased vascularity always found at the tumour base compared with the tumour as a whole. In relation to the adjacent normal dermis, vascularity was generally found to be higher at the tumour base but either higher or lower in the tumour overall. Tumour recurrence could not be predicted by any of the derived vascular parameters either independently or together with other histological and clinical features. This study suggests that tumour vascularity is of no prognostic significance in melanoma of the above thickness range. The highly variable extent of tumour vascularity was not correlated with other clinical or histological parameters, but may have implications for the delivery of pharmaceutical agents used for diagnosis or therapy. Images Figure 1 Figure 2

Season of birth and diagnosis of children with leukaemia: An analysis of over 15 000 UK cases occurring from 1953-95

March 2001


43 Reads

If infections are involved in the aetiology of childhood leukaemia then seasonal variation in the birth or onset dates of the malignancy may be apparent. Previous studies that have examined seasonality of these dates have produced conflicting results. Using population-based data from the National Registry of Childhood Tumours we conducted a larger study than any to date of 15 835 cases of childhood leukaemia born and diagnosed in the UK between 1953-95. We found no evidence of seasonality in either month of birth or month of diagnosis overall or in any subgroups by age, sex, histology or immunophenotype. We did however find a significant (P = 0.01) February peak in month of birth for cases born before 1960 and a significant (P = 0.02) August peak in month of diagnosis for those diagnosed before 1962. Whilst these findings may be due to chance they are also consistent with changes over time in the seasonality of exposure, or immunological response, to a relevant infection. Changes in the seasonal variation in the fatality rate of a pre-leukaemic illness, such as pneumonia, could be another explanation.

Table 1 Testicular cancer incidence in relation to serum cholesterol in a 25-year follow-up study of the Värmland cohort (n ¼ 44 864) 
Wirehn AB, Tornberg S, Carstensen JSerum cholesterol and testicular cancer incidence in 45 000 men followed for 25 years. Br J Cancer 92: 1785-1786

May 2005


73 Reads

In a 25-year follow-up study of 44,864 men with measured serum cholesterol levels, the testicular cancer hazard ratios for the serum cholesterol categories 5.7-6.9 and > or = 7.0 mmol l(-1) vs the reference category (<5.7 mmol l(-1)) were 1.3 and 4.5, respectively; P-value for trend=0.005. This highly significant association suggests that high-serum cholesterol is a risk factor for testicular cancer.

Figure 1: Flow diagram depicting outcomes of patients presenting with human chorionic gonadotrophin (hCG) >100 000 IU l−1.
The management and outcome of women with post-hydatidiform mole 'low-risk' gestational trophoblastic neoplasia, but hCG levels in excess of 100 000 IU l(-1)

February 2010


81 Reads


D Short





M J Seckl
Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l(-1) can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group. Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l(-1) and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded. Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l(-1) and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%. Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l(-1) can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l(-1) should receive multi-agent chemotherapy from the outset.

Table 1 Characteristics of the VHM&PP study cohort 
Table 3 Estimated HR and 95% CI for incident cancers diagnosed among female participants in the VHM&PP Study Cohort 1985 -2001, according to BMI at enrolment BMI (kg m À2 ) a 
Obesity and incidence of cancer: A large cohort study of over 145 000 adults in Austria

October 2005


102 Reads

We investigated the relation of overweight and obesity with cancer in a population-based cohort of more than 145 000 Austrian adults over an average of 9.9 years. Incident cancers (n=6241) were identified through the state cancer registry. Using Cox proportional-hazards models adjusted for smoking and occupation, increases in relative body weight in men were associated with colon cancer (hazard rate (HR) ratio 2.48; 95% confidence interval (CI): 1.15, 5.39 for body mass index (BMI) > or =35 kg m(-2)) and pancreatic cancer (HR 2.34, 95% CI: 1.17, 4.66 for BMI>30 kg m(-2)) compared to participants with normal weight (BMI 18.5-24.9 kg m(-2)). In women, there was a weak positive association between increasing BMI and all cancers combined, and strong associations with non-Hodgkin's lymphomas (HR 2.86, 95% CI: 1.49, 5.49 for BMI> or =30 kg m(-2)) and cancers of the uterine corpus (HR 3.93, 95% CI: 2.35, 6.56 for BMI> or =35 kg m(-2)). Incidence of breast cancer was positively associated with high BMI only after age 65 years. These findings provide further evidence that overweight is associated with the incidence of several types of cancer.

Figure 1: Age distribution of HPV-16, -18, -31, and -45 seroprevalence* and DNA-prevalence** in Guanacaste, Costa Rica women. *Population-based HPV-16, -18, -31, and -45 serology prevalence is shown in black lines and includes study virgins. Black dotted lines denote seroprevalence excluding study virgins. **HPV DNA prevalence does not include study virgins.
Table 4 Final logistic regression model demonstrating association between number of lifetime sexual partners, age at first sexual intercourse, smoking, OC use and HPV-16, -18, and -31 seropositivity, also adjusted for age and recent sexual partners (excluding study virgins)
of HPV-16, -18, -31, and -45 in the Costa Rican population-based cohort
Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10 000 women in Costa Rica

November 2003


117 Reads

Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n=9949), HPV-18 (n=9928), HPV-31 (n=9932), and HPV-45 (n=3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n=573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for HPV-16, -18, -31, or -45, seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA- and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.

Engeland A, Tretli S, Bjorge THeight, body mass index, and prostate cancer: a follow-up of 950 000 Norwegian men. Br J Cancer 89: 1237-1242

October 2003


60 Reads

The present study explored body mass index (BMI), height, and risk of prostate cancer in a large Norwegian cohort of 950000 men aged 20-74 years, whose height and weight were measured in a standardised way in the period 1963-1999. These were followed for an average of 21 years. The Cox proportional hazard models were used in the analyses. During follow-up, 33 300 histologically verified cases of prostate cancer were registered. The risk of prostate cancer increased by both BMI and height. The magnitude of the increase by BMI was modest, the relative risk (RR) of obese men (BMI>or=30) compared with normal weighted was 1.09 (95% CI: 1.04-1.15). However, the RR at age 50-59 years was 1.58 (95% CI: 1.29-1.94) in men being obese at about age 45 years compared with normal weighted men. The tallest men had an RR of 1.72 (95% CI: 1.46-2.04) compared with the shortest men. The overall effect of BMI on the incidence of prostate cancer was modest. The larger effect found in men aged 50-59 years might partly explain the previous inconsistent findings.

Figure 1: Age distribution of HPV-16 seroconversion and persistence in Guanacaste, Costa Rica women at midpoint age (years) during follow-up.
Determinants of human papillomavirus 16 serological conversion and persistence in a population-based cohort of 10 000 women in Costa Rica

November 2004


95 Reads

Determinants of human papillomavirus (HPV)-16 serological conversion and persistence were assessed in a population-based cohort of 10 049 women in Guanacaste, Costa Rica. Serologic responses to HPV-16 were measured in 7986 women by VLP-based enzyme-linked immunosorbent assay at both study enrollment (1993/94) and at 5-7 years of follow-up. Seropositive women were defined as >/=5 standard deviations above the mean optical density obtained for studied virgins at enrollment (n=573). Seroconnversion (n=409), persistence (n=675), and clearance (n=541) were defined based on enrollment and follow-up serology measurements. Age-specific distributions revealed that HPV-16 seroconversion was highest among 18- to 24-year-old women, steadily declining with age; HPV-16 seropersistence was lowest in women 65+ years. In age-adjusted multivariate logistic regression models, a 10-fold risk increase for HPV-16 seroconversion was associated with HPV-16 DNA detection at enrollment and follow-up; two-fold risk of seroconversion to HPV-16 was associated with increased numbers of lifetime and recent sexual partners and smoking status. Determinants of HPV-16 seropersistence included a 1.5-fold risk increase associated with having one sexual partner during follow-up, former oral contraceptive use, and a 3-fold risk increase associated with HPV-16 DNA detection at both enrollment and follow-up. Higher HPV-16 viral load at enrollment was associated with seroconversion, and higher antibody titres at enrollment were associated with seropersistence.

Table 3 Standardised incidence ratios of selected second primary cancers after NHL by age at NHL 
Table 6 Summary of the major findings Trend (Po0.05) 
Second primary cancers among 109 000 cases of non-Hodgkin's lymphoma

August 2005


79 Reads

An analysis of other primary cancers in individuals with non-Hodgkin's lymphoma (NHL) can help to elucidate this cancer aetiology. In all, 109 451 first primary NHL were included in a pooled analysis of 13 cancer registries. The observed numbers of second cancers were compared to the expected numbers derived from the age-, sex-, calendar period- and registry-specific incidence rates. We also calculated the standardised incidence ratios for NHL as a second primary after other cancers. There was a 47% (95% confidence interval 43-51%) overall increase in the risk of a primary cancer after NHL. A strongly significant (P<0.001) increase was observed for cancers of the lip, tongue, oropharynx*, stomach, small intestine, colon*, liver, nasal cavity*, lung, soft tissues*, skin melanoma*, nonmelanoma skin*, bladder*, kidney*, thyroid*, Hodgkin's lymphoma*, lymphoid leukaemia* and myeloid leukaemia. Non-Hodgkin's lymphoma as a second primary was increased after cancers marked with an asterisk. Patterns of risk indicate a treatment effect for lung, bladder, stomach, Hodgkin's lymphoma and myeloid leukaemia. Common risk factors may be involved for cancers of the lung, bladder, nasal cavity and for soft tissues, such as pesticides. Bidirectional effects for several cancer sites of potential viral origin argue strongly for a role for immune suppression in NHL.

Figure 1: Patient flow through the trial.
Table 1 . Tumour and patient characteristics at trial entry N (%)
Figure 2: Progression-free survival (A) and overall survival (B) in months since trial entry.
Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001)

October 2013


160 Reads

Background: Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. Methods: Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m−2 day 1, cisplatin 60 mg m−2 day 1, 5-flurouracil 750 mg m−2 per day days 1–5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. Results: 10/26 evaluable patients (38.5%, 95% CI: 20.2–59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. Conclusion: Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.

Figure 1: Expression of smooth-muscle actin in desmoplastic stroma. The figure illustrates examples with weak (A, C) and strong (B) staining intensity.
Figure 2: Patterns of density of desmoplastic stroma. (A) Loose connective tissue with myxoid appearance. (B) Moderate density. (C) Tightly packed connective tissue fibres (same cases as in ).
Figure 3: Kaplan–Meier curves: α-SMA expression. High α-SMA expression is associated with decreased DFS and OS in the overall study population.
Figure 4: Kaplan–Meier curves: stromal density. A dense stroma is a positive prognostic biomarker for DFS and OS in patients that received no adjuvant treatment but not in patients who received adjuvant treatment with gemcitabine. Stroma density as well as DFS and OS are indicated by the different rows, treatment arms by the different columns.
??-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: Results from the CONKO-001 study

October 2014


676 Reads

Background: Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients. Methods: CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome. Results: High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival. Conclusions: Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.

Figure 1: Kaplan–Meier estimates of survival among patients with KRAS or BRAF mutations detected in archival tumour tissue (A) and in plasma (B) in the prospective cohort.
Table 1 . Patient characteristics
Table 2 . Univariate analysis of outcome parameters according to KRAS and BRAF mutations
MC13-0026 KRAS mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer

November 2013


56 Reads

Background: We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy. Methods: Two hundred and eleven patients receiving second-line irinotecan (350 mg m−2 q3w) were included in two independent cohorts. Plasma was obtained from pretreatment EDTA blood-samples. Mutations were detected in archival tumour and plasma with qPCR methods. Results: Mutation status in tumor did not correlate to efficacy in either cohort, whereas none of the patients with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF and KRAS demonstrated a strong influence on both PFS and OS. The median OS was 13.0 mo in pKRAS wt patients and 7.8 in pKRAS-mutated, (HR=2.26, P<0.0001). PFS was 4.6 and 2.7 mo, respectively (HR=1,69, P=0.01). Multivariate analysis confirmed the independent prognostic value of pKRAS status but not KRAS tumor status. Conclusion: Tumor KRAS has minor clinical impact, whereas plasma KRAS status seems to hold important predictive and prognostic information.

Table 2 . Dose level evaluated and encountered DLTs
Table 3 . Common treatment related adverse events
Table 5 . Pharmacokinetic parameters of cediranib at different DLs
Duration of exposure as of data cutoff date on 6 November 2012. *Patient continues on treatment. Abbreviation: DL, dose level.
Concentration of circulating angiogenic factors measured in the sera of patients during cycle 1 of treatment. (A) VEGF-A, (B) VEGF-C and (C) SDF-1. Increases in these factors were detected after dosing with cediranib, but there was no suggestion of relationship with dose or time to treatment failure.
A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503)

July 2013


114 Reads

Background: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. Methods: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. Results: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. Conclusion: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.

Figure 1 Typical examples of a diploid (A) and aneuploid (B) flow cytometry profile. The dot plot (left) shows the region delineating BrdUrdlabelled cells. The histograms (right) show the DNA profile of all single nuclei (A) and of BrdUrd-labelled nuclei only. See text for description of markers  
Table 1 Summary of kinetic parameters obtained from each centre for all 102 specimens. The numbers in parentheses represent the data obtained from 90 patients excluding the censored T s data
's correlation analysis of sample specimens in which there was consensus in ploidy classification. 'All' refers to tumours that were uniformly classified as diploid or aneuploid with the same DNA index and 'dip' and 'aneu' refer to the subgroups of diploid or aneuploid tumours only
Reproducibility of measurements of potential doubling time of tumour cells in the multicentre National Cancer Institute protocol T92-0045

February 1999


195 Reads

We compared the flow cytometric measurement and analysis of the potential doubling time (Tpot) between three centres involved in the National Cancer Institute (NCI) protocol T92-0045. The primary purpose was to understand and minimize the variation within the measurement. A total of 102 specimens were selected at random from patients entered into the trial. Samples were prepared, stained, run and analysed in each centre and a single set of data analysed by all three centres. Analysis of the disc data set revealed that the measurement of labelling index (LI) was robust and reproducible. The estimation of duration of S-phase (T(S)) was subject to errors of profile interpretation, particularly DNA ploidy status, and analysis. The LI dominated the variation in Tpot such that the level of final agreement, after removal of outliers and ploidy agreement, reached correlation coefficients of 0.9. The sample data showed poor agreement within each of the components of the measurement. There was some improvement when ploidy was in agreement, but correlation coefficients failed to exceed values of 0.5 for Tpot. The data suggest that observer-associated analysis of T(S) and tissue processing and tumour heterogeneity were the major causes of variability in the Tpot measurement. The first two aspects can be standardized and minimized, but heterogeneity will remain a problem with biopsy techniques.

Schematic representation of 26S proteasome composition: The three primary proteolytic activities (CT-L, T-L, and C-L) reside within the β-subunits of 20S and interact with proteasome inhibitors. Bortezomib and NPI-0052 are structurally distinct with different active sites.
NPI-0052- and Bortezomib-induced cell-death signalling pathways. Both NPI-0052 and Bortezomib trigger intrinsic (caspase-9-mediated) and extrinsic (caspase-8-mediated) apoptotic signalling pathways. Deletion of Bax/Bak results in significant loss of response to Bortezomib, but not NPI-0052.
A novel proteasome inhibitor NPI-0052 as an anticancer therapy
Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/refractory MM patients.

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study

December 2004


88 Reads

Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, < or =75 years, ECOG PS < or =2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.

Figure 1 The effect of bisphosphonate exposure on proliferation of UMR 106-01 cells grown in monolayer. Cells were detached by trypsinization and counted by coulter counter on the days indicated. Points are mean of three samples. Experiments were performed more than three times with similar results and low standard error of means (not discernible at this resolution). (A) -Pamidronate exposure. 10 8 M to 10 5 M. (B) -Clodronate exposure.
Figure 5 Mechanisms via which the bisphosphonates may affect osteoclast function. Downregulation of RANKL mRNA expression in the presence of continued OPG mRNA production accounts for a net reduction in osteoclast differentiating signals from osteoblasts as the relatively abundant OPG saturates RANKL. RANKL binding to the receptor on osteoclast progenitor cells is thus inhibited. Direct apoptotic effects on mature osteoclasts are known and differentiation of osteoclasts is also thought to be directly suppressed.
Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line

May 2001


184 Reads

Local growth of osteosarcoma involves destruction of host bone by proteolytic mechanisms and/or host osteoclast activation. Osteoclast formation and activity are regulated by osteoblast-derived factors such as the osteoclast differentiating factor, receptor activator of NF-kappaB ligand (RANKL) and the inhibitor osteoprotegerin (OPG). We have investigated the in vitro effects of bisphosphonates on a clonal rat osteosarcoma cell line. The aminobisphosphonate pamidronate was added to UMR 106-01 cell cultures (10(-8)M to 10(-4)M up to 5 days). The non-aminobisphosphonate clodronate was administered for the same time periods (10(-6)M to 10(-2)M). Cell proliferation, apoptosis and mRNA expression was assessed. Both agents inhibited cell proliferation in a time- and dose-dependent manner. ELISA analysis demonstrated an increase in DNA fragmentation although there was no significant dose-related difference between the doses studied. Bisphosphonate-treated cultures had a greater subpopulation of cells exhibiting morphological changes of apoptosis. Expression of mRNA for osteopontin and RANKL was down-regulated by both agents, while the expression of mRNA for alkaline phosphatase, pro-alpha1(I) collagen and OPG was not altered. Out in vitro work suggests the bisphosphonates not only have direct effects on osteosarcoma cell growth and apoptosis, but also, by altering the relative expression of osteoclast-regulating factors, they may inhibit the activity of osteoclasts and their recruitment.

A phase II study of sequential 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel in advanced breast cancer (Protocol PV BC 97/01)

August 2001


40 Reads

Sequential administration of the association of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and paclitaxel could be better tolerated than the association of an anthracycline and paclitaxel while having a similar antitumour effect. 69 patients with advanced breast cancer previously untreated with anthracyclines or paclitaxel entered a phase II multicentre study in which FEC was followed by paclitaxel. Both regimens were administered 4 times every 21 days. The median follow-up is 20 months and 38/69 patients have died. Grade III-IV toxicity was acceptable. Leukopenia occurred in 26% of patients, thrombocytopenia in 2% and anaemia in 4%. One patient had reversible heart failure during FEC therapy. Peripheral neuropathy and arthralgia-myalgia occurred in 9% and 4% of patients, respectively and one patient had respiratory hypersensitivity during paclitaxel treatment. 9 patients did not complete therapy because of: treatment refusal (n = 1), cardiac toxicity (n = 1), early death during FEC chemotherapy (n = 1), major protocol violations (n = 4), hypersensitivity reaction (n = 1) and early death during paclitaxel chemotherapy (n = 1). The overall response rate was 65% (95% CI = 53-76), and 7% of patients had stable disease. Therapy was defined as having failed in 28% of patients because they were not evaluable (13%) or had progressive disease (15%). The median time to progression and survival are 13.2 and 23.5 months, respectively. Sequential FEC-paclitaxel is a suitable strategy for patients with metastatic breast cancer who have not been previously treated with anthracyclines and/or taxanes. In fact, it avoids major haematologic toxicity and has a good antitumour effect.

Figure 1: Trial schema.
Table 1 Patient and tumour characteristics
Figure 2: Trial profile.
Figure 3: Kaplan–Meier curve of progression-free survival by treatment arm as a function of time.
Table 4 Delivery of therapy by treatment arm
Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumors; A multicentre randomized phase II study - The UK ABC-01 study

September 2009


194 Reads

We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

Radiosensitisation of carcinomas HT29 and SW480 by UCN-01. Survival of the HT29 (A) and SW480 (C) carcinoma cell lines, which have mutant p53, was assessed by attached cell yield after 7 days treatment with 5 Gy IR and/or 50 nM UCN-01. Treatment with UCN-01 alone had no effect on the attached cell yield compared to untreated control cells. IR alone reduced cell yield and this was further significantly reduced by combined treatment with IR and UCN-01. Data represents means of three independent experiments±s.d.; *Significant reduction in cell yield in IR and UCN-01 (combined) cultures compared to IR alone, P<0.05. Induction of apoptosis of the HT29 (B) and SW480 (D) carcinoma cell lines was assessed by determining the percentage of cells which had detached from the monolayer and were floating, these cells were then determined to be apoptotic as described previously (Bracey et al, 1995), also see Materials and Methods. Treatment with UCN-01 alone had no effect on levels of apoptosis. After treatment with both 5 Gy IR and 50 nM UCN-01 (combined) there was a significant increase in apoptosis compared to IR alone. Data represents means of three independent experiments±s.d.; *Significant increase in floating cells in IR and UCN-01 (combined) cells compared to IR alone, *=P<0.05, **=P<0.01.
UCN-01 did not radiosensitise adenoma S/RG/C2. (A) Attached cell yield was determined as a measure of cell survival 7 days after 5 Gy IR and/or treatment with 25 nM UCN-01. Treatment with 25 nM UCN-01 alone had no effect on attached cell yield compared to untreated controls. IR alone reduced cell yield and this was not further increased by IR in combination with UCN-01. Data represents the mean of three independent experiments±s.d. (B) Induction of apoptosis was assessed by the percentage of floating cells as described previously (Bracey et al, 1995) and in Materials and Methods. Treatment with UCN-01 alone had no effect on levels of apoptosis. Five Gy IR induced apoptosis but this was not further significantly increased by IR in the presence of UCN-01. There was no evidence of an increase in apoptosis in the attached population in cells treated with IR and UCN-01 compared to IR alone, nor was there any evidence of cell death via formation of giant polyploid cells – see Results.
Long-term survival studies of HT29 and SW480. After continuous 7 day treatment with IR and/or UCN-01 colorectal cell lines HT29 and SW480 were trypsinised and a known number of cells was re-seeded into control medium without UCN-01. After a further 14 days of growth cells were fixed, stained and colony forming efficiency (CFE) was calculated (as described in Materials and Methods). (A) The CFE of colorectal carcinoma-derived cell line HT29 was not significantly affected by treatment with UCN-01 alone. IR reduced CFE. Cells which had been treated with IR and UCN-01 had a significantly reduced CFE compared to cells treated with IR alone (P<0.05). (B) The CFE of colorectal carcinoma-derived cell line SW480 was not affected by treatment with UCN-01 alone. IR reduced CFE. Cells which had been treated with IR and UCN-01 had a significantly reduced CFE compared to cells treated with IR alone (P<0.001).
Abrogation of the radiation-induced G2 checkpoint by the staurosporine derivative UCN-01 is associated with radiosensitisation in a subset of colorectal tumour cell lines

August 2002


80 Reads

Ionising radiation is commonly used in the treatment of colorectal cancer. Tumour cells with mutant p53 undergo cell cycle arrest at G2/M after ionising radiation and evidence suggests that abrogation of this G2 arrest can lead to a premature, aberrant mitosis, thus enhancing ionising radiation-induced cell killing. The G2 checkpoint inhibitor UCN-01 was thus investigated to determine whether it would abrogate the G2 checkpoint induced by 5 Gy ionising radiation in a range of colorectal tumour cell lines. Data presented show that, at doses that are alone non-toxic to the cells, UCN-01 inhibits the ionising radiation-induced G2 checkpoint in five colorectal tumour cell lines with mutant p53. The ability of UCN-01 to sensitise cells to ionising radiation-induced growth inhibition and apoptosis was also investigated and UCN-01 was found to radiosensitise two out of five cell lines. These results were confirmed by long-term colony forming efficiency studies. These results demonstrate that abrogation of the ionising radiation-induced G2 checkpoint is not necessarily associated with sensitisation to ionising radiation, however, some colorectal tumour cell lines can be radiosensitised by UCN-01. Although the mechanism of radiosensitisation is not clear, this may still be an important treatment strategy. British Journal of Cancer (2002) 87, 352–358. doi:10.1038/sj.bjc.6600492 © 2002 Cancer Research UK

Figure 1: Ladder plots of (A) change in SUVmax with NAC (B) change in SUVmean 40% isocontour with NAC. Those achieving either a pCR or near pCR are classified as responders and all others as non-responders.
Figure 2: FLT-PET images representing SUVmax (300 dpi CT, PET, colour-fused and MIP images) for a 55-year-old female presenting with a 7-cm ER +ve, PR −ve, Her 2+ve breast cancer (A) pre-chemotherapy SUVmax of 13 and Ki-67 of 59.5 (B) post 1 cycle of FEC with a SUVmax of 8.5 (−35%). She went on to have a pathological CR and is alive and disease free at a follow-up of 16 months.
Figure 3: Correlation of baseline Ki-67 and SUVmax with line of best fit (r=0.604, P=0.006).
Figure 4: Box and whisker plot of SUVmean for 30, 40, 50, and 60% isocontours. Whiskers represent range, box represents interquartile range, line represents median, ° indicate outliers and * indicate extreme outliers. (A) Pre-NAC and (B) post 1 cycle of NAC.
Abstract P4-01-07: Evaluation of FLT PET-CT as an imaging biomarker of proliferation in primary breast cancer

May 2014


161 Reads

Background: [18F]fluorothymidine (FLT) has been proposed as a positron emission tomography (PET)-imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT-PET-CT as a technique for predicting the response to neoadjuvant chemotherapy (NAC) in primary breast cancer and to compare baseline FLT with Ki-67. Methods: Twenty women with primary breast cancer had a baseline FLT-PET-CT scan that was repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified. From the FLT-PET-CT scans lesion maximum and mean standardised uptake values (SUVmax, SUVmean) were calculated. Results: Mean baseline SUVmax was 7.3, and 4.62 post one cycle of NAC, representing a drop of 2.68 (36.3%). There was no significant association between baseline, post chemotherapy, or change in SUVmax and pathological response to NAC. There was a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (P=0.006). Conclusions: Baseline SUVmax measurements of FLT-PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value nor the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

June 2006


39 Reads

Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kappaB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kappaB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62-10.0 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC(50) values: 4.1-6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5-20-fold upregulation of transcriptional activity of NF-kappaB was substantially (50-90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (<20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60-90% of cells underwent apoptosis following exposure to combinations of VA+kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kappaB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kappaB by Parthenolide drastically synergised with VA to induce apoptosis (VA+Parthenolide: 60-90% compared to <20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kappaB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kappaB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: A Japan Clinical Oncology Group trial (JCOG 0102)

May 2013


133 Reads

Background: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. Methods: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. Results: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). Conclusion: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

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