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Background: Accuracy can be improved by taking multiple synchronous samples from each subject in a study to estimate the endpoint of interest if sample values are not highly correlated. If feasible, it is useful to assess the value of this cluster approach when planning studies. Multiple assessments may be the only method to increase power to an acceptable level if the number of subjects is limited., Methods: The main aim is to estimate the difference in outcome between groups of subjects by taking one or more synchronous primary outcome samples or measurements. A summary statistic from multiple samples per subject will typically have a lower sampling error. The number of subjects can be balanced against the number of synchronous samples to minimize the sampling error, subject to design constraints. This approach can include estimating the optimum number of samples given the cost per subject and the cost per sample., Results: The accuracy improvement achieved by taking multiple samples depends on the intra-class correlation (ICC). The lower the ICC, the greater the benefit that can accrue. If the ICC is high, then a second sample will provide little additional information about the subject's true value. If the ICC is very low, adding a sample can be equivalent to adding an extra subject. Benefits of multiple samples include the ability to reduce the number of subjects in a study and increase both the power and the available alpha. If, for example, the ICC is 35%, adding a second measurement can be equivalent to adding 48% more subjects to a single measurement study., Conclusion: A study's design can sometimes be improved by taking multiple synchronous samples. It is useful to evaluate this strategy as an extension of a single sample design. An Excel workbook is provided to allow researchers to explore the most appropriate number of samples to take in a given setting., (© 2021. The Author(s).)

Hazard ratios are commonly used when comparing survival between two groups and make the assumption that the relative event rates do not change markedly during follow-up, i.e. that event rates are proportional. However, there is currently debate about the use of the proportional hazards assumption to summarise the treatment effect in survival analysis compared with restricted mean survival time (RMST) analysis, particularly in cancer trials. In many situations it is unrealistic to assume that relative event rates in two groups will be proportional throughout follow-up and, hence, RMST analysis, which does not make this assumption, may be preferable. Several benefits of the latter approach have been identified but the biological perspective is not often discussed. Biological features such as the patterns of tumour growth and response can also contribute to assessing the relative merit of these two methods; such biological considerations are the subject of this paper. The observation that the most commonly observed approximation to the underlying distribution of time to event data, the lognormal distribution, does not reliably show proportional hazards in the comparison of two groups, lends weight to a statistical approach that is not based on proportional hazards. The proportional hazards assumption should be viewed more critically when estimating treatment effects. An optimum approach may be to include both proportional hazards analysis and RMST analysis when comparing time to event endpoints., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The TACT trial is the largest study assessing the benefit of taxanes as part of adjuvant therapy for early breast cancer. The goal of this translational study was to clarify the predictive and prognostic value of Tau within the TACT trial. Tissue microarrays (TMA) were available from 3,610 patients. ER, PR, HER2 from the TACT trial and Tau protein expression was determined by immunohistochemistry on duplicate TMAs. Two parallel scoring systems were generated for Tau expression ('dichotomised' vs. 'combined' score). The positivity rate of Tau expression was 50 % in the trial population (n = 2,483). Tau expression correlated positively with ER (p < 0.001) and PR status (p < 0.001); but negatively with histological grade (p < 0.001) and HER2 status (p < 0.001). Analyses with either scoring systems for Tau expression demonstrated no significant interaction between Tau expression and efficacy of docetaxel. Contrary to the hypothesis that taxane benefit would be enriched in Tau negative/low patients, the only groups with a suggestion of a reduced event rate in the taxane group were the HER2-positive, Tau positive subgroups. Tau expression was seen to be a prognostic factor on univariate analysis associated with an improved DFS, independent of the treatment group (p < 0.001). It had no prognostic value in ER-negative tumours and the weak prognostic effect of Tau in ER-positive tumours (p = 0.02) diminished, when considering ER as an ordinal variable. On multivariable analyses, Tau had no prognostic value in either group. In addition, no significant interaction between Tau expression and benefit from docetaxel in patients within the PR-positive and negative subsets was seen. This is now the second large adjuvant study, and the first with quantitative analysis of ER and Tau expression, failing to show an association between Tau and taxane benefit with limited utility as a prognostic marker for Tau in ER-positive early breast cancer patients.

Chromosomal instability, which is a characteristic of many human cancers, contributes to intratumour heterogeneity and has been functionally implicated in resistance to taxane therapy in tumour models. However, defining the status of tumour chromosomal instability in a given tumour to test this hypothesis remains challenging. Measurements of numerical and structural chromosomal heterogeneity demonstrate that histological grade correlates with chromosomal instability in oestrogen receptor (ER)-positive breast cancer. Using data on adjuvant taxane therapy in women with breast cancer, we propose that patients with low-grade ER-positive tumours, which are thought to be chromosomally stable, might derive unexpected benefit from taxane therapy. We discuss the implications of the relationships between tumour grade, chromosomal instability and intratumour heterogeneity, the development of high-throughput methods to define tumour chromosomal instability and the potential use of chromosomal instability to tailor therapy.

Purpose: To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole., Patients and Methods: Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed., Results: Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study., Conclusion: The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.

Purpose: The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials., Patients and Methods: Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis., Results: The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality., Conclusion: Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

Background: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia., Methods: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537., Findings: 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival., Interpretation: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck., Funding: Cancer Research UK (CRUK/03/005)., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The purpose of this study was to assess the pattern and significance of tumour calcification in ovarian carcinoma. Patients with calcifying ovarian carcinoma were identified from radiological reports. Their tumour characteristics, serum calcium levels, treatment and survival were compared with a control group of patients with non-calcifying disease. Patterns and distribution of calcification were assessed. Available serial CT scans were reviewed for changes in both soft-tissue and calcified disease according to RECIST (response evaluation criteria in solid tumours) criteria where feasible. Temporal changes in calcification were correlated with changes in soft tissue disease and CA125 levels. The calcified group numbered 122 (22 other patients had calcifying tumour but insufficient clinical data). Calcification in ovarian carcinoma had a prevalence of 8% (144/1721) in our series. There was a significant difference (p<0.001) between the two groups in the distribution of histological type, with serous tumours being more common in the calcified group (74/122 (61%)) than in the controls (509/1498 (34%)). The calcified tumour patients tended to have lower grade disease (p<0.001). No differences between the groups were found for age, treatment or serum calcium levels. Distribution of calcification was diffusely peritoneal in 34 patients, in association with a pelvic mass in 15, nodal in 11 and within the anterior abdominal wall in 2. There was no correlation between changes in calcification on serial CT scans and corresponding CA125 levels. In conclusion, calcification tends to occur most commonly in serous cystadenocarcinomata and in tumours of lower grade. Changes in calcification cannot be used as a marker of disease response.

Aims: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC., Materials and Methods: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day., Results: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months)., Conclusions: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Aims: Sweat-gland tumours (SGTs) are uncommon, but malignant varieties are very rare. We have added our data on 30 new cases seen at the Royal Marsden NHS Foundation Trust to the published literature, particularly concentrating on clinical issues. We include a literature review., Materials and Methods: The Royal Marsden NHS Foundation Trust database was searched for cases of SGT from 1972. Data were collected on all cases, including patient demographics and tumour characteristics, treatment and outcome., Results: Thirty cases were confirmed histologically to be SGTs. Fourteen were malignant, 15 benign and the degree of malignancy in one was histologically indistinguishable. Mean age was 55 years (64 for malignant, 47 for benign tumours). The 15 patients with benign tumours were almost all treated with complete excision. Those with local relapse underwent successful re-excision. Their 5-year disease-free survival was 78% and cause-specific survival was 100%. Twelve of the 14 malignant tumours had localised disease at diagnosis, one had nodal disease and one had metastatic tumour nodules. All except one were treated with wide local excision. The patient with nodal involvement also had a lymph-node dissection. Two received adjuvant radiotherapy to the tumour bed. One received a melphalan limb perfusion. Eight of the 14 had no relapse. Six had locoregional relapse, and four of these also developed distant metastases. Visceral disease was always fatal. Radiotherapy and chemotherapy at relapse were unsuccessful. Five-year disease-free survival was 45%, and cause-specific survival was 57%., Conclusion: These rare tumours should be treated initially with complete wide local excision. In malignant tumours, lymph-node involvement is a poor prognostic sign. Wide local excision remains the primary treatment. Adjuvant radiotherapy may be useful in high-risk cases.

Antibodies to the cell surface disaccharide galactose(alpha1,3)galactose (alphaGal) are the most prevalent natural antibodies in human serum. The anti-alphaGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes alphaGal become sensitive to human serum. A prerequisite for anti-alphaGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-alphaGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-alphaGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-alphaGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-alphaGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-alphaGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of alphaGal-expressing cells correlated with anti-alphaGal immunoglobulin M titre (P < 0.0001). Anti-alphaGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-alphaGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.

To assess the level of activity and toxicity of gefitinib (ZD1839, Iressatrade mark) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day(-1). Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18-93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study.

Background: Vinorelbine is active and well tolerated against advanced breast cancer but there are no published efficacy studies in early breast cancer. We have therefore carried out a randomised phase III neoadjuvant trial in operable breast cancer., Patients and Methods: Patients with > or =3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m(2) on days 1 and 8 and epirubicin 60 mg/m(2) on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate., Results: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy., Conclusions: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.

Background: Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN., Methods and Findings: We systematically searched databases (MEDLINE 1966-2004, EMBASE 1988-2004, CINAHL 1982-2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat. Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25. This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, "strong" opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated. Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as "not yet adequately tested" rather than demonstrating "no evidence of efficacy." Topical aspirin/diethyl ether has not been adequately tested., Conclusion: The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.

To determine the outcome of patients with metastatic malignant melanoma (MMM) treated with palliative whole brain radiotherapy (WBRT) and to identify factors that predict treatment outcome to assist future trial design, a retrospective study was performed on patients with MMM who received WBRT at the Royal Marsden Hospital between 1998 and 2003. Data regarding patient factors, tumour factors and survival were collected. A total of 112 patients were identified and full data were available for 102 patients. The median age was 53 years (range 25-81 years), 66.7% were male and 33.3% female. The median dose prescribed was 20 Gy in five fractions as a mid-plane dose. The median survival after WBRT for the whole group was 51 days (range 3-1386). In an attempt to define prognostic groups, we used the validated RTOG recursive partitioning analysis (RPA) classification for brain metastasis (class 1: Karnofsky Performance Score (KPS) >/=70%, age <65 years with no extracranial metastasis; class 3: KPS <70%; class 2: all others). The median survivals were 151, 71 and 21 days for RPA class 1, 2 and 3, respectively (P<0.001). Multivariate analysis showed that RPA class, leptomeningeal involvement, presence and number of extracranial metastatic sites and progressive disease in the brain on imaging before WBRT are important independent predictive factors. A prognostic index was derived from these factors that allowed identification of patients unlikely to benefit from WBRT. In conclusion, the RTOG RPA classification is valid when applied to patients with MMM. Patients in RPA class 1 and good prognosis class 2 are likely to benefit from palliative WBRT and should be considered for entry into trials that aim to improve duration of response. We identified that patients with RPA class 3, leptomeningeal involvement or RPA class 2 with poor prognostic index are unlikely to benefit from palliative WBRT.

This paper presents a method for undertaking Phase II trials in which not all patients are considered equally likely to respond to treatment. In ovarian cancer, for example, it has been shown that response is less likely in patients who have failed the previous treatment after only a short interval compared to those who have a protracted failure-free interval [Gynecol. Oncol. 36 (1990) 207]. The method is analogous to those used in phase III trials which estimate relative rather than absolute effects; a constant odds ratio, for example, encompasses multiple relationships between response rates. Phase II trials commonly test the null hypothesis H(0): Por=p(1), where the response rate p(1) is the minimum required level of efficacy and p(0) the highest level which would indicate that the treatment is of no further interest. This approach can be extended by using the arcsine transformation to allow p(0) and p(1) to vary between patients, thus for the ith patient p(0i)=(sin c(i))(2) and the efficacy level is set to p(1i)=(sin (c(i)+b))(2). The value of the arcsine parameter b therefore determines efficacy and the test for efficacy in the trial then becomes a test of the null hypothesis H(0): Bor=b. The value of b is determined by considering representative values of p(0) and p(1) and setting b=(sin(-1) radical p(1)-sin(-1) radical p(0)); b is thus the constant arcsine difference (CAD) between p(0i) and p(1i). The variance of B is 1/4n, which is independent of P, trial designs are therefore independent of P, implying that all patients for whom this difference is identical can be entered into the same trial. This paper considers single-stage and two-stage CAD Phase II trials.

Background: To compare the efficacy of continuous infusional 5-fluorouracil (5-FU)-based chemotherapy against conventional bolus chemotherapy in the preoperative treatment of patients with large operable early breast cancer., Patients and Methods: Four hundred and twenty-six women with histologically proven 3 cm invasive early breast cancer were randomised to receive pre-operative infusional 5-FU 200 mg/m(2) by daily 24 h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m(2) intravenous (i.v.) bolus on day 1 and cisplatin 60 mg/m(2) i.v. bolus on day 1, both repeating 3-weekly (infusional ECisF), or conventional bolus doxorubicin 60 mg/m(2) i.v. on day 1 and cyclophosphamide 600 mg/m(2) i.v. on day 1, both repeating 3-weekly (AC), both schedules for six courses. Patients subsequently had local therapy (surgery or radiotherapy or both) and tamoxifen 20 mg orally daily as appropriate., Results: The 5 year results for AC and infusional ECisF, respectively, were as follows: overall response, 75% and 77%; complete clinical remission, 31% and 34%; pathological complete remission (pathCR), 16% for both; and pathCR with residual ductal carcinoma in situ (DCIS), 25% and 24%. Mastectomy rates were 37% and 34%, respectively. Five-year overall survival was 74% for AC and 82% for infusional ECisF (hazard ratio 0.76, 95% confidence interval 0.51-1.13; P = 0.18). Both treatments were well tolerated. Grade III/IV lethargy, vomiting, alopecia and plantar-palmar erythema were significantly greater for infusional ECisF; grade III/IV leucopenia was significantly greater for AC., Conclusions: Preoperative continuous infusional 5-FU-based chemotherapy is no more active than conventional AC for early breast cancer; with a median 5 year follow-up, the infusion-based schedule shows a non-significant trend towards improved survival.

A quality-of-life study was carried out to test the hypothesis that melanoma patients treated with a 3-cm margin of excision suffer greater impairment of their quality of life than those treated with a 1-cm margin. The secondary aim was to determine the predictors of a poor patient perception of their excision scar. A postal questionnaire study was carried out using Hospital Anxiety and Depression (HAD), Psychosocial Adjustment of Illness Scale-Self-Report (PAIS-SR), Medical Outcomes Survey-Short Form 36 (MOS-SF36), and the Cassileth Scar questionnaires. Data were collected from 426 of the 537 patients who were mailed the questionnaires (response rate 79%). Fourteen percent had clinically significant anxiety and 5% had significant depression. A poor attitude toward quality of health care was associated with youth. Patients treated with a 3-cm margin excision had significantly poorer mental and physical function 1 mo after surgery, which disappeared within 6 mo. The greater difficulties experienced by the 3-cm margin group were particularly in their domestic, sexual, and social roles. Women, younger patients, those with poor physical and mental function after surgery, and those treated by a 3-cm margin were more likely to report a poorer perception of their scar. The poorer scar perception of patients in the 3-cm group persisted throughout the study period. Use of a 3-cm margin of excision for melanoma is associated with significantly more morbidity than use of a 1-cm margin, but this effect disappears in 6 mo. Patients treated by 3-cm excision were more likely, however, to have a persistent poor view of their scar. Youth and being female were also predictors of poor perception of the scar.

Staging systems and laboratory features help predict survival in chronic lymphocytic leukaemia but they do not distinguish patients who will progress from those whose disease will remain indolent. CD38 expression has emerged as an independent prognostic factor, yet there is debate as to what level of CD38 affects prognosis. We plotted the hazard ratios for the treatment-free interval (TFI) between the higher and lower groups defined by CD38 cut-offs from 0 to 100%. The maximum hazard ratio was achieved for a cut-off of 7%. We examined by triple colour analysis the values for CD38 in 289 untreated patients using both >or=30 and >or=7% as thresholds for prognosis. Using a >or=7% threshold (but not >or=30%), we showed a significant correlation with advanced stage and male sex. The interval from diagnosis to first therapy or TFI was longer (median 36 months) in patients with <7% CD38 positive cells than those with >or= 30% (8.7 months) or with intermediate values between 7 and 29% (P<0.00005). The <7% threshold also identified patients in stage A with a long TFI (P=0.0001). Multivariate analysis showed that CD38 has independent prognostic value for TFI in all patients. In 135 patients tested for deletions of p53, 13q14 and 11q23 and for trisomy 12, we showed a correlation between 13q14 deletion and <30%/<7% CD38 positive cells and a tendency for trisomy 12 to be associated with >or=30%/>or=7% CD38 positive cells. We conclude that 7% may be a more useful threshold for disease progression than higher values of CD38.

Purpose: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site., Patients and Methods: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases., Results: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P <.001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P <.001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time., Conclusion: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing.

Objective: Using neuropeptide and enzyme markers to autonomic nerves, we sought to demonstrate and quantify the nerve types contained within the uterosacral ligaments (USLs) and cardinal ligaments (CLs) that are divided during radical hysterectomy (RH)., Methods: Cross-sectional biopsies were collected from the lateral third of the USL and the CL in 24 women who had an RH for cervical cancer, and from the uterine insertion of these ligaments in 11 women who had a simple hysterectomy for benign disease. We applied indirect immunofluorescence with FITC-conjugated secondary antibodies, using polyclonal primary antibodies to neuropeptide markers that predominate within somatic and autonomic nerves, to show different populations of the following nerve types within the biopsies: neuropeptide Y (NPY) and tyrosine hydroxylase (TH) for sympathetic nerves; vasoactive intestinal polypeptide (VIP) for parasympathetic nerves; substance P (SP) for nociceptive and sensory-motor nerves; and calcitonin gene-related peptide (CGRP) for sensory and sensory-motor nerves. The percentage area of immunoreactivity (PAI), determined by a computer-assisted image analyzer attached to a fluorescent microscope, was used as an objective quantitative measure of nerve density. Confocal microscopy was used to determine the composition and spatial arrangement of nerve fibers in the ligaments., Results: The PAI was greater for all markers tested in both the USL and CL (P <.001) in RH compared with simple hysterectomy biopsies. For RH specimens, the PAI was greater for the sympathetic, sensory, and sensory-motor nerve markers in the USL compared with the CL (P <.01), but the PAI for VIP was similar (P >.05). Conversely, excluding the large trunks and associated ganglia, the free nerve fiber PAI in the CL was greater than that of the USL for all nerve markers (P <.001). The staining of peripheral autonomic ganglia and associated fibers, for NPY and TH, indicates that some sympathetic nerves are preganglionic with their cell bodies within the pelvic plexus., Conclusions: Significantly more autonomic nerves are transected in the more lateral division of the uterine supporting ligaments during a radical hysterectomy than during a simple hysterectomy. Sympathetic, parasympathetic, sensory, and sensory-motor nerve types are present within the CL and USL. The proportions of each nerve type differ between the two ligaments, and sympathetic nerves in the USL are the single largest nerve type. The uterine supporting ligaments are a major pathway for autonomic nerves to the pelvic organs.

Tables for single-phase II trials based on the exact binomial distribution are presented. These are preferable to those generated using Fleming's design, which are based on the normal approximation and can give rise to anomalous results. For example, if the upper success rate is accepted, the lower success rate, which the trial is designed to reject, may be included in the final confidence interval for the proportion being estimated., (Copyright 2001 John Wiley & Sons, Ltd.)

A retrospective review was undertaken of the medical records of 52 women with stage II carcinoma of the endometrium who received adjuvant radiotherapy following surgery. The information was obtained from medical notes and a hospital database. Actuarial disease-free survival was 68% at 5 years for those women with stage IIA disease, and 70% at 5 years for those women with stage IIB disease. 6 of the women (11.5%) had side effects from treatment. In contrast to the literature, the only statistically significant prognostic factor in this study was histological differentiation; patients with poorly differentiated tumours fared worse (p = 0.05). This may indicate that a greater number than 52 women is needed to demonstrate weaker prognostic factors such as substage. A larger review is being undertaken of the remaining women recorded on the database, with stage I, III and IV disease.

Background: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy., Patients and Methods: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days., Results: Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha., Conclusions: The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.

Background: A major cause of the pelvic morbidity after a radical hysterectomy (RH) is thought to be damage to the pelvic nerve plexus, but direct evidence is lacking. We set out to determine the nerve content of the uterosacral ligaments (USLs) and cardinal ligaments (CLs) at the level at which they are divided during a radical hysterectomy and a simple hysterectomy., Methods: Intraoperative cross-sectional biopsies were collected from the lateral third of the uterosacral ligaments (USLs) and cardinal ligaments (CLs) in 20 women undergoing radical hysterectomy (RH) and from the uterine insertion of these ligaments in 11 women undergoing a simple hysterectomy. Quantitative immunocytochemistry was utilized to demonstrate and quantify the nerve content of the uterine supporting ligaments at the level at which they are divided in a RH and in a simple hysterectomy. Indirect immunofluorescence staining of frozen cryostat sections was performed using primary antibodies to PGP 9.5 (a pan-neuronal marker). A computer-assisted image analyzer measured the percentage area of immunoreactivity (PAI) that was used to quantify the nerve density. Confocal microscopy was used to determine the composition and spatial arrangement of nerve fibers in the ligaments., Results: The PAI was significantly greater in the RH biopsies than in the simple hysterectomy biopsies, for both the CLs (P < 0.001) and the USLs (P < 0.001). In the RH biopsies, more nerve tissue was present in the USL than CL (P = 0.01), and compared with the CL more of the nerve fibers in the USL were concentrated in large trunks. Excluding these trunks and autonomic ganglia, the free nerve content of the USL was lower than that of the CL (P < 0.001). The presence of nerve trunks, autonomic ganglia, and free nerve fibers within the lateral third of the USL and CL is consistent with extension of the inferior hypogastric plexus along these ligaments to the pelvic organs., Conclusions: The uterine supporting ligaments contain autonomic nerves and ganglia, as extensions of the inferior hypogastric plexus. The USLs have a greater nerve density than the CLs. Because RH disrupts more nerve tissue than a simple hysterectomy, these data provide further evidence for the neurogenic etiology of pelvic morbidity after RH., (Copyright 2000 American Cancer Society.)

Distinguishing true precursor lesions on the basis of clinical or histological features alone is unreliable but is important so that appropriate intervention can be instigated. Preliminary studies have shown that a microsatellite assay may provide important new prognostic information. To build on these observations, we have performed a case-control study to establish whether we can be confident about incorporating this new information into clinical practice. We have determined the frequency of allelic imbalance (AI) within key chromosomal regions, by matching 39 cases with dysplastic oral lesions that developed a tumor on the same side of the mouth, for as many variables as possible, with controls presenting with similar lesions that did not progress to malignancy when followed for the same period. Our findings confirm that the group that developed tumor had precursor lesions that harbor AI at more loci (P = 0.002). However, no consistent patterns of AI were associated with the three grades of dysplasia: mild, moderate, and severe. One-third of the tumors developed at the same site as the dysplastic lesion and two-thirds at a different site, which revealed that the presence of these aberrations in a dysplastic lesion provided information about the risk of malignant change within a larger field. This suggests that the process of field cancerization is more widespread than previously recognized. On the basis of these findings, we advocate complete excision of all suspicious areas that show AI at two or more key loci, regardless of the degree of dysplasia. However, because the remaining mucosa is also "at risk," these cases should also be targeted to receive dietary advice and chemoprevention, to minimize their risk of tumor formation at a distant site.