Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

Geographical access to healthcare in Northern England and post-mortem diagnosis of cancer.

BACKGROUND: There is some previous evidence that diagnosis of cancer at death, recorded as registry death certificate only records, is associated with problems of access to care. METHODS: Records from the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung, ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time to general practitioner and hospital services, and social deprivation. Logistic regression was used to identify predictors of records where diagnosis was at death. RESULTS: There was no association between the odds diagnosis at death and access to primary care. For all sites except breast, the highest odds of being a cancer diagnosed at death fell among those living in the highest quartile of hospital travel time, although it was only statistically significant for colorectal and ovary tumours. Those in the most deprived and furthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death case compared with those in the most affluent and proximal areas. CONCLUSIONS: There is some evidence that poorer geographical access to tertiary care, in particular when coupled with social disadvantages, may be associated with increased odds of diagnosis at death.

Social and geographical factors affecting access to treatment of lung cancer.

BACKGROUND: UK residents' healthcare is free of charge but uptake varies. Cancer survival is inferior to that of other Western European countries. We have used cancer registry data to assess factors associated with access to diagnosis and treatment of lung cancer in northern England. METHOD: We assigned 34 923 lung cancer patients diagnosed between 1994 and 2002 to quartiles for the deprivation score associated with their postcode and for the travel time to the relevant healthcare facility. Odds ratios, adjusted for age and sex, for undergoing interventions were calculated relative to the least deprived quartile living closest to the facility. The odds ratio for receiving chemotherapy for small-cell lung cancer (SCLC) was calculated according to the type of hospital where it was diagnosed. RESULTS: The odds ratio for attainment of a histological diagnosis for the least deprived/furthest residence group was 0.83 (95% confidence 0.70-0.97) for the most deprived/nearest residence group was 0.74(0.62-0.87) and for the most deprived/furthest residence group it was 0.61 (0.49-0.75). The corresponding odds ratios for receipt of any active treatment were 0.93 (0.80-1.07), 0.74 (0.64-0.86), and 0.55 (0.46-0.67). The odds ratios for receipt of chemotherapy for SCLC were 1.27 (0.89-1.82), 1.21 (0.85-1.74) and 0.81 (0.52-1.28). Odds ratios for undergoing surgery for non-small cell lung cancer using (1) travel time to diagnosing hospital were 0.88 (0.70-1.11), 0.74 (0.59-0.94) and 0.60 (0.44-0.84). Using (2) travel time to a thoracic surgery facility they were 0.83 (0.65-1.06), 0.70 (0.55-0.89) and 0.55 (0.49-0.76). CONCLUSION: Living in a deprived locality reduces the likelihood of undergoing definitive management for lung cancer with the exception of chemotherapy for SCLC. This is amplified by travel time to services.

Travel times to health care and survival from cancers in Northern England.

The aim was to assess the effect of geographical accessibility on the stage of cancer at diagnosis and survival. Records of 117,097 cases of breast, colorectal, lung, ovary and prostate cancer diagnosed in Northern England between 1994 and 2002 were supplemented with estimates of travel times to the patients' general practitioners (GPs) and hospitals attended, together with measures of access to public transport. Logistic regression and Cox proportional hazards models were used, adjusting for age, sex, whether the first hospital visited was a cancer centre and deprivation of area of residence. Late stage at diagnosis was associated with increasing travel time to GP for breast and colorectal cancers and risk of death was associated with travel time to GP for prostate cancer. Travel times to hospital and other accessibility measures showed no consistent associations with stage at diagnosis or survival, so travel to GP was the only influential factor.

Travel time to hospital and treatment for breast, colon, rectum, lung, ovary and prostate cancer.

The aim was to examine the effect of geographical access to treatment services on cancer treatment patterns. Records for patients in northern England with breast, colon, rectal, lung, ovary and prostate tumours were augmented with estimates of travel time to the nearest hospital providing surgery, chemotherapy or radiotherapy. Using logistic regression to adjust for age, sex, tumour stage, selected tumour pathology characteristics and deprivation of place of residence, the likelihood of receiving radiotherapy was reduced for all sites studied with increasing travel time to the nearest radiotherapy hospital. Lung cancer patients living further from a thoracic surgery hospital were less likely to receive surgery, and both lung cancer and rectal cancer patients were less likely to receive chemotherapy if they lived distant from these services. Services provided in only a few specialised centres, involving longer than average patient journeys, all showed an inverse association between travel time and treatment take-up.

Travel time to radiotherapy and uptake of breast-conserving surgery for early stage cancer in Northern England.

Patients with early stage breast cancer can opt for either mastectomy or breast-conserving surgery (BCS), but BCS requires daily radiotherapy for some weeks. The hypothesis that ease of access to radiotherapy might affect choice of surgery was investigated using records of 6014 breast cancer patients in Northern England. Adjusting for the effects of age, deprivation and hospital type, the choice of BCS was not associated with the estimated car journey time to radiotherapy for most women but there was an association for patients living in places without a regular bus service, so transport problems might influence surgery choice for a minority of women.

Centralisation of services for the management of ovarian cancer: arguments against.

In 2000, the Commissioning Guidance for gynaecological cancer services relied on a subset analysis within a retrospective study to support its requirement that surgery for carcinoma of the ovary be centralised. We have reviewed the literature covering this issue, especially that published in the past 6 years. There is no evidence for an advantage for specialist gynaecological oncologists over general gynaecologists for these women; studies that suggest that one exists fail to separate patients presenting to general surgeons, whose patients are at a clear disadvantage, from those seen by gynaecologists. There is evidence for the need for appropriate surgery in women with less extensive disease where the diagnostic difficulties are greatest. We argue for investment in the diagnosis of ovarian cancer and the provision of services for its medical treatment over a prolonged period.

Cancer of Unknown Primary: a Cancer Registry Study of Factors Affecting Access to Diagnosis.

AIM: A potential impact of the centralisation of cancer services in the UK is difficulty in gaining access for members of the population living far from them. This could lead to delayed presentation of cancer with more advanced disease and clinical deterioration at diagnosis. A patient may be recorded in the cancer registry as having cancer of unknown primary (CUP) if the clinical state at presentation precludes investigation. Other patients may be so recorded if investigation identifies sites of metastatic tumour but the primary is not found. We hypothesised that the first group would include more patients who experienced difficulties in gaining access to health services through residing in deprived areas or through poorer geographical access to healthcare facilities. MATERIALS AND METHODS: We compared the diagnosis of CUP with a comparator tumour, carcinoma of the rectum, where diagnosis is facilitated by an alarm symptom and where variations in access are lower. Records from the Northern and Yorkshire Cancer Registry from 1994 to 2002 with ICD 10 C77-C80 (CUP, including categories where investigations may have been incomplete or no primary cancer was found) and C20 (malignant neoplasm of rectum) were combined with travel time to services (primary care, secondary and tertiary services) and the Index of Multiple Deprivation. Logistic regression modelled predictors of CUP were compared with C20 and, within CUP, the odds of a histological basis of diagnosis. RESULTS: The registry classified 7428 patients as C80, 8849 as C77-C79, and 10 804 as C20. Compared with C20, the number of cases of C80 showed a statistically significant increasing trend with increasing travel time to primary care. Risk also increased strongly with age and deprivation. The results for C77-C79 were similar to those for C80, except that the travel time to primary care showed no effect. Considering all CUP alone, histological diagnosis significantly declined with travel time to the nearest hospital. There was no association with gender and the likelihood of histological diagnosis, but a marked decline with age, a downward trend with deprivation, and an increase when the nearest hospital was a cancer centre. CONCLUSIONS: These findings facilitate the understanding of factors associated with the group of patients that includes those with the least effective access to cancer services.

Docetaxel and cisplatin in combination as first-line chemotherapy for advanced epithelial ovarian cancer. Scottish Gynaecological Cancer Trials Group.

PURPOSE: A prospective, nonrandomized, multicenter, open feasibility study of cisplatin and docetaxel as first-line chemotherapy in International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV epithelial ovarian cancer was conducted. The primary end point was the incidence of severe fluid retention that necessitated treatment withdrawal. PATIENTS AND METHODS: Cisplatin and docetaxel were administered every 3 weeks for six planned cycles, with a 5-day prophylactic dexamethasone regimen (8 mg two times per day). One hundred patients (median age, 53 years; range, 24 to 71 years) received a total of 512 cycles of chemotherapy in two cohorts: cohort 1, 49 patients, 258 cycles (cisplatin 75 mg/m(2) and docetaxel 75 mg/m(2)); cohort 2, 51 patients, 254 cycles (cisplatin 75 mg/m(2) and docetaxel 85 mg/m(2)). RESULTS: No patients were taken off study because of fluid retention. Sixty-six patients completed six cycles of protocol therapy; 16 stopped early because of toxicity (neurotoxicity in six patients, nephrotoxicity in three, neutropenia in two, and hypersensitivity, diarrhea and vomiting, skin rash, clinical deterioration, and patient's wishes in one patient each). Grade 3/4 neutropenia was observed in more than 75% of patients and seemed to be cumulative. Patients in cohort 2 had significantly more severe neutropenia and lethargy than those in cohort 1. In addition, there were five treatment-related deaths in cohort 2 (three neutropenia and two upper gastrointestinal hemorrhage). Neurotoxicity (mainly sensory, > grade 1) was observed in 23 patients. The overall clinical response rate was 69% (complete response, 38%; partial response, 31%); CA-125 response rate was 73%. Median progression-free survival for the group was 12 months. CONCLUSION: Cisplatin and docetaxel can be administered at doses of 75 mg/m(2) and 75 mg/m(2), respectively, every 3 weeks, and the utility of this regimen is not limited by fluid retention. However, 33 of 100 patients were unable to complete the planned six cycles, which may explain, in part, the poor overall progression-free survival. Increasing the docetaxel dose to 85 mg/m(2) adds unacceptable hematologic toxicity and potential risks to the patient.

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Cushing's syndrome associated with recurrent endometrioid adenocarcinoma of the ovary.

Ectopic production of adrenocorticotrophic hormone (ACTH) by malignant neoplasms is a well recognised cause of Cushing's syndrome but is extremely rare in ovarian carcinoma. A patient who underwent surgery for ovarian carcinoma followed by a course of chemotherapy is reported. The tumour was a bilateral moderately differentiated endometrioid adenocarcinoma and contained numerous chromogranin immunoreactive endocrine cells as well as small foci of ACTH immunoreactivity. She subsequently presented with Cushing's syndrome in association with extensive pelvic recurrence of the tumour.

Acute neurological toxicity of intrathecal cytosine arabinoside. A case report.

A patient developed severe neurological toxicity, with peripheral and cerebral components and hyponatraemia following one intrathecal injection of 80 mg cytosine arabinoside. The severity of his symptoms may reflect heavy prior neurotoxic chemotherapy.

A phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a new dihydrofolate reductase inhibitor.

A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue.

A phase I/II study of the 5-HT3 antagonist GR38032F in the anti-emetic prophylaxis of patients receiving high-dose cisplatin chemotherapy.

A total of 24 patients who were receiving combination chemotherapy (POMB) including cisplatin at a dose of 100-120 mg/m2 were treated with the 5HT3 antagonist GR38032F (GR) as an anti-emetic prophylaxis. GR was given as a 15-min loading infusion followed by a 24-h infusion at three escalating dose levels of 1, 2 and 4 mg/h. In the first 24 h after commencing treatment, six patients had complete control of nausea and vomiting (CR), two had 1-2 emetic episodes (MR) and five had 3-5 emetic episodes (mR). The major response rate (CR + MR) was thus 35%. Eight responding patients (CR or MR) went on to receive oral GR at 8 or 12 mg t.i.d. for 5 days. In this group there was one CR, one MR, two mRs and four failures (F). There was no evidence of an improved therapeutic effect with increasing dose in either the infusion or the oral section of the study, although numbers were limited in the latter part of the trial. Toxicity was mild, with low-grade headache affecting 25% of patients being the most frequent side effect. Pharmacokinetic data was obtained in six patients at each dose level. There was a progressive rise in clearance with increasing dose, indicating that the kinetics are non-linear. However, there was no evidence of an association between high plasma levels and therapeutic efficacy. GR38032F is well tolerated and has promising single-agent activity in preventing vomiting induced by high-dose cisplatin.

Salbutamol and cardiac arrhythmias.

A study was carried out in 7 patients with chronic obstructive airways disease to investigate the possibility of serious cardiovascular effects after the intravenous infusion of salbutamol. Patients received salbutamol starting at 5 micrograms/min and increasing gradually to 20 micrograms/min. There results of blood gas analysis showed that all but one of the patients were hypoxic and there was evidence of improved ventilation at the end of the first hour of infusion in most, with a mean reduction of 0.43 kPa in PaCO2. The patients' ECGs were monitored continuously before and during the infusion. There was an increase in mean heart rate, but not significant arrhythmias clearly provoked by salbutamol were seen. It is concluded that these findings indicate that any cardiovascular risks with parenteral salbutamol are negligible.

Metabolic and anthropometric changes with weight cycling in wrestlers.

Repeated cycles of weight loss and regain have come to be known as weight cycling. This phenomenon is frequently observed in athletes who must meet specific weight categories to qualify for competition. The purpose of this study was to determine the metabolic and anthropometric changes that occur with rapid weight loss/regain cycles in competitive wrestlers. Collegiate wrestlers were divided into two groups, "cyclers" (N = 8) and "noncyclers" (N = 6), based on their reported dieting history. Measurements included a 3-d diet record, resting energy expenditure (REE), skinfold and girth measures, and biochemical tests at three time points: preseason, peak season, and off-season. All anthropometric measures changed with time, and a diet group by time interaction was observed for the trunk to extremity skinfolds ratio (T/E) (P < 0.05), with greater fat loss and regain from the trunk area of the cyclers. There were no differences in REE within or between groups. Serum triiodothyronine (T3) values decreased over time (P < 0.01). Large weight losses appear to have occurred due to both dieting and short-term dehydration, and although physiological changes were observed, a training effect may have overridden any metabolic influence of weight cycling.

A revised spatial serial learning and memory procedure using Corsi's Block-tapping apparatus.

The purpose of this study was to use Corsi's Block Tapping Test as a spatial analog of Benton's Serial Digit Learning Test, using the cognitive neuroscience approach utilized in the California Verbal Learning Test. 60 normal participants, ages 19-52 years, were included and administered an 8-block sequence for 9 trials or until they recalled the entire sequence for 3 consecutive errorless trials. The score was the number of blocks tapped in the correct serial order. An interference trial was administered. Following a 10-min. delay, free recall of the original sequence, cued recall, and recognition measures were obtained. Retroactive interference was significant, but no proactive interference emerged. Scores showed a strong primacy effect. Most participants who learned the sequence to the criterion of three successive errorless trials recalled the sequence after the 10-min. delay. Scores on the cued recall and recognition trials tended to support their validity as less demanding retrieval tasks. The use of this spatial learning and memory procedure allows finer discriminations among nonverbal memory deficits and may facilitate direct comparisons with scores on verbal memory tasks such as Serial Digit Learning and the California Verbal Learning Test.