Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.

AIMS: Stereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival. MATERIALS AND METHODS: A retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre. RESULTS: In total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7-23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER-/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm3), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months. CONCLUSIONS: This single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2- histology, metastatic volumes >10 cm3 and progressive extracranial disease at the time of SRS were associated with worse survival.

The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Patients' experiences following breast cancer treatment: an exploratory survey of personal and work experiences of breast cancer patients from three European countries.

Improved treatments for early breast cancer have led to a significant increase in overall survival. While evidence regarding potential long-term sequelae of adjuvant treatments exists, relatively little research reports patients' own perceptions of change before and after adjuvant chemotherapy (AC). This study aimed to identify key ongoing issues associated with AC in daily life. An online survey developed for this study was completed by 198 women (mean age 49.7 years) in the UK, France and Germany who had AC 1-5 years previously for oestrogen receptor positive, HER2 negative early breast cancer. Women without AC and endocrine therapy, those treated with Trastuzumab or who had recurrent disease were excluded. A third of women who responded were currently unable to perform their former family role. The majority had needed support, particularly with child care, during treatment. While 54% were in full-time employment before diagnosis this had reduced to 32% following AC. Of those women still working, over half reported difficulties with tiredness or concentration. Most (85.8%) were satisfied with healthcare professionals' treatment information, but only 29.7% received information about returning to work. This exploratory survey highlights areas of women's lives affected 1-5 years following AC for early breast cancer. The impact on returning to work and issues surrounding childcare particularly, require further study.

The weekend effect: short-term mortality following admission with a hip fracture.

We retrospectively reviewed 2989 consecutive patients with a mean age of 81 (21 to 105) and a female to male ratio of 5:2 who were admitted to our hip fracture unit between July 2009 and February 2013. We compared weekday and weekend admission and weekday and weekend surgery 30-day mortality rates for hip fractures treated both surgically and conservatively. After adjusting for confounders, weekend admission was independently and significantly associated with a rise in 30-day mortality (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.02 to 1.9; p = 0.039) for patients undergoing hip fracture surgery. There was no increase in mortality associated with weekend surgery (OR 1.2, 95% CI 0.8 to 1.7; p = 0.39). All hip fracture patients, whether managed surgically or conservatively, were more likely to die as an inpatient when admitted at the weekend (OR 1.4, 95% CI 1.02 to 1.80; p = 0.032), despite our unit having a comparatively low overall inpatient mortality (8.7%). Hip fracture patients admitted over the weekend appear to have a greater risk of death despite having a consultant-led service.

Survival analysis of elderly patients with a fracture of the odontoid peg.

Fractures of the odontoid peg are common spinal injuries in the elderly. This study compares the survivorship of a cohort of elderly patients with an isolated fracture of the odontoid peg versus that of patients who have sustained a fracture of the hip or wrist. A six-year retrospective analysis was performed on all patients aged > 65 years who were admitted to our spinal unit with an isolated fracture of the odontoid peg. A Kaplan-Meier table was used to analyse survivorship from the date of fracture, which was compared with the survivorship of similar age-matched cohorts of 702 consecutive patients with a fracture of the hip and 221 consecutive patients with a fracture of the wrist. A total of 32 patients with an isolated odontoid fracture were identified. The rate of mortality was 37.5% (n = 12) at one year. The period of greatest mortality was within the first 12 weeks. Time made a lesser contribution from then to one year, and there was no impact of time on the rate of mortality thereafter. The rate of mortality at one year was 41.2% for male patients (7 of 17) compared with 33.3% for females (5 of 15). The rate of mortality at one year was 32% (225 of 702) for patients with a fracture of the hip and 4% (9 of 221) for those with a fracture of the wrist. There was no statistically significant difference in the rate of mortality following a hip fracture and an odontoid peg fracture (p = 0.95). However, the survivorship of the wrist fracture group was much better than that of the odontoid peg fracture group (p < 0.001). Thus, a fracture of the odontoid peg in the elderly is not a benign injury and is associated with a high rate of mortality, especially in the first three months after the injury.

A comparative study of the outcomes of primary and revision lumbar discectomy surgery.

The outcome of surgery for recurrent lumbar disc herniation is debatable. Some studies show results that are comparable with those of primary discectomy, whereas others report worse outcomes. The purpose of this study was to compare the outcome of revision lumbar discectomy with that of primary discectomy in the same cohort of patients who had both the primary and the recurrent herniation at the same level and side.A retrospective analysis of prospectively gathered data was undertaken in 30 patients who had undergone both primary and revision surgery for late recurrent lumbar disc herniation. The outcome measures used were visual analogue scales for lower limb (VAL) and back (VAB) pain and the Oswestry Disability Index (ODI).There was a significant improvement in the mean VAL and ODI scores (both p < 0.001) after primary discectomy. Revision surgery also resulted in improvements in the mean VAL (p < 0.001), VAB (p = 0.030) and ODI scores (p < 0.001). The changes were similar in the two groups (all p > 0.05).Revision discectomy can give results that are as good as those seen after primary surgery.

Hormone replacement therapy after endometrial cancer.

Endometrial cancer is the fourth most common female cancer in the UK and the most common gynaecological cancer. Quality of life and symptom control needs to be considered in women who enter a surgically induced menopause. Hormone replacement in this population has been controversial to date. The current evidence regarding the safety of estrogen only and combined hormone replacement therapy is discussed in this review. The use of topical vaginal therapies, alternate therapies and the current data regarding testosterone use for symptom control is also outlined.

Is cauda equina syndrome linked with obesity?

No previous studies have examined the physical characteristics of patients with cauda equina syndrome (CES). We compared the anthropometric features of patients who developed CES after a disc prolapse with those who did not but who had symptoms that required elective surgery. We recorded the age, gender, height, weight and body mass index (BMI) of 92 consecutive patients who underwent elective lumbar discectomy and 40 consecutive patients who underwent discectomy for CES. On univariate analysis, the mean BMI of the elective discectomy cohort (26.5 kg/m2 (16.6 to 41.7) was very similar to that of the age-matched national mean (27.6 kg/m2, p = 1.0). However, the mean BMI of the CES cohort (31.1 kg/m2 (21.0 to 54.9)) was significantly higher than both that of the elective group (p < 0.001) and the age-matched national mean (p < 0.001). A similar pattern was seen with the weight of the groups. Multivariate logistic regression analysis was performed, adjusted for age, gender, height, weight and BMI. Increasing BMI and weight were strongly associated with an increased risk of CES (odds ratio (OR) 1.17, p < 0.001; and OR 1.06, p < 0.001, respectively). However, increasing height was linked with a reduced risk of CES (OR 0.9, p < 0.01). The odds of developing CES were 3.7 times higher (95% confidence interval (CI) 1.2 to 7.8, p = 0.016) in the overweight and obese (as defined by the World Health Organization: BMI ≥ 25 kg/m2) than in those of ideal weight. Those with very large discs (obstructing > 75% of the spinal canal) had a larger BMI than those with small discs (obstructing < 25% of the canal; p < 0.01). We therefore conclude that increasing BMI is associated with CES.

The epidemiology of cervical spondylotic myelopathy.

OBJECTIVES: This is an observational study looking at the epidemiology of cervical spondylotic myelopathy of patients presenting to our hospital. MATERIALS AND METHODS: The notes and MRI scans of 41 patients presenting to the Leicester General Hospital with a clinical diagnosis of cervical myelopathy between January 2004 and December 2008 were reviewed retrospectively. RESULTS: Cervical myelopathy was found to be more common in male patients to the ratio of approximately 2.7:1, with an average age at diagnosis of 63.8 years. Multi-level disease was seen in the majority of patients, with C5/6 being the most commonly affected level. CONCLUSIONS: Cervical myelopathy predominantly affects men in their 7th decade of life. It is often a multi-level disease with C5/6 being the most commonly affected. It has little in common with cervical radiculopathy and is more analogous to lumber spinal stenosis.

Lumbar vertebral haemangioma causing pathological fracture, epidural haemorrhage, and cord compression: a case report and review of literature.

CONTEXT: Vertebral haemangiomas are recognized to be one of the commonest benign tumours of the vertebral column, occurring mostly in the thoracic spine. The vast majority of these are asymptomatic. Infrequently, these can turn symptomatic and cause neurological deficit (cord compression) through any of four reported mechanisms: (1) epidural extension; (2) expansion of the involved vertebra(e) causing spinal canal stenosis; (3) spontaneous epidural haemorrhage; (4) pathological burst fracture. Thoracic haemangiomas have been reported to be more likely to produce cord compression than lumbar haemangiomas. FINDINGS: A forty-nine year old male with acute onset spinal cord compression from a pathological fracture in a first lumbar vertebral haemangioma. An MRI delineated the haemangioma and extent of bleeding that caused the cord compression. These were confirmed during surgery and the haematoma was evacuated. The spine was instrumented from T12 to L2, and a cement vertebroplasty was performed intra-operatively. Written consent for publication was obtained from the patient. CLINICAL RELEVANCE: The junctional location of the first lumbar vertebra, and the structural weakness from normal bone being replaced by the haemangioma, probably caused it to fracture under axial loading. This pathological fracture caused bleeding from the vascularized bone, resulting in cord compression.

A prospective randomised phase II trial of thalidomide with carboplatin compared with carboplatin alone as a first-line therapy in women with ovarian cancer, with evaluation of potential surrogate markers of angiogenesis.

OBJECTIVES: To compare the safety and efficacy of thalidomide in combination with carboplatin to carboplatin alone as a first-line therapy in women with ovarian cancer and to evaluate the anti-angiogenic effects of thalidomide by measurement of surrogate markers of angiogenesis. METHODS: Forty patients with Stage IC-IV ovarian cancer were randomly assigned to receive either carboplatin (AUC 7) intravenously every four weeks for up to six doses (n = 20) or carboplatin at the same dose and schedule, plus thalidomide 100 mg orally daily for six months (n = 20). RESULTS: After median follow-up of 1.95 years, there was no difference in the overall response rate (90% in carboplatin arm, 75% in combination arm; p = 0.41). Increased incidence of symptoms of constipation, dizziness, tiredness and peripheral neuropathy was observed in the combination arm. There was a significant fall in CA-125 and E-selectin in both arms after treatment and VCAM-1 in the carboplatin arm. No significant difference between the two arms was observed in any of the markers analysed. CONCLUSIONS: In our trial the addition of thalidomide to carboplatin was well tolerated with no increased efficacy. The fall in some of the angiogenic markers in both groups may reflect tumour response rather than any specific anti-angiogenic effect of thalidomide.

The preferences and experiences of different bisphosphonate treatments in women with breast cancer.

OBJECTIVE: The objective of this study was to examine women's experiences with oral and intravenous (i.v.) bisphosphonate therapy, the impact that treatment had on bone pain and Quality of Life (QoL), and their preferences if choice were available between oral and i.v. administration. METHODS: This was a prospective study of women with metastatic breast cancer receiving either oral or i.v. bisphosphonate therapy. Semi-structured interview techniques and QoL questionnaires were employed. Participants in the study were interviewed three times, once in person and twice by telephone. RESULTS: A total of 79 patients from eight UK hospitals participated in the study; 35 were receiving oral bisphosphonate medication and 44 i.v. treatments. Self-reported adherence to oral therapy was good although 21% had chosen not to take their drugs at some time. Most had adapted their lifestyle to accommodate oral therapy with 29/37(74%) completely satisfied. However 9/37(24%) expressed dissatisfaction with constraints especially the time required to stand upright after taking their tablets. By 6 months 23/25 (91%) of patients receiving (i.v.) therapies were generally satisfied with the frequency and 22/25 (88%) with the convenience especially if given concurrently with chemotherapy. Overall 25/54 (46%) patients reported improved bone pain scores on the validated FACT-BP scale from baseline to 6 months. CONCLUSIONS: Both oral and i.v. therapies have disadvantages but were acceptable to most patients some of whom had reduced bone pain over time. More data regarding acceptability, adherence, and patients' preference for bisphosphonate therapies are required. Until randomised trials demonstrate superior efficacy for one mode of bisphosphonate therapy over another, we suggest offering patients a choice of bisphosphonate therapy.

Dupuytren's contracture: an audit of the outcomes of surgery.

This multi-centre postal questionnaire study was conducted by the Audit Committee of the BSSH to assess the outcomes of surgery for Dupuytren's Contracture using subjective data provided by 1177 patients at a mean follow-up of 27 (SD 8) months after surgery. Surgery for Dupuytren's contracture achieved a high rate of full, or almost full, correction in 826 patients (75%) but had a high incidence of post-operative patient-reported complications of 46%. A higher complication rate was seen in those patients with worse initial deformities. The rate of contracture recurrence or persistence was 158 of 1037 (15%). The severity of contracture correlated with the final hand function measured using the PEM score. Recurrence was more common in patients with greater initial deformity. Recurrence was less common if good correction was achieved at surgery. The relevance and limitations of this data are discussed.

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer.

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents.

The aims of this study were to identify prognostic variables for toxicity and survival in patients with cancer participating in phase I clinical trials and compare characteristics of those treated with cytotoxic chemotherapy (CT) and non-cytotoxic drugs (non-CT). Data were collected from 420 (114 CT, 306 non-CT) patients enrolled in 16 phase I trials (five CT and 11 non-CT trials) in one cancer centre. Analyses of all patients were used to compare treatment groups, identify predictive variables for toxicity and to estimate prognostic factors in overall survival (OS). These were used to develop a prognostic index (PI). Multivariate analysis found those patients with better performance status, fewer sites of metastases, baseline Hb>12 g dl(-1) and WBC or LDH in the normal range had significantly better OS. Male gender, platelet count <450 x 10(9) l(-1), high WBC or treatment with a non-CT phase I agent significantly reduced the chance of grade 3/4 toxicity. Overall survival was not significantly different between the CT and non-CT groups (260 vs 192 days, P=0.47) except for those with liver metastases (228 vs 137 days, P=0.02). Overall tumour response was 4.9% (95% CI: 2.7-7.0%). The PI identified three distinct patient groups with median survival of 321, 257 and 117 days. In conclusion, entry into a phase I trial of a non-CT drug is a safe option for heavily pretreated patients with cancer. The PI generated from these data can estimate the survival probability for patients entering phase I studies.