The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer.

INTRODUCTION: SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. PATIENTS AND METHODS: A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. RESULTS: The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N-) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N- cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N- cases, 4.1% of all cases). CONCLUSIONS: These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Association between underestimation of tumour size by imaging and incomplete excision in breast-conserving surgery for breast cancer.

BACKGROUND: Completeness of excision is the most important factor influencing local recurrence after breast-conserving surgery (BCS). The aim of this case-control study was to determine factors influencing incomplete excision in patients undergoing BCS. METHODS: Women with invasive breast cancer treated by BCS between 1 June 2008 and 31 December 2009 were identified from a prospectively collected database in the Edinburgh Breast Unit. The maximum size of the tumour, measured microscopically, was compared with the size estimated before operation by mammography and ultrasound imaging. A multivariable analysis was performed to investigate factors associated with incomplete excision. RESULTS: The cohort comprised 311 women, of whom 193 (62·1 per cent) had a complete (CE group) and 118 (40·7 per cent) an incomplete (IE group) excision. Mammography underestimated tumour size in 75·0 per cent of the IE group compared with 40·7 per cent of the CE group (P < 0·001). Ultrasound imaging underestimated tumour size in 82·5 per cent of the IE group compared with 56·5 per cent of the CE group (P < 0·001). The risk of an incomplete excision was greater when mammography or ultrasonography underestimated pathological size: odds ratio (OR) 4·38 (95 per cent c.i. 2·59 to 7·41; P < 0·001) for mammography, and OR 3·64 (2·03 to 6·54; P < 0·001) for ultrasound imaging. For every 1-mm underestimation of size by mammography and ultrasonography, the relative odds of incomplete excision rose by 10 and 14 per cent respectively. CONCLUSION: Underestimation of tumour size by current imaging techniques is a major factor associated with incomplete excision in women undergoing BCS.

Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer.

BACKGROUND: We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial. METHODS: The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years. RESULTS: We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21. CONCLUSIONS: Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: the International Society of Geriatric Oncology (SIOG) task force.

Radiotherapy (RT) is a key component of the management of older cancer patients. Level I evidence in older patients is limited. The International Society of Geriatric Oncology (SIOG) established a task force to make recommendations for curative RT in older patients and to identify future research priorities. Evidence-based guidelines are provided for breast, lung, endometrial, prostate, rectal, pancreatic, oesophageal, head and neck, central nervous system malignancies and lymphomas. Patient selection should include comorbidity and geriatric evaluation. Advances in radiation planning and delivery improve target coverage, reduce toxicity and widen eligibility for treatment. Shorter courses of hypofractionated whole breast RT are safe and effective. Conformal RT and involved-field techniques without elective nodal irradiation have improved outcomes in non-small-cell lung cancer (NSCLC) without increasing toxicity. Where comorbidities preclude surgery, stereotactic body radiotherapy (SBRT) is an option for early-stage NSCLC and pancreatic cancer. Modern involved-field RT for lymphoma based on pre-treatment positron emission tomography data has reduced toxicity. Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer (PC). For intermediate-risk disease, 4-6 months of hormones are combined with external beam radiotherapy (EBRT). For high-risk PC, combined modality therapy (CMT) is advised. For high-intermediate risk, endometrial cancer vaginal brachytherapy is recommended. Short-course EBRT is an alternative to CMT in older patients with rectal cancer without significant comorbidities. Endorectal RT may be an option for early disease. For primary brain tumours, shorter courses of postoperative RT following maximal debulking provide equivalent survival to longer schedules. MGMT methylation status may help select older patients for temozolomide alone. Stereotactic RT provides an alternative to whole-brain RT in patients with limited brain metastases. Intensity-modulated radiation therapy provides an excellent technique to reduce dose to the carotids in head and neck cancer and improves locoregional control in oesophageal cancer. Best practice and research priorities are summarised.

Postmastectomy radiotherapy for all node positive patients: The case against.

Postmastectomy radiotherapy (PMRT) is accepted as the standard of care for women with early breast cancer with 4 or more involved axillary nodes. However the role of PMRT in women with 1-3 involved nodes remains controversial and guidelines vary. We present the arguments against advocating postmastectomy radiotherapy for all women with node positive breast cancer.

Breast radiotherapy: considerations in older patients.

With an ageing population, the number of older women with breast cancer eligible for adjuvant irradiation after breast conserving surgery and mastectomy is rising. There is a dearth of level 1 data on the effect of adjuvant irradiation on local control, quality of life and survival. In large part this reflects the exclusion of patients over the age of 70 years from randomised trials. The prevention of local recurrence may reduce the risks of dissemination. However, older women with early breast cancer and a life expectancy of less than 5 years are unlikely to derive a survival benefit from adjuvant radiotherapy. Rates of access of older patients to adjuvant irradiation are lower than for younger patients. Physician and patient bias and co-morbidities are contributory factors. There are also competing risks of mortality from co-morbidities, particularly in women over the age of 80 years. Postoperative radiotherapy after breast conserving surgery does not seem to compromise overall quality of life of older patients. Although the absolute reduction in local recurrence from adjuvant radiotherapy is modest in lower risk older patients after breast conserving surgery and adjuvant systemic therapy, there has to date been no group of fitter old patients defined from whom radiotherapy can be reasonably omitted. Guidelines for postmastectomy radiotherapy should not differ from younger patients. Adequately powered randomised trials are needed to assess the effect of adjuvant irradiation in older patients on outcomes after breast conserving surgery and mastectomy to provide a more robust basis for evidence-based radiotherapy practice.

Implantable biosensors and their contribution to the future of precision medicine.

Precision medicine can be defined as the prevention, investigation and treatment of diseases taking individual variability into account. There are multiple ways in which the field of precision medicine may be advanced; however, recent innovations in the fields of electronics and microfabrication techniques have led to an increased interest in the use of implantable biosensors in precision medicine. Implantable biosensors are an important class of biosensors because of their ability to provide continuous data on the levels of a target analyte; this enables trends and changes in analyte levels over time to be monitored without any need for intervention from either the patient or clinician. As such, implantable biosensors have great potential in the diagnosis, monitoring, management and treatment of a variety of disease conditions. In this review, we describe precision medicine and the role implantable biosensors may have in this field, along with challenges in their clinical implementation due to the host immune responses they elicit within the body.

TELEMAM: a cluster randomised trial to assess the use of telemedicine in multi-disciplinary breast cancer decision making.

AIM: The TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs). METHODS: Over 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of 'in-person' meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach. RESULTS: Levels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year. CONCLUSION: Telemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard 'in-person' meetings.

A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

OBJECTIVES: To assess whether omission of postoperative radiotherapy in women with 'low-risk' axillary node negative breast cancer (T0-2) treated by breast-conserving surgery and endocrine therapy improves quality of life and is more cost-effective. DESIGN: A randomised controlled clinical trial, using a method of minimisation balanced by centre, grade of cancer, age, lymphatic/vascular invasion and preoperative endocrine therapy, was performed. A non-randomised cohort was also recruited, in order to complete a comprehensive cohort study. SETTING: The setting was breast cancer clinics in cancer centres in the UK. PARTICIPANTS: Patients aged 65 years or more were eligible provided that their cancers were considered to be at low risk of local recurrence, were suitable for breast-conservation surgery, were receiving endocrine therapy and were able and willing to give informed consent. INTERVENTIONS: The standard treatment of postoperative breast irradiation or the omission of radiotherapy. MAIN OUTCOME MEASURES: Quality of life was the primary outcome measure, together with anxiety and depression and cost-effectiveness. Secondary outcome measures were recurrence rates, functional status, treatment-related morbidity and cosmesis. The principal method of data collection was by questionnaire, completed at home with a research nurse at four times over 15 months. RESULTS: The hypothesised improvement in overall quality of life with the omission of radiotherapy was not seen in the EuroQol assessment or in the functionality and symptoms summary domains of the European Organisation for Research in the Treatment of Cancer (EORTC) scales. Some differences were apparent within subscales of the EORTC questionnaires, and insights into the impact of treatment were also provided by the qualitative data obtained by open-ended questions. Differences were most apparent shortly after the time of completion of radiotherapy. Radiotherapy was then associated with increased breast symptoms and with greater fatigue but with less insomnia and endocrine side-effects. Patients had significant concerns about the delivery of radiotherapy services, such as transport, accommodation and travel costs associated with receiving radiotherapy. By the end of follow-up, patients receiving radiotherapy were expressing less anxiety about recurrence than those who had not received radiotherapy. Functionality was not greatly affected by treatment. Within the randomised controlled trial, the Barthel Index demonstrated a small but significant fall in functionality with radiotherapy compared with the no radiotherapy arm of the trial. Results from the non-randomised patients did not confirm this effect, however. Cosmetic results were better in those not receiving radiotherapy but this did not appear to be an important issue to the patients. The use of home-based assessments by a research nurse proved to be an effective way of obtaining high-quality data. Costs to the NHS associated with postoperative radiotherapy were calculated to be of the order of 2000 pounds per patient. In the follow-up in this study, there were no recurrences, and the quality of life utilities from EuroQol were almost identical. CONCLUSIONS: Although there are no differences in overall quality of life scores between the patients treated with and without radiotherapy, there are several dimensions that exhibit significant advantage to the omission of irradiation. Over the first 15 months, radiotherapy for this population is not a cost-effective treatment. However, the early postoperative outcome does not give a complete answer and the eventual cost-effectiveness will only become clear after long-term follow-up. Extrapolations from these data suggest that radiotherapy may not be a cost-effective treatment unless it results in a recurrence rate that is at least 5% lower in absolute terms than those treated without radiotherapy. Further research is needed into a number of areas including the long-term aspects of quality of life, clinical outcomes, costs and consequences of omitting radiotherapy.

When may adjuvant radiotherapy be avoided in operable breast cancer?

Randomised trials in which the omission of radiotherapy has been tested after breast-conserving surgery, with or without adjuvant systemic therapy, show a significant four- to five-fold reduction in local recurrence. As yet, no subgroup of women managed by breast-conserving surgery has been identified from whom radiotherapy can be withheld. Few randomised data have been published on the effect of omission of radiotherapy on local control, quality of life and costs, particularly in older women for whom the risk of local recurrence is generally lower. Ongoing trials are evaluating the role of radiotherapy in this population of low risk, older women. Adjuvant radiotherapy after breast-conserving surgery or mastectomy significantly reduces the incidence of local recurrence. In women who have had a mastectomy at high risk of recurrence (> 20% risk of recurrence at 10 years), adjuvant radiotherapy improves survival if combined with adjuvant systemic therapy. Among women with T3 tumours, and those with four or more involved axillary nodes treated by mastectomy, postoperative radiotherapy is the standard of care. For women at intermediate risk of recurrence (i.e. <15% 10-year risk of recurrence after surgery and systemic therapy alone), with one to three involved nodes or node negative with other risk factors, the role of radiotherapy is unclear. Clinical trials to assess the role of postmastectomy radiotherapy (PMRT) in this setting are needed. For pT1-2, pNO tumours without other risk factors, there is no evidence at present that PMRT is needed.

A study of margin width and local recurrence in breast conserving therapy for invasive breast cancer.

PURPOSE: Debate continues on what is an adequate margin width to define a clear margin and whether there is a need to excise pectoral fascia or remove skin in breast conserving surgery. This study set out to provide answers to these questions. PATIENTS AND METHODS: 1411 patients with invasive breast cancer were treated by breast conserving surgery and post-operative whole breast radiotherapy from January 2000 to December 2005. Distance from each margin to any in situ or invasive cancer was measured and recorded. If full thickness of breast tissue was removed no re excision of anterior and posterior margins was performed even if disease was <1 mm from a margin. Patients ≤50 years of age and those with anterior or posterior margins <1 mm to invasive cancer had a radiation boost. Median follow-up time was 6.4 years. RESULTS: Local in breast tumour relapse (IBTR) occurred in 50 patients. The overall actuarial IBTR rate at 5 years was 2.2%. There was no difference in IBTR when comparing patients with radial margins of 1-5 mm or 5-10 mm. Anterior and posterior margins <1 mm or with ink on tumour cells were not associated with an increase in IBTR. CONCLUSION: There is no justification for radial margins of greater than 1 mm. If the anterior or posterior margin is <1 mm and full thickness of breast tissue has been removed, then re excision of these margins is unnecessary if boost radiotherapy is delivered.

Attitudes of breast cancer professionals to conventional and telemedicine-delivered multidisciplinary breast meetings.

We surveyed the attitudes of breast cancer professionals to standard face-to-face and future telemedicine-delivered breast multidisciplinary team (MDT) meetings. Interviews, which included the Group Behaviour Inventory, were conducted face-to-face (n = 19) or by telephone (n = 26). The mean total score on the Group Behaviour Inventory was 96 (SD 19) for 33 respondents, which indicated satisfaction with standard MDT meetings, irrespective of role and base hospital. Positive attitudes to videoconferencing were more common among participants with previous experience of telemedicine (Spearman's rank correlation 0.26, P = 0.91). Common themes emerging from the interviews about telemedicine-delivered MDTs included group leadership, meeting efficiency, group interaction, group atmosphere and technical quality of communication. Most participants were satisfied with standard breast MDTs. Nurses and allied health professionals were least supportive of telemedicine.

A comprehensive approach for evaluating telemedicine-delivered multidisciplinary breast cancer meetings in southern Scotland.

Multidisciplinary team (MDT) meetings for decisions on cancer management are a cornerstone of UK cancer policy. We have proposed a comprehensive methodology to assess the clinical and economic effectiveness of telemedicine in this setting, which is being tested in a randomized breast cancer trial. Pre- and post-telemedicine assessment includes attitudes to and expectations of telemedicine, based on semistructured interviews. The communication content of videotapes of the MDT meeting is being scored using Borgatta's revised Interaction Process Analysis System. The technical performance of the telemedicine equipment is reported on a standardized pro forma. A short questionnaire captures key elements of professional satisfaction for each patient discussion (consensus on future management, confidence in and sharing of decision), added value of linkage, group atmosphere, overall conduct of the meeting and compliance with SIGN guidelines. A cost-minimization analysis will be used for economic assessment.

The use of compensators to optimise the three dimensional dose distribution in radiotherapy of the intact breast.

BACKGROUND AND PURPOSE: Dose heterogeneity in tangential breast irradiation has been shown to be as high as 20% and may lead to problems in local control and cosmesis. In this study, dose heterogeneity in three dimensions (3D) in the breast irradiated with wedged tangential beams is assessed and the improvement which can be made by the use of individualised two dimensional (2D) compensators is established. The compensation required is calculated in two ways: (I) by an iterative technique giving a uniform dose on a plane through the isocentre normal to the central axis of each beam, and (II) by inverse planning using an optimisation technique based on simulated annealing. MATERIALS AND METHODS: A total of 17 patients with histologically proven T0-3, N0, N1, M0 breast cancer undergoing breast irradiation following wide local excision, were CT scanned using contiguous 1 cm slices from approximately 2 cm superior to 2 cm inferior of the irradiated volume. The dose distributions are determined using a 3D algorithm that calculates primary and scatter dose separately using a differential scatter air ratio method and corrects both for the presence of heterogeneities. The iterative technique achieves a dose variation of better than 0.5% on the plane through the isocentre with compensation on both beams. Compensation for the lateral beam only is calculated using the optimisation technique in order to minimise the scatter dose to the contralateral breast. The optimisation algorithm minimises the dose variance over the target and sets upper dose limits for the lung and the remainder of the irradiated volume. RESULTS: For the group of patients the average dose heterogeneity in 3D using wedges is 12% (range 8-17%), which reduces to 8% (5-16%) using compensation on a plane and to 5% (4-7%) using the optimisation technique. CONCLUSIONS: Inverse planning is normally used for complex radiotherapy techniques but when applied to tangential breast irradiation, can reduce the dose heterogeneity through the breast as a whole to as little as 4%, with potential benefits in local control and cosmesis.

Combined radiotherapy and surgery: local control and complications in early carcinoma of the uterine cervix--the Villejuif experience, 1975-1984.

From January 1975 to December 1984, 441 patients were treated by combined radiotherapy and surgery at the Institut Gustave Roussy (IGR) for Stage IB (288) and II (proximal) (103) carcinoma of the uterine cervix. Standard treatment consisted of pre-operative utero-vaginal brachytherapy (60 Gy) using a mould technique followed by a colpo-hysterectomy and external iliac lymphadenectomy. Overall 5 year actuarial survival for the whole population was 87% and disease-free survival 85%. Loco-regional relapse occurred in 23 patients (5%). Of these, 12 were central pelvic failures, 8 regional failures and 3 combined central and regional failures. There were 36 systemic relapses (8%) of which 12 relapsed concurrently in the pelvis. Five year actuarial pelvic disease-free, disease-free and overall survival was 87, 85 and 87%, respectively, for the whole population. 340 patients developed one or more complications [Grade 1: 198/441 (44%), Grade 2: 121/441 (27%) and Grade 3 or 4: 21/441 (4.7%)]. Five year actuarial survival for the whole population was poorer for histologically node positive than for node negative (89 vs. 55%, p less than 0.0001). Pre-operative brachytherapy followed by surgery can provide good local control with acceptable morbidity in early cervical cancer.

What is the evidence for a reduced risk of local recurrence with age among older patients treated by breast conserving therapy?

With the rising age of the population and the proposed extension of the breast screening programme to older women, increasing numbers of older patients are becoming eligible for breast conserving surgery and post-operative breast irradiation. Women over the age of 70 have traditionally been omitted from randomized controlled trials for assessing the role of breast radiotherapy after local surgery. The majority of trials suggest that local recurrence rates do decline with age. Similar conclusions are suggested by many non-randomized studies. Comparison of randomized and non-randomized studies is limited by differing extent of classifying tumour margins, nodal status, use of adjuvant systemic therapy, sample size, analytical approaches and duration of follow-up. Large randomized trials in older women are needed to assess whether, with careful attention to obtaining clear tumour margins, radiotherapy is required in low risk, ER positive, node negative breast cancer patients following wide excision and adjuvant tamoxifen. Within both randomized and non-randomized studies, only a few studies have failed to demonstrate an impact of age on recurrence rates following breast conserving treatment, with the majority finding a reduction in local recurrence rates with increasing age. Importantly for interpretation, no studies suggest that recurrence rates increase with age. The variation in analytical approaches and sample sizes are such that the variety of conclusions is not surprising. The results are compatible with a tendency for local recurrence rates to fall with age, but the variability is such that one cannot quantify this change with any precision.

Carcinoma of the male breast metastatic to the mandible.

A case is reported of male breast carcinoma which, among other bony sites, metastasized to the mandible. This case and the review of the literature illustrate the need to include the mandible in bone scans for metastatic disease in breast cancer.