A digital pathway for genetic testing in UK NHS patients with cancer: BRCA-DIRECT randomised study internal pilot.

BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.

POSNOC-POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomised controlled trial of axillary treatment in women with early-stage breast cancer who have metastases in one or two sentinel nodes.

INTRODUCTION: ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. METHODS AND ANALYSIS: POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. ETHICS AND DISSEMINATION: Protocol was approved by the National Research Ethics Service Committee East Midlands-Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN54765244; NCT0240168Cite Now.

Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy.

AIM: The aim was to assess the health utility of lung metastasectomy in the treatment of patients with colorectal cancer (CRC) using the EQ-5D-3L questionnaire. METHODS: Multidisciplinary CRC teams at 14 sites recruited patients to a two-arm randomized controlled trial-Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). Remote randomization was used, stratified by site and with minimization for seven known confounders. Participants completed the EQ-5D-3L questionnaire together with other patient reported outcome measures at randomization and then again at 3, 6, 12 and 24 months. These were returned by post to the coordinating centre. RESULTS: Between December 2010 and December 2016, 93 participants were randomized, 91 of whom returned questionnaires. Survival and patient reported quality of life have been published previously, revealing no significant differences between the trial arms. Described here are patient reported data from the five dimensions of the EQ-5D-3L and the visual analogue scale (VAS) health state. No significant difference was seen at any time point. The estimated difference between control and metastasectomy patients was -0.23 (95% CI -0.113, 0.066) for the composite 0 to 1 index scale based on the descriptive system and 0.123 (95% CI -7.24, 7.49) for the 0 to 100 VAS scale. CONCLUSIONS: Following lung metastasectomy for CRC, no benefit was demonstrated for health utility, which alongside a lack of a survival or quality of life benefit calls into question the widespread use of the procedure.

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial.

BACKGROUND: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT). METHODS: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. RESULTS: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). CONCLUSIONS: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010.

The CEA Second-Look Trial: a randomised controlled trial of carcinoembryonic antigen prompted reoperation for recurrent colorectal cancer.

OBJECTIVE: In patients who have undergone a potentially curative resection of colorectal cancer, does a 'second-look' operation to resect recurrence, prompted by monthly monitoring of carcinoembryonic antigen, confer a survival benefit? DESIGN: A randomised controlled trial recruiting patients from 1982 to 1993 was recovered under the Restoring Invisible and Abandoned Trials (RIAT) initiative. SETTING: 58 hospitals in the UK. PARTICIPANTS: From 1982 to 1993, 1447 patients were enrolled. Of these 216 met the criteria for carcinoembryonic antigen (CEA) elevation and were randomised to 'Aggressive' or 'Conventional' arms. INTERVENTIONS: 'Second-look' surgery with intention to remove any recurrence discovered. PRIMARY OUTCOME MEASURE: Survival. RESULTS: By February 1993, 91/108 patients had died in the 'Aggressive arm' and 88/108 in the 'Conventional' arm (relative risk=1.16, 95% CI 0.87 to 1.37). By 2011 a further 25 randomised patients had died. Kaplan-Meier analysis showed no difference in long-term survival. CONCLUSIONS: The trial was closed in 1993 following a recommendation from the Data Monitoring Committee that it was highly unlikely that any survival advantage would be demonstrated for CEA prompted second-look surgery. This conclusion was confirmed by repeat analysis of survival times after 20 years. TRIAL REGISTRATION NUMBER: ISRCTN76694943.

Group recruitment sessions enhance patient understanding in a small multi-centre phase III clinical trial.

INTRODUCTION: There is continuing concern that patient information leaflets, tailored to current regulatory requirements, fail to meet patients' needs. Provision of comprehensible information is vital if patients are to provide valid informed consent. The design of the ARIX (acupuncture for radiation induced xerostomia) trial provided an opportunity to deliver researcher led, enhanced patient information to groups of potential participants. METHODS: Between November 2009 and September 2010, 149 patients attended a trial introduction meeting at their local site. All meetings followed the same format. The study coordinator delivered a PowerPoint presentation containing standard trial information together with customised local details. This was followed by group questions and answers. Patients could sign a consent form immediately afterwards or with local staff at a later date. Participants who completed the study were invited to feedback their views on these meetings. RESULTS: One hundred and forty nine patients attended a meeting of whom 116 ultimately participated in ARIX and provided feedback. Eighty four (72%) reported that the meeting helped their understanding of the trial 'very much'. Fourteen attendees reported feeling uncomfortable at having the information presented in a group setting but of these, only one felt under pressure to join the trial. Eighty three patients (71%) felt 'not at all' uncomfortable and 111 (95%) 'not at all' under pressure to participate. CONCLUSION: Trial introduction meetings involving researcher led presentation of information, followed by group discussion, can help enhance the information provided in the patient information leaflet in a useful and non coercive manner.

Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.

PURPOSE: The Cancer Research UK "Over 50s" trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years. PATIENTS AND METHODS: Between 1987 and 1997, 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010). RESULTS: There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant. CONCLUSION: Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.

Chemoradiotherapy for locally advanced head and neck cancer: 10-year follow-up of the UK Head and Neck (UKHAN1) trial.

BACKGROUND: Between 1990 and 2000, we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy. We aimed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy, or both, affected clinical outcome. Here we report survival and recurrence after 10 years of follow-up. METHODS: Between Jan 15, 1990, and June 20, 2000, 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey. Patients with locally advanced head and neck cancer, and who had not previously undergone surgery, were randomly assigned to one of four groups in a 3:2:2:2 ratio, stratified by centre and chemotherapy regimen: radical radiotherapy alone (n=233); radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy (SIM alone; n=166); or 14 and 28 days after completing radiotherapy (SUB alone, n=160); or both (SIM+SUB; n=154). Chemotherapy was either methotrexate alone, or vincristine, bleomycin, methotrexate, and fluorouracil. Patients who had previously undergone radical surgery to remove their tumour were only randomised to radiotherapy alone (n=135) or SIM alone (n=118), in a 3:2 ratio. The primary endpoints were overall survival (from randomisation), and event-free survival (EFS; recurrence, new tumour, or death; whichever occurred first) among patients who were disease-free 6 months after randomisation. Analyses were by intention to treat. This trial is registered at www.Clinicaltrials.gov, number NCT00002476. FINDINGS: All 966 patients were included in the analyses. Among patients who did not undergo surgery, the median overall survival was 2.6 years (99% CI 1.9-4.2) in the radiotherapy alone group, 4.7 (2.6-7.8) years in the SIM alone group, 2.3 (1.6-3.5) years in the SUB alone group, and 2.7 (1.6-4.7) years in the SIM+SUB group (p=0.10). The corresponding median EFS were 1.0 (0.7-1.4), 2.2 (1.1-6.0), 1.0 (0.6-1.5), and 1.0 (0.6-2.0) years (p=0.005), respectively. For every 100 patients given SIM alone, there are 11 fewer EFS events (99% CI 1-21), compared with 100 given radiotherapy, 10 years after treatment. Among the patients who had previously undergone surgery, median overall survival was 5.0 (99% CI 1.8-8.0) and 4.6 (2.2-7.6) years in the radiotherapy alone and SIM alone groups (p=0.70), respectively, with corresponding median EFS of 3.7 (99% CI 1.1-5.9) and 3.0 (1.2-5.6) years (p=0.85), respectively. The percentage of patients who had a significant toxicity during treatment were: 11% (radiotherapy alone, n=25), 28% (SIM alone, n=47), 12% (SUB alone, n=19), and 36% (SIM+SUB, n=55) among patients without previous surgery; and 9% (radiotherapy alone, n=12) and 20% (SIM alone, n=24) among those who had undergone previous surgery. The most common toxicity during treatment was mucositis. The percentage of patients who had a significant toxicity at least 6 months after randomisation were: 6% (radiotherapy alone, n=13), 6% (SIM alone, n=10), 4% (SUB alone, n=7), and 6% (SIM+SUB, n=9) among patients who had no previous surgery; and 7% (radiotherapy alone, n=10) and 11% (SIM alone, n=13) among those who had undergone previous surgery. The most common toxicity 6 months after treatment was xerostomia, but this occurred in 3% or less of patients in each group. INTERPRETATION: Concurrent non-platinum chemoradiotherapy reduces recurrences, new tumours, and deaths in patients who have not undergone previous surgery, even 10 years after starting treatment. Chemotherapy given after radiotherapy (with or without concurrent chemotherapy) is ineffective. Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy. FUNDING: Cancer Research UK, with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre.

Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer.

BACKGROUND: Systematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer. METHODS: We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen. RESULTS: Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant. CONCLUSIONS: Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.