Intraoperative radiotherapy for breast cancer

Intra-operative radiotherapy (IORT) as a treatment for breast cancer is a relatively new technique that is designed to be a replacement for whole breast external beam radiotherapy (EBRT) in selected women suitable for breast-conserving therapy. This article reviews twelve reasons for the use of the technique, with a particular emphasis on targeted intra-operative radiotherapy (TARGIT) which uses X-rays generated from a portable device within the operating theatre immediately after the breast tumour (and surrounding margin of healthy tissue) has been removed. The delivery of a single fraction of radiotherapy directly to the tumour bed at the time of surgery, with the capability of adding EBRT at a later date if required (risk-adaptive technique) is discussed in light of recent results from a large multinational randomised controlled trial comparing TARGIT with EBRT. The technique avoids irradiation of normal tissues such as skin, heart, lungs, ribs and spine, and has been shown to improve cosmetic outcome when compared with EBRT. Beneficial aspects to both institutional and societal economics are discussed, together with evidence demonstrating excellent patient satisfaction and quality of life. There is a discussion of the published evidence regarding the use of IORT twice in the same breast (for new primary cancers) and in patients who would never be considered for EBRT because of their special circumstances (such as the frail, the elderly, or those with collagen vascular disease). Finally, there is a discussion of the role of the TARGIT Academy in developing and sustaining high standards in the use of the technique

An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial)

BACKGROUND: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. OBJECTIVE: To compare TARGIT within a risk-adapted approach with whole breast external beam radiotherapy over several weeks (EBRT). DESIGN AND SETTING: The TARGIT-A trial was a pragmatic, prospective, international, multicenter, non-inferiority, non-blinded, randomised (1:1 ratio), clinical trial from 33 centres in 11 countries. Originally, randomisation occurred before initial lumpectomy (prepathology) and if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added, in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but needed a reoperation to reopen the wound to give TARGIT as delayed procedure. Risk-adapted approach meant that in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, then EBRT was recommended. Pragmatically, this reflected how TARGIT would be practiced in the real world. PARTICIPANTS: Women who were >=45 years of age with unifocal invasive ductal carcinoma preferably <= 3.5cm in size; 3451 patients were recruited between March 2000 and June 2012. OUTCOMES: Primary: absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary: included toxicity, breast cancer specific and non-breast-cancer mortality. RESULTS: Values below are 5-year Kaplan-Meier rates for TARGIT vs. EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall (3·3%(2·1–5·1) vs. 1·3%(0·7–2·5),p=0.04,Pnoninferiority =0.00000012) and in the prepathology stratum(n=2298) when TARGIT was given concurrently with lumpectomy(2·1%(1·1–4·2) vs. 1·1%(0·5–2·5),p=0.31,Pnoninferiority =0.0000000013). With delayed TARGIT postpathology,(n=1153) the between-group difference was larger than 2·5% and non-inferiority was not established for this stratum((5·4%(3·0–9·7) vs. 1·7%(0·6–4·9),p=0.069,Pnoninferiority= 0.06640). The local-recurrence-free survival when TARGIT was given with lumpectomy was 93.9%(95%CI 90.9 – 95.9) vs. EBRT: 92.5%(95%CI 89.7 – 94.6),p=0.35. In a planned subgroup analysis, progesterone (PgR) receptor status was found to be the only predictor of outcome - hormone responsive patients (PgRpositive) had similar 5-year local recurrence with TARGIT during lumpectomy 1.4%(0.5-3.9) vs. EBRT 1.2%(0.5-2.9),p=0.77. Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (2·6%[1·5–4·3] vs. 1·9%[1·1–3·2];p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5%[2·3–5·2];p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm 37 deaths, 3·9%(2·7–5·8) vs. 51 deaths, 5·3%(3·9–7·3),p=0.099). Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar QALYs, had a positive incremental Net Monetary Benefit that was borderline statistically significant from zero, and had a probability of over 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health care providers by £8 million to £9.1 million each year. This does not include environmental, patient and societal costs. LIMITATIONS: The number of local recurrences is small however, the number of events for local-recurrence-free survival is not small (59 vs. 61); Occurrence of only a few events implies that the treatments are effective and any difference is unlikely to be large. The follow up not all 3451 patients is 5 years, although the number required to answer the main trial question (n=585) have more than 5 years follow up. FUTURE WORK: We shall repeat the analyses with longer follow up. Although this may not change the primary result, the larger number of events may confirm the effect on mortality and allow more detailed subgroup analyses. The TARGIT-B trial is testing whether TARGIT-Boost is superior to EBRT boost. CONCLUSION: For patients with breast cancer (women who are 45 years of age and older with hormone sensitive invasive ductal carcinoma that is up to 3.5cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective, safer and less expensive alternative to postoperative EBRT. TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov NCT00983684

Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radiofrequency Device to Treat Prostate Cancer

PURPOSE: To determine early efficacy of bipolar radiofrequency ablation with a coil design (bRFA) for focal ablation of clinically significant localised prostate cancer (sPCa)visible at mpMRI. MATERIAL AND METHODS: A prospective IDEAL phase 2 development study (NCT02294903) recruited treatment naive patients with a single focus of localised sPCa (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multi-parametric MRI. Intervention was a focal ablation with a bRFA system (Encage®, Trod Medical) encompassing the lesion and a predefined margin using nonrigid MRI-ultrasound fusion. Primary outcome was the proportion of men with absence of sPCa on biopsy at 6 months. Trial follow up comprised serum PSA, mpMRI at 1 week, 6 and 12 months post ablation. Validated patient reported outcome measures (PROMs) for urinary, erectile and bowel functions and adverse events monitoring system were used. Analyses were done on a per-protocol basis. RESULTS: 20 of 21 patients recruited received the intervention. Baseline characteristics were a median age of 66 years (IQR 63-69), pre-operative median PSA of 7.9 ng/ml (5.3-9.6), 18 (90%) had Gleason 7 with median maximum cancer of 7 mm (IQR 5-10) for a median 2.8 cc mpMRI lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores=6, IQR 5-8) showed absence of sPCa in 16/20 men (80%), concordant with mpMRI. There was a low profile of side effects at PROMs analysis and no serious adverse events. CONCLUSIONS: Focal therapy of sPCa associated with an MRI lesion using bRFA showed early efficacy to ablate cancer with low rates of genitourinary and rectal side-effects

Protocol for a feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients

IntroductionOxygen is the most commonly administered drug to mechanically ventilated critically ill adults, yet little is known about the optimum oxygen saturation (SpO2) target for these patients; the current standard of care is an SpO2of 96% or above. Small pilot studies have demonstrated that permissive hypoxaemia (aiming for a lower SpO2than normal by using a lower fractional inspired oxygen concentration (FIO2)) can be achieved in the critically ill and appears to be safe. This approach has not been evaluated in a National Health Service setting. It is possible that permissive hypoxaemia may be beneficial to critically ill patients thus it requires robust evaluation.Methods and analysisTargeted OXygen therapY in Critical illness (TOXYC) is a feasibility randomised controlled trial (RCT) to evaluate whether recruiting patients to a study of permissive hypoxaemia is possible in the UK. It will also investigate biological mechanisms that may underlie the links between oxygenation and patient outcomes. Mechanically ventilated patients with respiratory failure will be recruited from critical care units at two sites and randomised (1:1 ratio) to an SpO2target of either 88%–92% or ≥96% while intubated with an endotracheal tube. Clinical teams can adjust FIO2and ventilator settings as they wish to achieve these targets. Clinical information will be collected before, during and after the intervention and blood samples taken to measure markers of systemic oxidative stress. The primary outcome of this study is feasibility, which will be assessed by recruitment rate, protocol adherence and withdrawal rates. Secondary outcomes will include a comparison of standard critical care outcome measures between the two intervention groups, and the measurement of biomarkers of systemic oxidative stress. The results will be used to calculate a sample size, likely number of sites and overall length of time required for a subsequent large multicentre RCT.Ethics and disseminationThis study was approved by the London - Harrow Research Ethics Committee on 2 November 2017 (REC Reference 17/LO/1334) and received HRA approval on 13 November 2017. Results from this study will be disseminated in peer-reviewed journals, at medical and scientific meetings, in the NIHR Journals Library and patient information websites.Trial registration numberNCT03287466; Pre-results.</jats:sec

The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients

AIM: We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung metastases are or are not resected. METHODS: Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible patients were invited to consent for randomization in the PulMiCC randomized controlled trial (Stage 2). Sites were provided with case report forms for non-randomized patients to record adverse events and death at any time. They were all reviewed at 1 year. Baseline and survival data were analysed for the full cohort. RESULTS: Twenty-five clinical sites recruited 512 patients from October 2010 to January 2017. Data collection closed in October 2020. Before analysis, 28 patients with non-CRC lung lesions were excluded and three had withdrawn consent leaving 481. The date of death was known for 292 patients, 136 were alive in 2020 and 53 at earlier time points. Baseline factors and 5-year survival were analysed in three strata: 128 non-randomized patients did not have metastasectomy; 263 had elective metastasectomy; 90 were from the randomized trial. The proportions of solitary metastases for electively operated and non-operated patients were 69% and 35%. Their respective 5-year survivals were 47% and 22%. CONCLUSION: Survival without metastasectomy was greater than widely presumed. Difference in survival appeared to be largely related to selection. No inference can be drawn about the effect of metastasectomy on survival in this observational study

Mix methods approach to explore patients' perspectives on the acceptability of a urinary biomarker test in replacement of cystoscopy in bladder cancer surveillance

OBJECTIVE: To determine the minimal accepted sensitivity (MAS) of a urine biomarker that patients are willing to accept to replace cystoscopy and to qualitatively assess their views and reasons. PATIENT AND METHODS: Patients were part of a prospective multi-center observational study recruiting patients with bladder cancer for a urine biomarker study (DETECT II; ClinicalTrials.gov: NCT02781428). A mix methods approach comprising of 1) Questionnaire to assess patients' experience with cystoscopy and patients' preference for cystoscopy vs urinary biomarker and 2). Semi-structured interviews to understand patient views, choice and reasons for their preference. RESULTS: A urine biomarker with MAS of 90% would be accepted by 75.8% of patients. This is despite a high self-reported prevalence of hematuria (51.0%), dysuria/ lower urinary tract symptoms (69.1%) and urinary tract infection requiring antibiotics (25.8%). There was no association between MAS with patient demographics, adverse events experienced, cancer characteristics and distance of patients' home to hospital. Qualitative analysis suggest that patients acknowledge that cystoscopy is invasive, embarrassing and associated with adverse events but are willing to tolerate the procedure due to a high sensitivity. Patients have confidence in cystoscopy and appreciate the visual diagnosis of cancer. Both low and high-risk patients would consider a biomarker with a reported sensitivity similar to cystoscopy. CONCLUSION: Patients value the high sensitivity cystoscopy accords despite the reported discomfort and adverse events experienced following cystoscopy. The sensitivity of a urinary biomarker must be close to cystoscopy before patients' acceptance

Pulmonary Metastasectomy in Colorectal Cancer burden of care study: analysis of local treatments for lung metastases and systemic chemotherapy in 220 patients in the PulMiCC cohort

AIM: To examine the burden of further treatments in patients with colorectal cancer (CRC) following a decision about lung metastasectomy. METHODS: Five teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) provided details on subsequent local treatments for lung metastases including the use of chemotherapy. For patients in three groups (no metastasectomy, one metastasectomy or multiple local interventions), baseline factors and selection criteria for additional treatments were examined. RESULTS: The five teams recruited 220 patients between October 2010 and January 2017. No lung metastasectomy was performed in 51 patients, 114 had one, and 55 patients had multiple local interventions. Selection for initial metastasectomy was associated with non-elevated CEA, fewer metastases, and no prior liver metastasectomy. These patients also had better ECOG scores and lung function at baseline. Four sites provided information on chemotherapy in 139 patients: 79 (57%) had 1-5 courses of chemotherapy, to a total of 179 courses. The patterns of survival after one or multiple metastasectomy interventions showed evidence of guarantee-time bias contributing to an impression of benefit over no metastasectomy. After repeated metastasectomy, a significantly higher risk of death was observed with no apparent reduction in chemotherapy usage. CONCLUSION: Repeated metastasectomy is associated with higher risk of death without reducing use of chemotherapy. Continued monitoring without surgery might reassure patients with indolent disease or allow response assessment during systemic treatment. Overall, the carefully collected information from the PulMICC study provides no indication of an important survival benefit from metastasectomy

Exploring patients’ experience and perception of being diagnosed with bladder cancer: A mixed methods approach

OBJECTIVE: To determine patient experience and perception following a diagnosis of non-muscle invasive bladder cancer (NMIBC). PATIENT AND METHODS: Patients were part of a prospective multi-centre observational study recruiting patients with NMIBC for a urine biomarker study (DETECT II; ClinicalTrials.gov: NCT02781428). A mix methods approach comprising 1) the Brief Illness Perception Questionnaire (Brief IPQ) and 2) semi-structured interviews to explore patients' experience of experiencing haematuria, initial and subsequent experience with NMIBC diagnosis. Both assessments were completed at 6 months following NMIBC diagnosis. RESULTS: A total of 213 patients completed the Brief IPQ. Patients felt that they had minimal symptoms (median [IQR: 2 [0-5]) and were not particularly affected emotionally (3 [1-6]) with a minimal effect to their daily life (2 [0-5]). However, they remained concern about their cancer diagnosis (5 [3-8]) and felt that they had no personal control over the cancer (2 [2-5]) and believed that their illness would affect them for some time (6 [3-10]). A significant association with a lower personal control of the disease (p70 years of age. A high number of patients were uncertain about the cause of their bladder cancer diagnosis. Qualitative analysis found that at initial presentation of haematuria, most patients were not aware of the risk of bladder cancer. Patients were most anxious and psychologically affected between the interval of cystoscopy diagnosis and transurethral resection of bladder tumour (TURBT). Following TURBT, most patients were positive about their cancer prognosis. CONCLUSION: NMIBC patients have a poor perception of disease control and believe that their disease will continue over a prolonged period of time. This is particularly more pertinent in the elderly. Patients are most psychologically affected during the interval between cancer diagnosis following cystoscopy and tumour resection at TURBT. Further, health awareness about the causes of bladder cancer remained poor with a significant number of patients unaware of the cause of bladder cancer. Psychological support and prompt TURBT following bladder cancer diagnosis would help improve the mental health of patients with NMIBC