Dataset Information

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.

ABSTRACT:

Background

The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses.

Methods

In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT.

Results

Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091.

Conclusion

TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect.

Trial registration

ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

SUBMITTER: Vaidya JS

PROVIDER: S-EPMC8329051 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.DesignProspective, open label, randomised controlled clinical trial.Setting32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.Participants2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).InterventionsRandom allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).Main outcome measuresNon-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.ResultsBetween 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).ConclusionFor patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.Trial registrationISRCTN34086741, NCT00983684.

Project description:Purpose/objectiveWe present our single-institution experience in the management of invasive breast cancer with targeted intraoperative radiotherapy (TARGIT-IORT), focusing on patient suitability for IORT determined by the American Society for Radiation Oncology (ASTRO) Accelerated Partial Breast Irradiation (APBI) consensus guidelines.Materials/methodsWe identified 237 patients treated for biopsy-proven early-stage invasive breast cancer using low energy x-ray TARGIT-IORT at the time of lumpectomy between September 2013 and April 2020 who were prospectively enrolled in an institutional review board (IRB) approved database. We retrospectively reviewed preoperative and postoperative clinicopathologic factors to determine each patient's ASTRO APBI suitability (suitable, cautionary or unsuitable) according to the 2017 consensus guidelines (CG). Change in suitability group was determined based on final pathology. Kaplan-Meier methods were used to estimate the survival probability and recurrence probability across time.Results237 patients were included in this analysis, based on preoperative clinicopathologic characteristics, 191 (80.6%) patients were suitable, 46 (19.4%) were cautionary and none were deemed unsuitable. Suitability classification changed in 95 (40%) patients based on final pathology from lumpectomy. Increasing preoperative lesion size or a body mass index (BMI) ≥ 30 kg/m2 were significant predictors for suitability group change. Forty-one (17.3%) patients received additional adjuvant whole breast radiotherapy after TARGIT-IORT. At a median follow up of 38.2 months (range 0.4 - 74.5), five (2.1%) patients had ipsilateral breast tumor recurrences (IBTR), including two (0.8%) true local recurrences defined as a recurrence in the same quadrant as the initial lumpectomy bed with the same histology as the initial tumor. IBTR occurred in 1/103 (0.09%) patient in the post-op suitable group, 4/98 (4.08%) patients in the post-op cautionary group, and no patients in the post-op unsuitable group. At 3-years, the overall survival rate was 98.4% and the local recurrence free survival rate was 97.1%.ConclusionThere is a low rate of IBTR after TARGIT-IORT when used in appropriately selected patients. Change in suitability classification pre to postoperatively is common, highlighting a need for further investigation to optimize preoperative patient risk stratification in this setting. Patients who become cautionary or unsuitable based on final pathology should be considered for additional adjuvant therapy.

Project description:To gather a deep qualitative understanding of the perceived benefits and impacts of External-Beam RadioTherapy (EBRT) and TARGeted Intraoperative radioTherapy (TARGIT-IORT) using Intrabeam to assess how the treatments affected patient/care partner experiences during their cancer treatment and beyond. A patient-led working group was established to guide study design and to help validate findings. Patients with experience of receiving EBRT or TARGIT-IORT were purposively sampled by Hampshire Hospitals NHS Foundation Trust. These patients had been offered both regimens as per their clinical features and eligibility. Semistructured interviews were conducted with 29 patients and care partners with lived experience of either EBRT (n=12, 5-day FAST-Forward regimen and n=3, 3-week regimen) or TARGIT-IORT (n=14). Thematic analysis was then carried out by two coders generating 11 themes related to EBRT or TARGIT-IORT. Semistructured interviews were conducted virtually via Zoom during February and March 2023. A number of procedural grievances were noted among EBRT patients. EBRT was perceived as being disruptive to normal routines (work, home and travel) and caused discomfort from side effects. TARGIT-IORT was perceived by patients and care partners as the safer option and efficient with minimal if any disruptions to quality of life. The need for timely accessible information to reduce anxieties was noted in both cohorts. This qualitative study found that patients perceived EBRT as being greatly disruptive to their lives. In contrast, the one-off feature of TARGIT-IORT given while they are asleep during surgery gives them the feeling of stamping out the cancer without conscious awareness. These insights can help healthcare staff and policy-makers further justify the incorporation of the treatment favoured by these patient perceptions (TARGIT-IORT) more widely in routine practice. Further research is planned to explore TARGIT-IORT in more diverse populations and in the 35 countries where it is an established treatment option.

Project description:ObjectiveThe clinical effectiveness of targeted intraoperative radiotherapy (TARGIT-IORT) has been confirmed in the randomised TARGIT-A (targeted intraoperative radiotherapy-alone) trial to be similar to a several weeks' course of whole-breast external-beam radiation therapy (EBRT) in patients with early breast cancer. This study aims to determine the cost-effectiveness of TARGIT-IORT to inform policy decisions about its wider implementation.SettingTARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy.MethodsCost-utility analysis using decision analytic modelling by a Markov model. A cost-effectiveness Markov model was developed using TreeAge Pro V.2015. The decision analytic model compared two strategies of radiotherapy for breast cancer in a hypothetical cohort of patients with early breast cancer based on the published health state transition probability data from the TARGIT-A trial. Analysis was performed for UK setting and National Health Service (NHS) healthcare payer's perspective using NHS cost data and treatment outcomes were simulated for both strategies for a time horizon of 10 years. Model health state utilities were drawn from the published literature. Future costs and effects were discounted at the rate of 3.5%. To address uncertainty, one-way and probabilistic sensitivity analyses were performed.Main outcome measuresQuality-adjusted life-years (QALYs).ResultsIn the base case analysis, TARGIT-IORT was a highly cost-effective strategy yielding health gain at a lower cost than its comparator EBRT. Discounted TARGIT-IORT and EBRT costs for the time horizon of 10 years were £12 455 and £13 280, respectively. TARGIT-IORT gained 0.18 incremental QALY as the discounted QALYs gained by TARGIT-IORT were 8.15 and by EBRT were 7.97 showing TARGIT-IORT as a dominant strategy over EBRT. Model outputs were robust to one-way and probabilistic sensitivity analyses.ConclusionsTARGIT-IORT is a dominant strategy over EBRT, being less costly and producing higher QALY gain.Trial registration numberISRCTN34086741; post results.

Project description:To quantify the journeys and CO2 emissions if women with breast cancer are treated with risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT) rather than several weeks' course of external beam whole breast radiotherapy (EBRT) treatment.(1) TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy, (2) 2 additional UK centres offering TARGIT.485 UK patients (249 TARGIT, 236 EBRT) in the prepathology stratum of TARGIT-A trial (where randomisation occurred before lumpectomy and TARGIT was delivered simultaneously with lumpectomy) for whom geographical data were available and 22 patients treated with TARGIT after completion of the TARGIT-A trial in 2 additional UK breast centres.The shortest total journey distance, time and CO2 emissions from home to hospital to receive all the fractions of radiotherapy.Distances, time and CO2 emissions were calculated using Google Maps and assuming a fuel efficiency of 40 mpg. The groups were compared using the Student t test with unequal variance and the non-parametric Wilcoxon rank-sum (Mann-Whitney) test.TARGIT patients travelled significantly fewer miles: TARGIT 21 681, mean 87.1 (SE 19.1) versus EBRT 92 591, mean 392.3 (SE 30.2); had lower CO2 emissions 24.7 kg (SE 5.4) vs 111 kg (SE 8.6) and spent less time travelling: 3 h (SE 0.53) vs 14 h (SE 0.76), all p<0.0001. Patients treated with TARGIT in 2 hospitals in semirural locations were spared much longer journeys (753 miles, 30 h, 215 kg CO2 per patient).The use of TARGIT intraoperative radiotherapy for eligible patients with breast cancer significantly reduces their journeys for treatment and has environmental benefits. If widely available, 5 million miles (8 000 000 km) of travel, 170 000 woman-hours and 1200 tonnes of CO2 (a forest of 100 hectares) will be saved annually in the UK.ISRCTN34086741; Post-results.

Project description:Importance:Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed. Objective:To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control. Design, Setting, and Participants:In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019. Interventions:The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound. Main Outcomes and Measures:A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. Results:Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P?=?.052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P?=?.38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P?=?.98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P?=?.80). Conclusions and Relevance:These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival. Trial Registration:ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684.

Project description:Intraoperative radiotherapy (IORT) for early stage breast cancer is a technique for partial breast irradiation. There are several technologies in clinical use to perform breast IORT. Regardless of technique, IORT generally refers to the delivery of a single dose of radiation to the periphery of the tumor bed in the immediate intraoperative time frame, although some protocols have performed IORT as a second procedure. There are two large prospective randomized trials establishing the safety and efficacy of breast IORT in early stage breast cancer patients with sufficient follow-up time on thousands of women. The advantages of IORT for partial breast irradiation include: direct visualization of the target tissue ensuring treatment of the high-risk tissue and eliminating the risk of marginal miss; the use of a single dose coordinated with the necessary surgical excision thereby reducing omission of radiation and the selection of mastectomy for women without access to a radiotherapy facility or unable to undergo several weeks of daily radiation; favorable toxicity profiles; patient convenience and cost savings; radiobiological and tumor microenvironment conditions which lead to enhanced tumor control. The main disadvantage of IORT is the lack of final pathologic information on the tumor size, histology, margins, and nodal status. When unexpected findings on final pathology such as positive margins or positive sentinel nodes predict a higher risk of local or regional recurrence, additional whole breast radiation may be indicated, thereby reducing some of the convenience and low-toxicity advantages of sole IORT. However, IORT as a tumor bed boost has also been studied and appears to be safe with acceptable toxicity. IORT has potential efficacy advantages related to overall survival related to reduced cardiopulmonary radiation doses. It may also be very useful in specific situations, such as prior to oncoplastic reconstruction to improve accuracy of adjuvant radiation delivery, or when used as a boost in higher risk patients to improve tumor control. Ongoing international clinical trials are studying these uses and follow-up data are accumulating on completed studies.