Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A

Sperk, Elena; Welzel, Grit; Keller, Anke; Kraus-Tiefenbacher, U.; Gerhardt, Anke; Sütterlin, Marc; Wenz, Frederik

doi:10.1007/s10549-012-2168-4

Cited by 101 publications

(83 citation statements)

References 29 publications

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“…26 IORT techniques may allow improved critical organ sparing compared with WBI. Lung fibrosis in the ELIOT trial 30 and deaths from cardiovascular causes in the TARGIT trial were lower in the IORT groups. 8 In some studies, low-energy radiographs followed by WBI was associated with double the risk of breast fibrosis (to 37.5%), increased patient-reported pain, and decreased patient-reported quality of life compared with WBI alone.…”

Section: Adverse Effectsmentioning

confidence: 82%

“…8 In some studies, low-energy radiographs followed by WBI was associated with double the risk of breast fibrosis (to 37.5%), increased patient-reported pain, and decreased patient-reported quality of life compared with WBI alone. [30][31][32][33] In contrast, other studies have reported outcomes with IORT followed by WBI that appear acceptable and comparable to either WBI alone or WBI with a conventional EBRT boost. [33][34][35] As such, the task force felt the combination of IORT and WBI should be used only with caution and limited to women with higher risk features on final pathology.…”

Section: Adverse Effectsmentioning

confidence: 95%

See 1 more Smart Citation

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement

Correa

Harris

Leonardi

et al. 2017

Practical Radiation Oncology

526

342

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Section: Adverse Effectsmentioning

confidence: 82%

Section: Adverse Effectsmentioning

confidence: 95%

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement

Correa

Harris

Leonardi

et al. 2017

Practical Radiation Oncology

526

342

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“…107,109,110 Mortality Although the number of breast cancer deaths did not differ significantly between groups, there were significantly fewer deaths from other causes in the TARGIT arm of the trial (number of deaths from causes other than breast cancer: TARGIT 17, EBRT 35). In particular, there were far fewer deaths from cancers other than breast cancer (TARGIT 8 vs. 16) or from cardiovascular disease (EBRT 2 vs. 11).…”

Section: Toxicitymentioning

confidence: 92%

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

Vaidya

Wenz

Bulsara

et al. 2016

Health Technol Assess

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BackgroundBased 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.ObjectiveTo compare TARGIT within a risk-adapted approach with whole-breast external beam radiotherapy (EBRT) over several weeks.DesignThe TARGeted Intraoperative radioTherapy Alone (TARGIT-A) trial was a pragmatic, prospective, international, multicentre, non-inferiority, non-blinded, randomised (1 : 1 ratio) clinical trial. Originally, randomisation occurredbeforeinitial lumpectomy (prepathology) and, if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added in which randomisation occurredafterinitial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but which needed a reoperation to reopen the wound to give TARGIT as a delayed procedure. The risk-adapted approach meant that, in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, EBRT was recommended. Pragmatically, this reflected how TARGIT would be practised in the real world.SettingThirty-three centres in 11 countries.ParticipantsWomen who were aged ≥ 45 years with unifocal invasive ductal carcinoma preferably ≤ 3.5 cm in size.InterventionsTARGIT within a risk-adapted approach and whole-breast EBRT.Main outcome measuresThe primary outcome measure was absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary outcome measures included toxicity and breast cancer-specific and non-breast-cancer mortality.ResultsIn total, 3451 patients were recruited between March 2000 and June 2012. The following values are 5-year Kaplan–Meier rates for TARGIT compared with EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall [TARGIT 3.3%, 95% confidence interval (CI) 2.1% to 5.1% vs. EBRT 1.3%, 95% CI 0.7% to 2.5%;p = 0.04; Pnon-inferiority = 0.00000012] and in the prepathology stratum (n = 2298) when TARGIT was given concurrently with lumpectomy (TARGIT 2.1%, 95% CI 1.1% to 4.2% vs. EBRT 1.1%, 95% CI 0.5% to 2.5%;p = 0.31; Pnon-inferiority = 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 (TARGIT 5.4%, 95% CI 3.0% to 9.7% vs. EBRT 1.7%, 95% CI 0.6% to 4.9%;p = 0.069; Pnon-inferiority = 0.06640]. The local recurrence-free survival was 93.9% (95% CI 90.9% to 95.9%) when TARGIT was given with lumpectomy compared with 92.5% (95% CI 89.7% to 94.6%) for EBRT (p = 0.35). In a planned subgroup analysis, progesterone receptor (PgR) status was found to be the only predictor of outcome: hormone-responsive patients (PgR positive) had similar 5-year local recurrence with TARGIT during lumpectomy (1.4%, 95% CI 0.5% to 3.9%) as with EBRT (1.2%, 95% CI 0.5% to 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 (TARGIT 2.6%, 95% CI 1.5% to 4.3% vs. EBRT 1.9%, 95% CI 1.1% to 3.2%;p = 0.56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1.4%, 95% CI 0.8% to 2.5% vs. 3.5%, 95% CI 2.3% to 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 (3.9%, 95% CI 2.7% to 5.8% vs. 5.3%, 95% CI 3.9% to 7.3%;p = 0.099]. Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar quality-adjusted life-years, had a positive incremental net monetary benefit that was borderline statistically significantly different from zero and had a probability of > 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 in the UK by £8–9.1 million each year. This does not include environmental, patient and societal costs.LimitationsThe number of local recurrences is small but the number of events for local recurrence-free survival is not as small (TARGIT 57 vs. EBRT 59); occurrence of so few events (< 3.5%) also implies that both treatments are effective and any difference is unlikely to be large. Not all 3451 patients were followed up for 5 years; however, more than the number of patients required to answer the main trial question (n = 585) were followed up for > 5 years.ConclusionsFor patients with breast cancer (women who are aged ≥ 45 years with hormone-sensitive invasive ductal carcinoma that is up to 3.5 cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than and less expensive than postoperative EBRT.Future workThe analyses will be repeated with longer follow-up. Although this may not change the primary result, the larger number of events may confirm the effect on overall mortality and allow more detailed subgroup analyses. The TARGeted Intraoperative radioTherapy Boost (TARGIT-B) trial is testing whether or not a tumour bed boost given intraoperatively (TARGIT) boost is superior to a tumour bed boost given as part of postoperative EBRT.Trial registrationCurrent Controlled Trials ISRCTN34086741 and ClinicalTrials.gov NCT00983684.FundingUniversity College London Hospitals (UCLH)/University College London (UCL) Comprehensive Biomedical Research Centre, UCLH Charities, Ninewells Cancer Campaign, National Health and Medical Research Council and German Federal Ministry of Education and Research (BMBF). From September 2009 this project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 73. See the NIHR Journals Library website for further project information.

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“…However, several safety issues must be addressed: 1) This technique delivers radiation immediately after surgery, leading to delay in the wound-healing process. According to IORT data about safety, that delay might not have to be concerned [25][26][27]; 2) This study was conducted in an Asian population and its findings cannot yet be generalized; 3) Infection is an issue because of the relatively long length of the catheters used. In this small cohort, all adverse events were mild and second surgery was not required in any case.…”

Section: Discussionmentioning

confidence: 98%

Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study

Sato¹,

Mizuno²,

Kato³

et al. 2012

JCT

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Background: Previous research has compared the efficacies of accelerated partial breast irradiation (APBI) and wholebreast irradiation (WBI). APBI immediately after surgery may provide more benefit after intraoperative insertion of catheters. Although balloon catheter-based APBI is available in the US, it is difficult in Japanese women, who have relatively small breasts. With the applicators being implanted during tumor removal, APBI can be started immediately after surgery. The aim of this study was to assess the safety and efficacy of APBI using the intraoperative open-cavity implant technique. Method: Patients (age ≥ 40 years) with invasive breast cancer (diameter ≤ 3 cm) were enrolled. Before lumpectomy, the insertion of applicators and delivery doses were simulated by computed tomography (CT). After confirmation of free margins and negative sentinel nodes (SNs) using frozen section analysis, applicators were inserted. Postoperative CT-based dose distribution analysis was performed using dose-volume histograms. APBI was started on the day of surgery, delivering 32 Gy in 8 fractions over the following 5 -6 days, and it covered a distance of 2 cm from tumor margins. This observational study was approved by the institutional review board of our hospital. Results: From October 2008 to July 2012, 157 women (160 lesions) were enrolled (age 55.0 years, <40:9, SN + : 25, for patients' request). The mean number of applicators used was 6.4 (2 -15) and mean planning target volume was 35.8 cm 3 (6.5 -137.1 cm 3 ). All radiotherapy-related toxicities were mild. However, 12 patients (7.5%) experienced wound breakdown because of surgical site infection. Two patients developed ipsilateral breast tumor recurrence (1 marginal, 1 at a distant site). Conclusions: Despite the small number of participants and a short follow-up period, our results suggest that this technique could be helpful in establishing clinical safety and efficacy.

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Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A

Cited by 101 publications

References 29 publications

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study

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