Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery

Kraus-Tiefenbacher, U.; Bauer, L.; Scheda, A.; Fleckenstein, Katharina; Keller, Anke; Herskind, Carsten; Steil, Volker; Melchert, F.; Wenz, Frederik

doi:10.1016/j.ijrobp.2006.05.042

Cited by 75 publications

(46 citation statements)

References 28 publications

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“…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: 96%

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

525

342

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Section: Adverse Effectsmentioning

confidence: 96%

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

525

342

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“…We had also ascertained that the combination of TARGIT and EBRT is safe, as tested in a 25-patient pilot study in UCL, London. 22,27 In fact, giving TARGIT at the time of surgery as a tumour bed boost followed by subsequent EBRT has been found to result in a very low 5-year recurrence rate of 1.73%, 27,28 with favourable toxicity and cosmetic outcome results; [29][30][31][32] furthermore, mathematical models of TARGIT have recently suggested that it could be superior in terms of local control to conventional radiotherapy. 33,34 This could be because of the radiotherapy limiting breast cancer cell proliferation normally caused by the trauma of surgery.…”

Section: Introductionmentioning

confidence: 99%

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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“…Local recurrence‐free survival was 92.9% for those treated with IB‐IORT and 92.5% for those treated with EBRT, P = 0.35. It is possible that with a select subgroup of patients, the difference in recurrence is small and acceptable and the benefits outweigh the risks 6, 7, 10. As this study will show, different treatment outcomes may have resulted from variation in cancer cell infiltrations.…”

Section: Introductionmentioning

confidence: 82%

Therapeutic analysis of Intrabeam‐based intraoperative radiation therapy in the treatment of unicentric breast cancer lesions utilizing a spherical target volume model

Schwid

Donnelly

Zhang

2017

J Applied Clin Med Phys

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It is postulated that the outcomes in treating breast cancer with intraoperative radiotherapy (IORT) would be affected by the residual cancer cell distribution within the tumor bed. The three‐dimensional (3D) radiation doses of IntrabeamTM (IB) IORT with a 4‐cm spherical applicator at the energy of 50 and 40 kV were calculated. The modified linear quadratic model (MLQ) was used to estimate the radiobiological responses of the cancer cells and interspersed normal tissues with various radiosensitivities. By comparing the average survival fraction of normal tissues in IB‐IORT and uniform dose treatment for the same level of cancer cell killing, the therapeutic ratios (TRs) were derived. The equivalent uniform dose (EUD) was found to increase with the prescription dose and decrease with the cancer cell infiltrating distance. For 50 kV beam at the 20 Gy prescription dose, the EUDs are 18.03, 16.49 and 13.56, 11. 29, and 9.28 Gy respectively, for 1.5, 3.0, 6.0, 9, and 15.0 mm of the cancer cell infiltrating distance into surrounding tissue. The dose rate of 50 kV is at least 1.87× higher than that of 40 kV beam. The EUDs of 50 kV beam are up to 15% higher than that of the 40 kV beam. The TR increases with the prescription dose, but decreases with the distance of cancer cell infiltration distance. Average TRs of 50 kV beam are up to 30% larger than that of 40 kV beam. In conclusion, IB‐IORT can provide a possible therapeutic advantage on sparing more normal tissue compared with the External Beam IORT (EB‐IORT) for shallowly populated unicentric breast lesion. Our data suggest that IB‐IORT dose size should be adjusted based on the individual patient's cancer cell infiltrating distance for delivering an effective dose, one dose‐fits‐all regimen may have undertreated some patients with large cancer infiltrating distance.

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Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery

Cited by 75 publications

References 28 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)

Therapeutic analysis of Intrabeam‐based intraoperative radiation therapy in the treatment of unicentric breast cancer lesions utilizing a spherical target volume model

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