Tammy Corica

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial

BACKGROUND After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy. METHODS Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002). INTERPRETATION For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF).

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial

BACKGROUND The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; 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. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Long-Term Results of Targeted Intraoperative Radiotherapy (Targit) Boost During Breast-Conserving Surgery

PURPOSE We have previously shown that delivering targeted radiotherapy to the tumour bed intraoperatively is feasible and desirable. In this study, we report on the feasibility, safety, and long-term efficacy of TARGeted Intraoperative radioTherapy (Targit), using the Intrabeam system. METHODS AND MATERIALS A total of 300 cancers in 299 unselected patients underwent breast-conserving surgery and Targit as a boost to the tumor bed. After lumpectomy, a single dose of 20 Gy was delivered intraoperatively. Postoperative external beam whole-breast radiotherapy excluded the usual boost. We also performed a novel individualized case control (ICC) analysis that computed the expected recurrences for the cohort by estimating the risk of recurrence for each patient using their characteristics and follow-up period. RESULTS The treatment was well tolerated. The median follow up was 60.5 months (range, 10-122 months). Eight patients have had ipsilateral recurrence: 5-year Kaplan Meier estimate for ipsilateral recurrence is 1.73% (SE 0.77), which compares well with that seen in the boosted patients in the European Organization for Research and Treatment of Cancer study (4.3%) and the UK STAndardisation of breast RadioTherapy study (2.8%). In a novel ICC analysis of 242 of the patients, we estimated that there should be 11.4 recurrences; in this group, only 6 recurrences were observed. CONCLUSIONS Lumpectomy and Targit boost combined with external beam radiotherapy results in a low local recurrence rate in a standard risk patient population. Accurate localization and the immediacy of the treatment that has a favorable effect on tumour microenvironment may contribute to this effect. These long-term data establish the long-term safety and efficacy of the Targit technique and generate the hypothesis that Targit boost might be superior to an external beam boost in its efficacy and justifies a randomized trial.

Abstract S4-2: Targeted intraoperative radiotherapy for early breast cancer: TARGIT-A trial- updated analysis of local recurrence and first analysis of survival

Background TARGIT-A, an international phase 3 randomised trial (Lancet 2010;376:91–102) compared outcomes in patients undergoing breast conserving surgery followed by either whole breast external beam radiotherapy (EBRT) over several weeks, or a risk-adaptive approach using single dose targeted intra-operative radiotherapy (TARGIT). Risk-adaptive approach meant that if the final pathology report demonstrated unpredicted pre-specified adverse features, then EBRT was to be added to TARGIT. Method 3451 women aged 45 years or older with invasive ductal carcinoma were enrolled from 33 centres in 10 countries between 2000 and 2012. Randomisation to TARGIT or EBRT arm was done either before lumpectomy (pre-pathology) or after lumpectomy (postpathology). If allocated to TARGIT, patients in the pre-pathology group received it immediately after surgical excision under the same anaesthesia; patients in the post-pathology group received it as a subsequent procedure. We pre-specified that analysis would be performed overall as the primary analysis and for these groups separately as a secondary analysis. The primary outcome was ipsilateral within breast recurrence (IBR) with an absolute non-inferiority margin of 2.5% at 5 years and secondary outcome was survival. We performed exploratory analyses for loco-regional recurrence, ‘all recurrence’ (ipsilateral or contralateral breast, axilla or distant), distant recurrence, and causes of death. Results 1721 patients were randomly allocated to receive TARGIT and 1730 to EBRT. 1010 patients have a minimum 4 years follow up and 611 patients have minimum 5 years follow up. Primary events have increased from 13 to 34 since 2010. For the primary outcome of ipsilateral breast recurrence, the absolute difference at 5-years was 2.0%, which was higher with TARGIT and reached the conventional levels of statistical significance (p = 0.042), but was within the pre-specified non-inferiority margin; in prepathology the absolute difference in 5-year IBR was 1%; in postpathology it was 3.7%. For the secondary outcome, there was a non-significant trend for improved overall survival with TARGIT (HR = 0.70(0.46–1.07)) due to fewer non-breast cancer deaths (17 vs. 35, HR 0.47 (0.26–0.84)). Cardiovascular deaths were 1 vs. 10 and deaths from cancers other than breast were 7 vs.16. Conclusion The risk-adapted approach using single dose TARGIT has a slightly higher local recurrence rate than EBRT for the primary endpoint of IBR, but was within the preset non-inferiority boundary, with the prepathology apparently performing better than the postpathology stratum. In addition there was a trend for improved overall survival in the TARGIT arm due to fewer non-breast cancer deaths. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-2.

Targeted intraoperative radiotherapy for breast cancer in patients in whom external beam radiation is not possible.

PURPOSE External beam radiation therapy (EBRT) following wide local excision of the primary tumor is the standard treatment in early breast cancer. In some circumstances this procedure is not possible or is contraindicated or difficult. The purpose of this study was to determine the safety and efficacy of targeted intraoperative radiotherapy (TARGIT) when EBRT is not feasible. METHODS AND MATERIALS We report our experience with TARGIT in three centers (Australia, Germany, and the United Kingdom) between 1999 and 2008. Patients at these centers received a single radiation dose of 20 Gy to the breast tissue in contact with the applicator (or 6 Gy at 1-cm distance), as they could not be given EBRT and were keen to avoid mastectomy. RESULTS Eighty patients were treated with TARGIT. Reasons for using TARGIT were 21 patients had previously received EBRT, and 31 patients had clinical reasons such as systemic lupus erythematosus, motor neuron disease, Parkinsons disease, ankylosing spondylitis, morbid obesity, and cardiovascular or severe respiratory disease. Three of these patients received percutaneous radiotherapy without surgery; 28 patients were included for compelling personal reasons, usually on compassionate grounds. After a median follow-up of 38 months, only two local recurrences were observed, an annual local recurrence rate of 0.75% (95% confidence interval, 0.09%-2.70%). CONCLUSIONS While we await the results of the randomized trial (over 2,000 patients have already been recruited), TARGIT is an acceptable option but only in highly selected cases that cannot be recruited in the trial and in whom EBRT is not feasible/possible.

PROSPECTIVE TRIAL OF INTRAOPERATIVE RADIATION TREATMENT FOR BREAST CANCER

Background:  A new device, Intrabeam, is available for intraoperative radiotherapy. We have prospectively examined its feasibility and tolerability in delivering adjuvant breast cancer treatment.

Intraoperative radiotherapy: the debate continues

In the April issue of The Lancet Oncology, Harry Bartelink commented on our recent review of intraoperative radiotherapy for breast cancer. It is heartening to note that Bartelink agrees with us that in a subgroup of patients, local irradiation of the tumour bed after breastconserving surgery might be sufficient. And we believe that advances in molecular biology need to be complemented by clinical trials to fully elucidate the biological sensitivity and natural history of breast cancers that can be safely treated by new therapies other than the current standards. In particular, it is essential that randomised clinical trials are done, and the long-term results fully understood, before intraoperative radiotherapy is offered as the only radiation treatment. Hence the importance of the ongoing TARGIT and the ELIOT studies. We disagree with Bartelink’s remark, however, that “the biological arguments used [in our review] to defend intraoperative radiotherapy have several shortcomings”. Over the past 20 years, follow-up data from patients who received single-dose radiotherapy (such as radiosurgery) for brain, liver, and lung cancer has been accumulated. Results on structural damage (eg, necrosis) as well as the functional consequences (eg, cognitive effects) are available. The Swedish and Dutch rectal-cancer trials prescribed five 5-Gy fractions to the pelvis. Thousands of patients have been treated and long-term follow-up data are available. On the basis of these data, severe long-term side-effects would not be expected after administration of 5 Gy to 1 cm of breast tissue surrounding an excision cavity, although caution should be exercised when giving high single doses to skin and ribs. When debating whether a dose of 20 Gy to the surface of an excision cavity and 5 Gy to 1 cm of tissue is adequate, it is important to remember that external-beam radiotherapy after breast-conserving surgery reduces local recurrence from about 30% to about 10% after 10 years. The effectiveness of a fractionated dose of 50 Gy, starting 6–8 weeks after surgery (or even later if a patient is scheduled to receive systemic therapy as well), is decreased by tumour-cell repopulation during this time. We know from the experiences reported in radiosurgery that a single dose of 20 Gy is sufficient to sterilise even macroscopic tumours, and that model calculations (despite their limitations) estimate recurrences of fewer than 1% in the region of tissue close to the radiation applicator during intraoperative radiotherapy. This hypothetical recurrence increases with distance from the applicator because of a decrease in dose and can theoretically reach 30% in those regions of the breast that receive no irradiation (assuming a homogeneous distribution of tumour cells irrespective of the distance to the centre of the original tumour—which is a worst case scenario). Therefore, there must be a region of equivalence around the tumour in which intraoperative radiotherapy results in the same recurrence to that seen after external-beam radiotherapy. We do not believe that patients enrolled in intraoperative radiotherapy trials would run the risk of increased mortality. Moreover, because the radiation dose to the heart and lungs during intraoperative radiotherapy is almost negligible, it is possible that death from cardiac ischaemia— commonly seen in conventional radiotherapy trials—could be reduced. Targeted intraoperative radiotherapy might reduce the number of deaths fom breast cancer as a consequence of administering timely and truly conformal radiation, thus avoiding geographic misses. Indeed, a study of 7800 patients found that a delay of conventional radiotherapy by 20–26 weeks after surgery resulted in decreased patient survival. The TARGIT trial is testing two approaches: conventional treatment with whole-breast radiotherapy for all patients versus a pragmatic therapy in which all patients receive intraoperative radiotherapy and some (depending on their risk of recurrence) also receive external-beam radiotherapy. If the latter group of patients were eventually found to have equivalent, or better, local control and cosmetic outcome, then the convenience, lower cost, and increased feasibility of breast-conserving surgery would tip the balance in favour of intraoperative radiotherapy. *Jayant S Vaidya, †Jeffrey Tobias, *Michael Baum, *Mohammed Keshtgar, ‡Joan Houghton, Frederik Wenz, ¶Tammy Corica, and ¶David Joseph

Intraoperative radiotherapy for early breast cancer: do health professionals choose convenience or risk?

BackgroundThe randomized TARGIT trial comparing experimental intra-operative radiotherapy (IORT) to up to 7 weeks of daily conventional external beam radiotherapy (EBRT) recruited participants in Western Australia between 2003 and 2012. We aimed to understand preferences for this evolving radiotherapy treatment for early breast cancer (EBC) in health professionals, and how they changed over time and in response to emerging data. Preferences for single dose IORT or EBRT for EBC were elicited in 2004 and 2011, together with factors that may be associated with these preferences.MethodsWestern Australian health professionals working with breast cancer patients were invited to complete a validated, self-administered questionnaire. The questionnaire used hypothetical scenarios and trade-off methodology to determine the maximum increase in risk of local recurrence health professionals were willing to accept in order to have a single dose of IORT in the place of EBRT if they were faced with this decision themselves.ResultsHealth professional characteristics were similar across the two time points although 2011 included a higher number of nurse (49% vs. 36%) and allied health (10% vs. 4%) participants and a lower number of radiation therapists (17% vs. 32% ) compared to 2004.Health professional preferences varied, with 7.5% and 3% judging IORT unacceptable at any risk, 18% and 21% judging IORT acceptable only if offering an equivalent risk, 56% and 59% judging IORT acceptable with a low maximum increase in risk (1-3%) and 19% and 17% judging a high maximum increase in risk acceptable (4-5%), in 2004 and 2011 respectively. A significantly greater number of nurses accepted IORT as a treatment option in 2011.ConclusionsMost Western Australian health professionals working with breast cancer patients are willing to accept an increase in risk of local recurrence in order to replace EBRT with IORT in a hypothetical setting. This finding was consistent over two time points spanning 7 years despite the duration of clinical experience with IORT and the publication of the early clinical results of IORT in 2010. These results need to be compared with preferences elicited from patient groups, and further investigation into the impact of personal preferences on health professionals’ advice to patients is warranted.

Breast cancer patients treated with intra-operative radiotherapy alone when conventional external beam radiation therapy was not possible

Background: Intra-operative radiotherapy (IORT) with Intrabeam system has been piloted since 1998 and used in the randomised TARGIT International trial since 2000. Some patients are suitable for off-trial therapy, particularly where external beam radiotherapy (EBRT) cannot be offered due to various reasons. Methods: Patients with invasive breast cancer underwent wide local excision followed by IORT (n=75) using the Intrabeam system containing a miniature electron gun and accelerator. Low energy x-rays (50kV) are emitted from the point source, delivering 20Gy to the breast tissue at the surface of the tumour bed using a spherical applicator (Figure 1). The procedure can be performed in an unmodified operating theatre. Patients who were deemed unfit for surgery received interstitial radiotherapy alone using Intrabeam, with only the point source placed at the tumour centre under stereo-guidance under local anaesthetic, and were followed up with serial MRI scans. Results: Over the past 7 years 78 patients have been treated in this way in centres in 3 countries (UK, Germany and Australia). To date there have been no local recurrences. One patient developed a second primary and subsequently died of brain metastases (Table). Conclusions: This cohort adds to the evidence that targeted radiotherapy using Intrabeam (either IORT or interstitial) could offer a safe and effective method of delivering radiotherapy to breast cancer patients in whom EBRT is not an option. Patients who are suitable for either EBRT or IORT can participate in the TARGIT Trial (Figure 2). Table

Theoretical versus Ex Vivo Assessment of Radiation Damage Repair: An Investigation in Normal Breast Tissue

In vivo validation of models of DNA damage repair will enable their use for optimizing clinical radiotherapy. In this study, a theoretical assessment was made of DNA double-strand break (DSB) induction in normal breast tissue after intraoperative radiation therapy (IORT), which is now an accepted form of adjuvant radiotherapy for selected patients with early breast cancer. DSB rates and relative biological effectiveness (RBE) were calculated as a function of dose, radiation quality and dose rate, each varying based on the applicator size used during IORT. The spectra of primary electrons in breast tissue adjacent to each applicator were calculated using measured X-ray spectra and Monte Carlo methods, and were used to inform a Monte Carlo damage simulation code. In the absence of repair, asymptotic RBE values (relative to 60Co) were approximately 1.5. Beam-quality changes led to only minor variations in RBE among applicators, though differences in dose rate and overall dose delivery time led to larger variations and a rapid decrease in RBE. An experimental assessment of DSB induction was performed ex vivo using pre- and postirradiation tissue samples from patients receiving breast intraoperative radiation therapy. Relative DSB rates were assessed via γ-H2AX immunohistochemistry using proportional staining. Maximum-likelihood parameter estimation yielded a DSB repair halftime of 25.9 min (95% CI, 21.5–30.4 min), although the resulting model was not statistically distinguishable from one where there was no change in DSB yield among patients. Although the model yielded an in vivo repair halftime of the order of previous estimates for in vitro repair halftimes, we cannot conclude that it is valid in this context. This study highlights some of the uncertainties inherent in population analysis of ex vivo samples, and of the quantitative limitations of immunohistochemistry for assessment of DSB repair.