Case selection for targeted intraoperative radiotherapy (TARGIT)

Background: The TARGIT-A randomised trial compared a risk-adapted approach using targeted intraoperative radiotherapy (TARGIT) with whole breast external beam radiotherapy (EBRT) after lumpectomy for early breast cancer. At the San Antonio update, it was suggested that the preferred option is to give TARGIT concurrently with lumpectomy (prepathology). In this analysis we describe patient and tumour factors that may help select patients for TARGIT based on the results of an a priori statistical analysis plan. Methods: In this large international trial, 3451 patients (age>=45, unifocal invasive ductal carcinoma, size 3.5 cm) from 33 centres in 10 countries were randomly allocated to either TARGIT or EBRT. Primary outcome was ipsilateral breast recurrence and secondary included mortality. Before unblinding for this analysis, we hypothesised that progesterone receptor (PgR) status, as an expression of a functionally active oestrogen receptor (ER), is a surrogate for radiation responsiveness and could predict a difference between the outcome for local control in the two randomised groups and pre-specified a detailed analysis by PgR status. We also assessed whether a Cox proportional hazard model including age, margin status, tumour grade, ER, PgR, HER2, vascular invasion and node positivity was consistent with our results. Results: For PgR positive cases, there was no significant difference in the primary outcome of Ipsilateral breast recurrence between TARGIT and EBRT (2.3%(1.3−4.3) vs. 1.5%(0.75−3.0) p = 0.51, while in PgR negative cases there were significantly more local recurrences after partial breast irradiation using TARGIT: 7.0%(3.5–13.6) vs. 0.5%(0.1−3.7) p = 0.017. By contrast, age, margin status, tumour grade, tumour size, vascular invasion, node positivity, ER and Her2 status were not found to be significant predictors. Even age younger than 50 or grade 3 cancers had similar outcome with TARGIT or EBRT. Exploratory analyses in conjunction with the timing of TARGIT, revealed that when TARGIT was given concurrently in PgR positive cases (n=1625) the results were (TARGIT vs. EBRT): ipsilateral breast recurrence 4 vs. 5, 5-year risk 1.4%(0.46−3.9) vs. 1.2%(0.48−2.9) HR 0.82(0.22–3.06), and overall mortality 18 vs. 31, 5-year risk 3.3%(1.83–6.04) vs. 6.4%(4.3−9.6) HR 0.60(0.34–1.08). Conclusions: It appears that progesterone receptor status is useful in selecting cases for using the TARGIT concurrently with lumpectomy for breast cancer. Progesterone receptor negative patients may fall in the cautious or unsuitable category and progesterone receptor positive cases are in the suitable category for partial breast irradiation with TARGIT. Conflict of interest: Other substantive relationships: Carl Zeiss (travel to meetings and honoraria)

Trial supports targeted radiotherapy for early breast cancer but protocol still requires 3 weeks of daily therapy

Commentary on: Coles CE, Griffin CL, Kirby AM, et al. IMPORT Trialists. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048–60. Context The evidence-based local treatment for early breast cancer is breast-conserving surgery and radiotherapy, requiring 3–6 weeks of daily whole breast external beam radiation therapy, which is inconvenient for patients and expensive. The suggestion that targeted radiation to the tumour bed with modern techniques may be adequate was proposed in 1995.1 This was heralded as a new standard2 with the publication of the TARGIT-A trial3 4 of single-dose targeted intraoperative radiotherapy (TARGIT-IORT), later confirmed by other European studies using brachytherapy5 that requires 5 days of inpatient stay or EBRT.6 Methods In this study,7 in 30 UK centres, from 2007 to 2010, women aged ≥50 years, who had undergone breast-conserving surgery for unifocal invasive ductal carcinoma ≤3 cm in size with a 2 mm non-cancerous excision margin, were randomly assigned (1:1:1) to receive daily over 3 weeks one of three regimens: (1) 40 Gy whole breast irradiation (WBI); (2) 36 Gy WBI with 40 Gy partial breast irradiation (PBI); or (3) 40 Gy PBI targeted to the tumour bed. The primary endpoint was ipsilateral local relapse with a non-inferiority margin of 2.5% at 5 years. For quality of life, 72 different patient-reported outcome measures (PROM) were analysed and radiotherapy toxicity was assessed by photographs and clinicians. Neither patients, clinicians nor data analysts were masked to treatment allocation. Findings Five-year estimated incidence of local relapse was 1.1% (95% CI 0.5 to 2.3) with WBI (n=674) and 0.5% (0.2–1.4) with PBI (n=669); non-inferiority was confirmed. Unlike in prior trials,3–6 radiotherapy toxicity was not reduced. Of the 72 PROMs assessed, only two (breast appearance and texture) were reported to have better cumulative scores with PBI. The incidence of only one PROM (‘breast appearance changed’) was reduced at 5 years (from 27% to 15%). Commentary IMPORT-LOW provides further mature randomised evidence supporting PBI. However, PBI with IMPORT-LOW protocol offers little advantage to patients or the healthcare system. The 2 mm clear margins this protocol requires render many patients ineligible; acceptable margins are currently much smaller, for example, >0 mm in USA.8 The authors emphasise the benefit in two quality of life domains, although 72 were tested, with 5-year benefit seen in only one. Clearly, IMPORT-LOW patients had considerably better prognosis cancers than in other trials that have proven non-inferiority of targeted radiation to whole breast radiation. Compared with TARGIT-A, for example, only 3% versus 16% were node positive, and 9% versus 15% were grade 3. Therefore, the low recurrence rate is not surprising. Who benefits from the IMPORT-LOW protocol? For patients and healthcare systems, the 3-week daily regimen has adverse physical, social, financial9 and environmental impacts10 and offers no advantage over conventional radiation. PBI using IMPORT-LOW is also resource consuming (and therefore expensive), and keeps radiotherapy departments very busy. Conversely, TARGIT-IORT delivered during the operation enables over 80% of patients to avoid visiting the radiotherapy centre at all. The relevance here is that although published twice in The Lancet, with an independent editorial concluding that it should be offered as an alternative to conventional EBRT, TARGIT-IORT is not even mentioned in the IMPORT-LOW paper. We find this surprising since the number of patients with a median follow-up of 5–6 years is similar (~1200 vs 1300), and both proved non-inferiority. Implications for practice Targeted radiation methods range from the 3-week daily course required for IMPORT-LOW with 16 hospital visits, to the single-dose TARGIT-IORT given during lumpectomy. Several other approaches are also available,5 6 and as all are effective, patients are entitled to choose what is right for them, based on convenience, personal cost, quality of life and side effects. Acknowledgments We thank Professor Michael Baum, Professor Michael Douek, Mr Nathan Coombs, Professor Max Bulsara, Dr Julian Singer, Dr David Morgan, Dr Shiroma D’Silva and Ms Marcelle Bernstein for valuable discussion about this manuscript

Rethinking neoadjuvant chemotherapy for breast cancer

Breast cancer is the most common cancer in women worldwide. In 2014, 55 000 women in the UK were given the diagnosis of breast cancer, and 11 000 died.1 Early breast cancer is traditionally treated with surgery, plus radiotherapy and adjuvant systemic therapy as required. Neoadjuvant chemotherapy for breast cancer is a new strategy that was introduced towards the end of the 20th century with the aim of reducing tumour size. It has four main rationales. Firstly, it should render an otherwise inoperable tumour operable or, secondly, allow more conservative surgery. Thirdly, starting systemic treatment preoperatively was hoped to lead to improved overall survival in patients with locally advanced cancers, who are at high risk of having distant disease. Finally, unlike adjuvant chemotherapy given in the absence of any measurable disease, neoadjuvant chemotherapy gives us the opportunity to observe the tumour shrink both palpably and on imaging, enabling a rapid assessment of clinical response. This could help test responses in vivo to new drug regimens, which could then be used as adjuvant therapies, in so called window of opportunity studies. A survey of multidisciplinary teams in Australia, Germany, Italy, the UK, and the US found that 7-27% of new breast cancers are treated with neoadjuvant chemotherapy (Saunders C, Cody H, Kolberg HC, et al, personal communication, 2017). With 1.7 million women receiving diagnoses annually, this translates into 120 000-460 000 women receiving neoadjuvant chemotherapy worldwide.1 Although data indicate that the first rationale remains valid, the others have not led to the desired outcomes. More conservative surgery after neoadjuvant chemotherapy can result in a higher rate of local recurrence, and, despite the earlier initiation of systemic treatment, no improvement in survival has been seen.234 Furthermore, neoadjuvant chemotherapy may not help test novel chemotherapies—although primary tumour response is a good indicator of prognosis for a particular treatment, it is counterintuitively a poor surrogate marker for the overall survival benefit when evaluating novel chemotherapy regimens. Finally, for 40-80% of patients, even the best neoadjuvant chemotherapy regimens extend the period the cancer remains in the breast and can make surgery more difficult, as the tumour is less easily palpable and the axillary lymph nodes are less distinct. We question the wisdom of the current widespread use of neoadjuvant chemotherapy

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

Principles of cancer treatment by radiotherapy

Radiotherapy (or radiation therapy) uses ionizing radiation to selectively kill cancer cells, especially for solid tumours. Like surgery, it is meant to be a ‘local’ treatment, although its beneficial systemic effects are being discovered. It is most commonly used in addition to surgery (adjuvant, e.g. breast), but its role in the neoadjuvant setting in combination with chemotherapy for some cancers (e.g. rectum) is also established. In early stages of cancer, it can be the definitive treatment, avoiding surgery and enabling organ preservation (e.g. larynx), while in late stages, it can provide excellent palliation (e.g. bone metastasis). Radiotherapy can be delivered at various energy levels (kiloVolts, megaVolts), with various subatomic particles (e.g. electrons, protons, and high-energy electromagnetic radiation). The traditional bulky equipment (e.g. linear accelerator) needs to be housed in an underground bunker and uses complex imaging to improve precision and avoid radiation to normal tissues. as well as Fractionated regimens spanning several days reduce individual doses. Modern techniques using mobile devices (e.g. TARGIT-IORT) can deliver radiotherapy during surgery with the highest precision and immediacy

Cosmesis and breast-related quality of life outcomes following intra-operative radiotherapy for early breast cancer - a sub-study of the TARGIT - a trial

Purpose: The international randomized TARGIT-A trial compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to 3-7 weeks of daily conventional external beam radiotherapy (EBRT) in women with early breast cancer treatable with breast conserving surgery. TARGIT-A showed TARGIT-IORT to be non-inferior compared to EBRT in terms of reducing the risk of local cancer recurrence and found no difference in breast cancer survival however its effect on patient reported cosmesis and breast-related quality of life (QOL) have not yet been described. Methods and Materials: Longitudinal cosmesis and QOL data were collected from a sub-set of TARGIT-A participants who received TARGIT-IORT as a separate procedure (post-pathology). Patients completed a cosmetic assessment before radiotherapy and annually thereafter for at least five years. Patients also completed the combined EORTC core questionnaire (QLQ-C30) and Breast Specific Module (BR23) in addition to the Body Image after Breast Cancer Questionnaire (BIABC) at baseline and annually thereafter. The combined EORTC questionnaires were also collected 3, 6, and 9 months after wide local excision (WLE). Results: An Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points. TARGIT-IORT patients reported better breast-related QOL than EBRT patients. Statistically and clinically significant differences were seen at month-6 and Year-1, with EBRT patients having moderately worse breast symptoms (a statistically significant difference of more than 10 in a 100 point scale) than TARGIT-IORT patients at these time points. Conclusion: Patients treated with TARGIT-IORT on the TARGIT-A trial have similar self-reported cosmetic outcome but better breast-related QOL outcomes than patients treated with EBRT. This important evidence can facilitate the treatment decision making process for patients who have early breast cancer suitable for breast conserving surgery and inform their clinicians

Global adoption of single-shot targeted intraoperative radiotherapy (TARGIT-IORT) for breast cancer – better for patients, better for health care systems

Introduction: TARGeted Intraoperative radioTherapy (TARGIT-IORT), developed in the late 1990s, delivers radiotherapy targeted to the fresh tumour bed exposed immediately after lumpectomy for breast cancer. Long-term results of the TARGIT-A trial found TARGIT-IORT during lumpectomy to be as effective as whole breast radiotherapy, and led to significantly fewer deaths from non-breast cancer causes. This paper documents its worldwide impact and provides interactive tools for clinicians and patients. / Method: Each centre provided the number of patients treated using TARGIT-IORT. These data were plotted on an interactive ‘My Google Map’. We also created an interactive web-based tool. Using the longterm outcomes from the TARGIT-A trial, we estimated the total savings in travel miles, time, carbon footprint, and the number of deaths from other causes that might be prevented. / Results: Data from 242 (93%) of the 260 centres treating patients from 35 countries were available. The first was treated in 1998 at University College London. As of early 2020, at least 44752 women with breast cancer have been treated with TARGIT-IORT. https://targit.org.uk/travel displays the Google-map of centres with number of cases and the interactive tool that enables patients to find the nearest centre offering TARGIT-IORT and their travel savings. Scaling the main benefits up to the already treated patients, >20 million miles of travel would have been saved, and about 2000 deaths prevented. / Discussion: One can ascertain the number of patients treated with a novel treatment. These data show how widely TARGIT-IORT has now been adopted and gives an indication of its beneficial worldwide impact on a large number of women with breast cancer