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)

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

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

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

Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy

Kolberg and colleagues have recently published a series of papers [1,2,3] that, for the first time, give some idea of the outcomes of targeted intraoperative radiotherapy (TARGIT IORT) as a tumour bed boost during lumpectomy after neoadjuvant chemotherapy (NACT). The last of these series is published in the current issue of BREAST CARE. We would like to discuss these from two perspectives - NACT and TARGIT IORT