Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial

Kunkler, Ian; Williams, Linda; Jack, W; Cameron, David; Dixon, JM

doi:10.1016/s1470-2045(14)71221-5

Cited by 773 publications

(552 citation statements)

References 28 publications

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“…101,103,104 It is much smaller than the 7.5% margin in the ELIOT trial 105 and lower than the difference considered 'acceptable' by the CALGB (5% difference) 11 and Post-operative Radiotherapy In Minimum-risk Elderly (PRIME) II (3% difference) 106 studies. At this boundary, TARGIT was non-inferior to EBRT (P non-inferiority < 0.00001).…”

Section: Non-inferiority For Local Recurrencementioning

confidence: 88%

“…one in every 11, vs. just 2% with radiotherapy). In a more recently reported PRIME II trial 106 with super-selected patients with an extremely good prognosis (much better than that of the TARGIT-A trial patients), there was a statistically significant reduction in disease-free survival when radiotherapy was omitted and local recurrence without radiotherapy was 4.1%. Even in these highly selected good-prognosis patients, the subgroup of patients who were ER positive had a local recurrence rate of 3.2% without compared with 0.8% with radiotherapy, which is relatively much higher than that achieved by TARGIT during lumpectomy in ER-positive, PgR-positive cancers (1.4% with TARGIT vs. 1.2% with EBRT).…”

Section: Risk-adapted Approachmentioning

confidence: 92%

“…Other studies testing the benefits of EBRT over no radiotherapy have enrolled patients whose tumour characteristics were far better than those in the TARGIT arm who did not receive EBRT have found that entirely omitting radiotherapy results in a significantly higher recurrence rate. 11,106,129 Additionally, as the postpathology stratum usually did not need additional EBRT, as this stratum was randomised after lumpectomy and pathology, these patients provided an internal control. As seen in Table 11, the tumour characteristics in this postpathology stratum were much better than those in the prepathology TARGIT arm who did not receive EBRT, but recurrence was much higher, again indicating that TARGIT, delivered at the correct time, is particularly good at avoiding local recurrence.…”

Section: Risk-adapted Approachmentioning

confidence: 99%

“…As can be seen clearly in the table, one in every 17-25 of even the most stringently selected low-risk patients would have a local recurrence if radiotherapy were omitted. 11,106,129 On the other hand, when TARGIT is given during lumpectomy local recurrence is rare -one in 48, which reduces to one in 71 when just a single selection criterion (ER positive) is applied. 5.…”

Section: Further Analysis As Requested By the National Institute Formentioning

confidence: 99%

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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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Section: Non-inferiority For Local Recurrencementioning

confidence: 88%

Section: Risk-adapted Approachmentioning

confidence: 92%

Section: Risk-adapted Approachmentioning

confidence: 99%

Section: Further Analysis As Requested By the National Institute Formentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…The PRIME 2 trial [20] randomized 1326 women ≥65 years with T1, T2 (≤3cm), pN0 tumours to 5-year adjuvant endocrine therapy (ET) ±WBRT. There was a modest but statistically significant reduction in local recurrence at 5 years from RT (4.1% vs. 1.3%, p=0.0002), and as in the CALGB 9343 trial, there was no compromise in OS.…”

Section: Role Of Radiotherapy (Rt) After Breast Conservative Surgmentioning

confidence: 99%

Controversial issues in the management of older adults with early breast cancer

Mislang

Cheung

Hamaker

et al. 2017

Journal of Geriatric Oncology

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It is well recognized that the incidence of breast cancer increases significantly with age.Despite this, older people remain under-represented in many clinical trials and their management relies on extrapolation of data from younger patients. Providing an aggressive intervention can be challenging, particularly in less fit older patients where a conservative approach is commonly perceived to be more appropriate. The optimal management of this population is unknown and treatment decision should be personalized. This review article will discuss several controversial issues in managing older adults with early breast cancer in a multidisciplinary setting, including the role of surgical treatment of the axilla in clinically node negative disease, radiotherapy after breast conservation surgery in low-risk tumors, personalizing adjuvant systemic therapy, and geriatric assessments in breast cancer treatment decisions.

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Breast Cancer Treatment

Waks

Winer

2019

JAMA

3,481

2,554

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orldwide, breast cancer is the most common cancer in women, other than nonmelanoma skin cancer. 1 More than 250 000 new cases of breast cancer were diagnosed in the United States in 2017, and breast cancer will be diagnosed in 12% of all women in the United States over their lifetimes. 2 This review summarizes evidence-based approaches to the systemic and local treatment of the 3 major breast cancer subtypes: hormone receptor positive/ERBB2 negative (HR+/ERBB2−), ERBB2 positive (ERBB2+), and triple-negative. MethodsWe searched PubMed for English-language articles related to the treatment of breast cancer, with a focus on large randomized clini-cal trials or meta-analyses and guidelines of major professional societies. The indices of major medical and oncology journals were comprehensively reviewed for articles published from January 1, 2013, to November 11, 2018, on the topic of breast cancer treatment. Articles agreed on by both authors to define modern practice were included, with priority given to prospective randomized trials and large meta-analyses that represent the first and/or the most important evidence establishing current standard of care in breast cancer. Clinical PresentationIn the modern era of widespread screening mammography, more than half of breast cancers in the United States are diagnosed on screening mammogram, and approximately one-third IMPORTANCE Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer.OBSERVATIONS Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerly HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer-specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor-positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performe...

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Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial

Cited by 773 publications

References 28 publications

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)

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)

Controversial issues in the management of older adults with early breast cancer

Breast Cancer Treatment

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