Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

Hughes, Kevin S.; Schnaper, Lauren; Bellon, Jennifer R.; Cirrincione, Constance; Berry, Donald A.; McCormick, Beryl; Muss, Hyman B.; Smith, Barbara L.; Hudis, Clifford A.; Winer, Eric P.; Wood, William C.

doi:10.1200/jco.2012.45.2615

Cited by 1,033 publications

(746 citation statements)

References 23 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: 99%

“…For example, the only other trial of IORT -the ELIOT trial 35 -was set up with the assumption that a difference of 7.5% in local recurrence between the experimental and the control groups would result in the two treatments being considered as equivalent. The Cancer and Leukemia Group B (CALGB) study 11 found that there was a 7% difference in local recurrence when radiotherapy was omitted in low-risk (T1N0) patients aged > 70 years and concluded that this difference was not significant. Furthermore, two patient preference studies conducted in parallel with the main trial have also corroborated that, given the convenience of a single treatment session, the median increase in local recurrence that patients would be ready to accept is 2.5%.…”

Section: Non-inferiority For Local Recurrencementioning

confidence: 99%

“…Although the complete omission of radiotherapy increases the risk of local recurrence, [8][9][10][11] the necessity of delivering radiation to the entire breast has been challenged. [12][13][14] In total, 90% of early breast recurrences occur at the site of the original primary tumour, regardless of margin involvement or adjuvant radiotherapy.…”

Section: Introductionmentioning

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: 99%

Section: Non-inferiority For Local Recurrencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

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“…The loco-regional recurrence rate in CALGB 9343 trial was 1% in irradiated (RT+) and 4% in non-irradiated patients (RT-) at 5 years, p=0.001 [16] and the difference had increased (2% RT+, 9% RT-) at a median follow-up of 10.5 years [17].…”

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

confidence: 99%

“…Results showed a very low axillary recurrence rate at a median follow-up of 12.6 years -none in those who underwent ALND and in those who did not undergo ALND but received tamoxifen plus WBRT, but 3% in those on tamoxifen alone [17].…”

mentioning

confidence: 98%

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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Screening Mammography in Older Women

Walter

Schonberg

2014

JAMA

206

231

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Importance Guidelines recommend individualizing screening mammography decisions for women 75 and older. However, little pragmatic guidance is available to inform this approach. Objective To provide an evidence-based approach to individualizing decision-making about screening mammography that considers older women's risk of breast cancer and the potential benefits and harms of screening in the context of varying life expectancies and preferences. Evidence Acquisition We searched PubMed for English-language studies in peer-reviewed journals published from January 1, 1990 to February 1, 2014 to identify risk factors for late-life breast cancer in women 65 and older and to quantify the benefits and harms of screening mammography for women 75 and older. Findings Age is the major risk factor for late-life breast cancer. In general, traditional breast cancer risk factors (e.g., age at first birth, age at menarche) that represent hormonal exposures in the distant past are less predictive of late-life breast cancer than factors indicating recent exposure to endogenous hormones (e.g., bone mass, obesity). None of the randomized trials of screening mammography included women over age 74, such that it is uncertain whether screening mammography is beneficial in these women. Observational data favor extending screening mammography to older women who have a life expectancy > 5-10 years. Modeling studies suggest approximately 2 fewer women per 1,000 die from breast cancer if women in their 70's continue biennial screening for 10 years, versus stopping screening at age 69. Potential benefits must be weighed with potential harms of continued screening over ten years, which include false-positive mammograms (~200 per 1,000 women screened) and overdiagnosis (~13 per 1,000 women screened). Providing these frequencies both verbally and graphically may help inform older women's decision-making. Conclusions and Relevance For women with less than a 5-10 year life expectancy, recommendations to stop screening mammography should be framed around increased harms and the need to refocus health promotion on interventions likely to be beneficial over a shorter timeframe. For women with a life expectancy > 5-10 years, the decision about whether potential benefits of screening outweigh harms is a value judgment that requires a realistic understanding of screening outcomes.

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Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

Cited by 1,033 publications

References 23 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

Screening Mammography in Older Women

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