Intraoperative radiotherapy for breast cancer: powerful evidence to change practice

Abstract

article (Sasieni, P. D. & Sawyer, E. J. Intraope\xad rative radiotherapy for early breast cancer — insufficient evidence to change practice. Nat. Rev. Clin. Oncol. 17, 723–724 (2020))1 about the TARGIT\xad A trial contains several factual and logical errors. This article overlooks both the long\xad term positive findings2 and the all\xad important patient perspective. Risk\xad adapted single\xad dose targeted intra\xad operative radiotherapy during lumpectomy (TARGIT\xad IORT) is a method of partial breast irradiation (PBI) for early breast cancer. Most patients (80%) receiving TARGIT\xad IORT2 during their lumpectomy complete their local treatment entirely during this single session, under the same anaesthetic. Supplemental whole breast external beam radiotherapy (WBRT) is only recommen ded for a minority of patients (20%) if unexpec\xad ted prespecified tumour\xad related factors such as invasive lobular cancer and positive margins are found postoperatively. However, most patients with conventional ‘high risk’ features were treated without supplemental WBRT, including four\xad fifths of those with grade 3 or ER\xad negative disease, and two\xad thirds of node\xadpositive cases. By contrast, traditional WBRT or other PBI approaches require up to 30 additional hospital visits — TARGIT\xad IORT involves far fewer clinic appointments3. Other benefits include fewer toxicities, less pain, better cosmetic results and better quality of life2. The TARGIT\xad A randomized trial com\xad pared risk\xad adapted TARGIT\xad IORT with WBRT. The long\xad term results2 revealed no significant differences in local and distant control, breast preservation or breast cancer mortality. Local control was also compa\xad rable to that achieved with TARGIT\xad IORT alone2. A significant reduction in non\xad breast cancer mortality (from cardiovascular causes and other cancers) was also observed with TARGIT\xad IORT, from 9.85% to 4.41% at 12 years2. For patients, who sit on the more uncomfortable side of the consultation desk, these are most welcome results, particularly in the COVID\xad19 era. concept. Instead, they promote1 the intensive ‘Fast\xad Forward’ whole\xad breast\xad radiotherapy approach, which we argue represents over\xad treatment for the majority of patients and comes with well\xad known hazards: the most important adverse effects of an increased irradiated volume and the associated scattered irradiation are the substantially increased risks of cardiovascular4,5 and cancer\xad related mortality4,6, which are avoided by PBI techniques7 such as TARGIT\xad IORT2,8. Conversely, as expected with WBRT tech\xad niques, there is no mortality benefit with Fast\xad Forward. Fast\xad Forward also entails inev\xad itable post\xad operative delay plus 7–15 hospital visits (for consultation and planning followed by daily WBRT with or without boost). The authors criticize the TARGIT\xad A non\xad inferiority margin of 2.5%2 and surpris\xad ingly claim1 that no radiotherapy (as used in PRIME\xad II, Supplemental information) is non\xad inferior to WBRT. We argue that the data disprove this claim — the actual differ\xad ence in 5\xadyear local recurrence in PRIME\xad II was 2.9%, with an upper confidence interval of 4.8% — both well above the 2.5% margin2. The 2.5% non\xad inferiority margin used in TARGIT\xad A2 is one of the most stringent (in both absolute and relative terms) among trials involving PBI (Supplementary infor\xad mation). Nonetheless, the actual difference in 5\xad year local recurrence between the two treatment arms of TARGIT\xad A was just 1.16%. The Kaplan\xad Meier model, which we used2 to analyse local control, includes all relevant events9,10 in addition to time of occurrence and length of follow\xad up monitoring, for every patient. This is not the case for a chi\xad square test, which was employed by the authors1 to test for superiority, even though TARGIT\xad A was a non\xad inferiority trial — a very different concept: “Non\xad inferiority trials ... test new treatments that have obvious non\xad oncological advantages ... The non\xad inferiority statistical test ... is not meant to check for superiority, but to assess if the difference is within an acceptable margin and the experimental treatment is not meaningfully worse than the control”2. The protocol\xad specified non\xad inferior 5\xad year local recurrence associated with TARGIT\xad IORT was clearly confirmed in TARGIT\xad A. Many countries across the world have enthusiastically embraced TARGIT\xad IORT, with > 45,000 patients treated so far. TARGIT\xad IORT is now recommended in many inter\xad national guidelines. Patient choice, informed by clearly presented evidence, is now recog\xad nized as being much more important than clin ician preferences, a point powerfully under scored by the UK Supreme Court (Mont\xad gomery v Lanarkshire Health Board, 2015), The authors complain1 that TARGIT\xad IORT was not compared with ‘no radio\xad therapy’; however, we emphasize that the TARGIT\xad A cohort had a much higher pro\xad portion of high\xad risk patients than trials investi gating this approach (Supplementary information). In fact, more than three\xadquarters of patients (1,737 of 2,298) in TARGIT\xad A2 would not have fulfilled the low\xad risk criteria for inclusion in a trial of ‘no radiotherapy’ such as PRIME\xad II (inclusion criteria: age >65 years, tumour diameter ≤3 cm, grade 1 or 2, node\xad negative and ER positive). Despite this higher\xad risk cohort, local recurrence with TARGIT\xad IORT was 2–3 times lower than with ‘no radiotherapy’ in those trials (Supplementary information). Crucially, for a more inclusive population such as this, which is more representative of clinical practice, a ‘no radiotherapy’ arm would be unethical. We agree that “discriminating ... those who can safely avoid radio therapy altogether remains a fundamental challenge”1, therefore, patients should not be recommended ‘no radiotherapy necessary’ without first discussing options such as TARGIT\xad IORT. We emphasize that with TARGIT\xad IORT completed during lumpectomy, 80% of patients do not need postoperative radiotherapy2. The proportion of high\xad risk patients in the TARGIT\xad A cohort (PBI versus WBRT) is remarkably similar to that of the Fast\xad Forward cohort (shorter\xad course WBRT versus 3\xad week daily WBRT) (Supplementary information), which the authors recommend1. The 5\xad year local recurrence with 3\xad week WBRT in Fast\xad Forward and TARGIT\xad IORT was virtually identical at 2.1%. If the authors1 seriously question whether TARGIT\xad IORT is better than ‘no radiotherapy’1, should the same question not also apply to the Fast\xad Forward WBRT regimen? In any event, ‘no radio therapy’ is not considered the standard of care for such patients and therefore is not the correct comparator. The effectiveness of PBI approaches such as TARGIT\xad IORT has been repeatedly demonstrated (Supplementary information), yet the authors do not mention this important Intraoperative radiotherapy for breast cancer: powerful evidence to change practice