Hypofractionated Radiotherapy Was Safe, Effective for Early Breast Cancer Treatment at 10-year Follow-up

This abstract will be presented at a press conference hosted by Carlos L. Arteaga, M.D. associate director for clinical research and director of the Breast Cancer Program at Vanderbilt Ingram Cancer Center, on Thursday, Dec. 6 at 7:30 a.m. CT in Room 217 A-C of the Henry B. Gonzales Convention Center. Reporters who cannot attend in person can call in using the following information:• U.S./Canada (toll free): 1 (800) 446-2782• International (toll call): 1 (847) 413-3235

Newswise — SAN ANTONIO — Appropriately dosed hypofractionated radiotherapy was gentle on healthy tissues and effective in controlling local-regional early breast cancer, according to 10-year follow-up results from the U.K. Standardization of Breast Radiotherapy Trials (START), presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8.

“Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard five-week schedules of curative radiotherapy in women with early breast cancer,” said John Yarnold, M.B.B.S., professor of clinical oncology at The Institute of Cancer Research in London and honorary consultant at The Royal Marsden NHS Foundation Trust.

Between 1999 and 2002, 4,451 women with completely excised invasive breast cancer were recruited to either the START A or START B randomized controlled trials. In START A, researchers compared 50 Gy of postsurgery radiotherapy given in 25 fractions for five weeks versus 41.6 Gy or 39 Gy in 13 fractions for five weeks. In START B, they compared 50 Gy in 25 fractions for five weeks versus 40 Gy in 15 fractions for three weeks.

Data revealed 139 local-regional tumor relapses among the 2,236 women in START A who were followed for an average of 9.3 years and 95 local-regional relapses in the 2,215 women in START B, followed for an average of 9.9 years.

The 10-year local-regional relapse rates for START A were 7.4 percent after 50 Gy, 6.3 percent after 41.6 Gy and 8.8 percent after 39 Gy. In previously published data from START B, the 10-year local-regional relapse rate was 5.5 percent after 50 Gy and 4.3 percent after 40 Gy.

“These long-term data from the START A trial confirm the findings of our earlier results that breast cancer is, on average, as sensitive to the radiation dose of each fraction as the dose-limiting normal tissues of the breast area and that this effect persists for at least 10 years,” Yarnold said.

However, a five-week, 13-fraction schedule does not offer shortened overall treatment times. “Hence, we also designed the START B trial, a pragmatic comparison of three-week and standard five-week schedules, testing for noninferiority,” said Yarnold. “The 15-fraction schedule is definitely gentler on the healthy tissues, and these long-term data confirm our earlier findings that it appears noninferior in terms of tumor control — a very favorable result.”

The three-week, 15-fraction schedule is now the standard of care in the United Kingdom and is becoming increasingly more common in other countries, according to Yarnold. Future research is focused on the molecular mechanisms that determine fraction size sensitivity, which may lead to individualization of fraction size.

“It is likely that some breast cancers are more or less sensitive than others,” Yarnold said. “We are also testing a one-week schedule of whole breast radiotherapy against our new three-week standard in the U.K. FAST-Forward Trial.”

The START trials were funded by Cancer Research U.K., the U.K. Medical Research Council and the U.K. Department of Health.

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The mission of the 2012 CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit www.sabcs.org.

Abstract:Publication Number: S4-1

Title: The UK START (Standardisation of Breast Radiotherapy) Trials: 10-year follow-up results

Joanne S Haviland1, Rajiv Agrawal2, Edwin Aird3, Jane Barrett4, Peter Barrett-Lee5, Jackie Brown6, John Dewar7, Jane Dobbs8, Penelope Hopwood1, Peter Hoskin3, Pat Lawton9, Brian Magee10, Judith Mills1, David Morgan11, Roger Owen12, Sandra Simmons1, Mark Sydenham1, Karen Venables3, Judith M Bliss1, John R Yarnold13 and On Behalf of the START Trialists14. 1Clinical Trials & Statistics Unit, The Institute of Cancer Research, Sutton, United Kingdom; 2Shrewsbury and Telford Hospital NHS Trust, United Kingdom; 3Mount Vernon Hospital, Northwood, United Kingdom; 4Royal Berkshire NHS Foundation Trust, Reading, United Kingdom; 5Velindre Hospital NHS Trust, Cardiff, United Kingdom; 6previously University of Bristol, now Eli Lilly & Company, United Kingdom; 7Formerly Ninewells Hospital, Dundee, United Kingdom; 8Formerly Guys and St Thomas' NHS Trust, London, United Kingdom; 9Nottingham City Hospital, United Kingdom; 10Formerly The Christie NHS Foundation Trust, Manchester, United Kingdom; 11Formerly Nottingham University Hospital NHS Trust, United Kingdom; 12Formerly Cheltenham General Hospital, United Kingdom and 13The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.

Body: Background: International standard adjuvant radiotherapy regimens following primary surgery for early breast cancer have historically delivered a high total dose (50Gy) in 25 small daily doses (fractions) over 5 weeks, however randomised trials, including START, indicate that a lower total dose delivered in fewer, larger fractions (Fr) is likely to be at least as safe and effective (START Trialists' Group, Lancet 2008 & Lancet Oncol 2008). With patients remaining at risk of local relapse for many years, information on long-term outcomes is needed to provide confidence in clinical practice. Here, we report 10-year follow-up of the UK START Trials testing 13- and 15-Fr regimens in terms of local cancer control and late adverse effects.

Methods: Between 1999 and 2002, 4451 women with completely excised invasive breast cancer (T1-3, N0-1, M0) were randomised after primary surgery to comparisons of 50Gy in 25Fr over 5 weeks vs 41•6Gy or 39Gy in 13Fr over 5 weeks (START A), or 50Gy in 25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks (START B). Women were eligible if aged over 18 years and did not have an immediate surgical reconstruction. Protocol-specified principal endpoints were local-regional (LR) tumour relapse and late normal tissue effects. Analysis was by intention to treat.

Findings: Median follow-up in survivors is now 9.3 years in START A and 9.9 years in START B, with 139 LR relapses in START A and 95 in START B. In START A, the 10-year rate of LR relapse was 7.4% (95%CI 5.5-10.0) after 50Gy, 6.3% (95%CI 4.7-8.5) after 41•6Gy and 8.8% (95%CI 6.7-11.4) after 39Gy. In START B, the 10-year rate of LR relapse was 5.5% (95%CI 4.2-7.2) after 50Gy and 4.3% (95%CI 3.2-5.9) after 40Gy. Clinician assessments suggested lower 10-year rates of any moderate/marked late normal tissue effects after 39Gy (43.9%; 95%CI 39.3-48.7) and similar rates after 41.6Gy (49.5%; 95%CI 44.9-54.3) compared with 50Gy (50.4%; 95%CI 45.8-55.3) in START A and lower rates after 40Gy in START B (37.9%; 95%CI 34.5-41.5) compared with 50Gy (45.3%; 95%CI 41.7-49.0). From a planned meta-analysis of START A and the START pilot trial (Owen et al, Lancet Oncol 2006), the adjusted estimate of /value for tumour control was 3.5Gy (95% CI 1.2-5.7) and for late change in photographic breast appearance was 3.1Gy (95% CI 2.0-4.2).

Interpretation: Long-term follow-up confirms that breast cancer and the surrounding dose-limiting healthy tissues respond similarly to radiotherapy fraction size and thus that appropriately-dosed hypofractionated radiotherapy is safe and effective in treatment of patients with early breast cancer. 41•6Gy in 13Fr and 40Gy in 15Fr each appear comparable to 50Gy in 25Fr in terms of local-regional tumour control and late normal tissue effects. These results support the continued use of 40Gy in 15Fr as standard of care (UK NICE Guidance 2009) for women requiring adjuvant radiotherapy for early breast cancer.