SummaryBackgroundThe international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size.MethodsBetween 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy versus 41·6 Gy or 39 Gy in 13 fractions of 3·2 Gy or 3·0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.Findings749 women were assigned to the 50 Gy group, 750 to the 41·6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5·1 years (IQR 4·4–6·0) the rate of local-regional tumour relapse at 5 years was 3·6% (95% CI 2·2–5·1) after 50 Gy, 3·5% (95% CI 2·1–4·3) after 41·6 Gy, and 5·2% (95% CI 3·5–6·9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0·2% (95% CI −1·3% to 2·6%) after 41·6 Gy and 0·9% (95% CI −0·8% to 3·7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0·69 (95% CI 0·52–0·91, p=0·01). From a planned meta-analysis with the pilot trial, the adjusted estimates of α/β value for tumour control was 4·6 Gy (95% CI 1·1–8·1) and for late change in breast appearance (photographic) was 3·4 Gy (95% CI 2·3–4·5).InterpretationThe data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41·6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

SummaryBackgroundThe international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2·0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2·0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy.MethodsBetween 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779.Findings1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy.InterpretationA radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

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The architecture of the desert rodent Psammomys obesus has been studied by means of standard histologic procedures and by single nephron injections. As other rodent kidneys (rat, mouse), the Psammomys kidney consists of two types of nephrons, 66% short looped and 34% long looped nephrons. The cortex is composed of 4 to 5 layers of glomeruli, which lie closely put together, the glomeruli often touch each other. The superficial and the midcortical glomeruli give rise to short looped neophrons, the juxtamedullary to long looped nephrons. In the strongly developed medulla the inner stripe shows the most striking pattern. It consists of two distinct compartments, that of the giant vascular bundles and that of the interbundle regions. The giant vascular bundles consist of about 8 to 14% arterial vasa recta and 39 to 47% venous vasa recta; furthermore they include the thin descending limbs of the short loops of Henle which amount to 44 to 51% of the bundle structures. The tubules of the interbundle regions surround the bundles in a regular pattern. The inner zone is almost completely surrounded by the renal pelvis; the long broad papilla protrudes into the ureter. The thin descending limbs of short looped nephrons traverse the inner stripe inside the giant vascular bundles. Leaving the bundles they turn back within the inner stripe; their ascending limbs lie in the interbundle region. Both limbs of the long loops of Henle run in the interbundle region, together with the ascending limbs of the short loops and the collecting ducts. The long loops penetrate deeply the inner zone. Many bends are found near the tip of the papilla. The renal pelvis has a very specialized form. It penetrates the inner stripe with many complexely shaped extensions, which surround the giant vascular bundles. Large parts of the bundles with their thin walled structures are thus separated from the pelvic urine only by a single layer of cuboidal epithelium. The possible functional importance of the described specializations of the Psammomys kidney (giant vascular bundles, large inner zone, special shape of the renal pelvis) for the urine concentrating and urea recyclng mechanisms is discussed.