

REVIEW ARTICLE 

Year : 2015  Volume
: 11
 Issue : 2  Page : 259263 

Hypofractionated radiotherapy in carcinoma breast: What we have achieved?
Tapesh Bhattacharyya, Rohit Mahajan, Sushmita Ghoshal, Budhi Singh Yadav, Bhavana Rai
Department of Radiation Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Date of Web Publication  7Jul2015 
Correspondence Address: Tapesh Bhattacharyya Department of Radiation Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh India
Source of Support: None, Conflict of Interest: None  Check 
DOI: 10.4103/09731482.157342
Healthy breast tissue is sensitive to radiation fraction size, such that small changes in fraction size can lead to larger changes in radiation effects on these tissues. Conventional breast and/or chest wall irradiation uses 2 Gy daily fractions, for 56 weeks. Such a long treatment schedule has major implications on both patient quality of life and burden of radiotherapy (RT) departments. Some investigators have hypothesized that breast cancer is as sensitive as normal breast tissue to fraction size. According to the hypothesis, small fraction sizes of 2.0 Gy or less offer no therapeutic advantage, and a more effective strategy would be to deliver fewer, larger fractions that result in a lower total radiation dose. This short (hypofractionated) RT schedule would be more convenient for patients (especially those coming from remote areas to RT facilities) and for healthcare providers, as it would increase the turnover in RT departments. This thought has prompted us to write a systematic review on role of hypofractionated RT in breast cancer in a developing country like ours where patient burden is an alarming problem. Keywords: Ca Breast, hypofractionation, radiotherapy
How to cite this article: Bhattacharyya T, Mahajan R, Ghoshal S, Yadav BS, Rai B. Hypofractionated radiotherapy in carcinoma breast: What we have achieved?. J Can Res Ther 2015;11:25963 
> Introduction   
Radiotherapy (RT) is offered to nearly all patients of early breast cancer after breast conserving surgery (BCS) and to selected patients after modified radical mastectomy. In women with early breast cancer, RT after BCS reduces the risk of local relapse by about 70% and reduces absolute breast cancer mortality by 5.4%. ^{[1]} The conventional RT dose is 50 Gy in 5 weeks delivering 200 cGy daily and for 5 days a week. This schedule has evolved pragmatically, and is based on an assumption that a high total dose delivered in small fractions of 2 Gy keeps the amount of normal tissue damage to a minimum, while gaining the maximum level of tumor control. The effective dose of radiation has to be adjusted to balance the risk of local relapse against the normal tissue toxicity. Alternative schedules based on a lower total dose delivered in fewer, larger fractions (hypofractionation) were tried; and radiobiologic models suggest that a larger daily dose (hypofractionation) given over a shorter time (accelerated therapy) might be just as effective and may also be more convenient for patients and less resource intensive than the standard schedule. Hypofractionation schedules were introduced in UK and Canada on empirical basis and 40 Gy in 15 fractions over 3 weeks was the most commonly used regimen. Those trials suggested that different fractionation radiation schemes will lead to minimum outcome differences for patients with invasive early breast cancer.
> Radiobiological basis of hypofractionation   
The relationship between the radiation dose per fraction and biological effect is well established. Normal and malignant tissues vary in their responses to RT fraction size, termed fractionation sensitivity. The distinct fractionation sensitivities of early and late responding normal tissues are well described using a linearquadratic model in which an endpointspecific quantity, the alpha/beta (α/β) ratio, offers a reliable way of describing these differences. ^{[2],[3]}
The lower the ratio of α/β (in Gy), the greater is the effect on normal and malignant tissues of changes in fraction size. Healthy tissues of breast and rib cage are sensitive to fraction size with α/β values 5Gyor less, so small changes in fraction size can produce relatively large changes in effects of RT on these tissues. ^{[4]} This sensitivity is typical of socalled latereacting normal tissues that take months or years to develop atrophy or fibrosis after RT. Ellis proposed when a regimen is changed from 252.0 Gy fractions to a 15fraction regimen delivered over the same overall treatment time, the Ellis formula estimated a dose reduction from 50 to 45 Gy in 15 fractions of 3.0 Gy to match acute skin reactions, but later it was realized that dose reductions estimated using the Ellis formula were insufficient for matching late sideeffects. Late effects such as subcutaneous fibrosis and skin telangiectasia are more sensitive than acute reactions to altered fraction size. Assuming a typical α/β value of 3.0 Gy for late normal tissue responses, a 15fraction regimen reproducing the effects of 25 fractions of 2.0 Gy requires a reduction in total dose from 50 to 42.8 Gy in fractions of 2.85 Gy. The linearquadratic model predicts that the Ellis formula estimate of 45 Gy in 15 fractions is equivalent to 54 Gy in 2.0 Gy fractions, or to 56.3 Gy in the case of tissues like the brachial plexus with an assumed α/β value of 2.0 Gy. Thus, using the Ellis formula for estimating biologically is oeffective doses for late effects leads to an overdose of the tissues where these effects are doselimiting. ^{[5],[6],[7]}
> Effect of hypofractionation on disease control   
Over the last 20 years, multiple randomized trials involving a combined total of more than 7,000 women compared hypofractionated RT to a standard regimen of 50 Gy in 25 fractions [Table 1].  Table 1: Randomized clinical trials testing fraction size in adjuvant external beam radiotherapy
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In Royal Marsden Hospital/Gloucestershire Oncology Centre (RMH/GOC) trial ^{[8]} between 1986 and 1998;1,410 women with invasive breast cancer who had had local tumor excision of early stage breast cancer were assigned to receive adjuvant 50 Gy RT given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions, all given over 5 weeks. From Cox proportional hazard regression, they estimated α/β ratios for local recurrence as 4 Gy. At 10 years of followup, ipsilateral breast tumor relapse rate was 12.1% in 50 Gy arm, 14.8% in 39 Gy arm, and 9.6% in 42.9 Gy arm. The 3.3 Gy/fraction schedule with a total dose of 42.9 Gy gave the best local control both at 5 and 10 years.
In START A trial ^{[9]} between 1998 and 2002; 2,236 women with early breast cancer (pT13a, pN01, M0) at 17 centers in the UK were randomly assigned after primary surgery (BCS ormastectomy) to receive 50 Gy in 25 fractions of 2 Gy each versus 41.6 or 39 Gy in 13 fractions of 3.2 or 3.0 Gy, respectively, over 5 weeks. The fractionation sensitivity of breast cancer was quantified by aα/β ratio of 4.6 Gy in this trial. After a median followup of 5.1 years, locoregional relapse rate was 3.6% after 50 Gy, 3.5% after 41.6 Gy, and 5.2% after 39 Gy. 41.6 Gy in 13 fractions schedule was similar to the control regimen of 50 Gy in 25 fractions in terms of locoregional control. Those two trials suggested that a 13fraction regimen can be as effective as 50 Gy in 25 fractions.
Results from the Ontario ^{[10]} and START B ^{[11]} trials are consistent with this interpretation. The Ontario trial compared 42.5 Gy in 16 fractions of 2.66 Gy (3.2 weeks) with 50 Gy in 25 fractions over 5 weeks. The risk of local recurrence at 10 years was 6.7% among the women assigned to standard irradiation as compared with 6.2% among the women assigned to the hypofractionated regimen. In UK START B trial between 1999 and 2001; 2,215 women with early breast cancer at 23 centers 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 2.67Gy over 3 weeks. After a median followup of 6.0 years, the rate of locoregional tumor relapse at 5 years was 2.2% in 40 Gy group and 3.3% in 50 Gy representing an absolute difference of − 0.7% (95% confidence limit (CI)−1.7 to 0.9%), that is, the absolute difference in locoregional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy.
Although there were only 2.9% locoregional tumor relapses in START B at the time of reporting, the HR for this endpoint was 0.79 (95% CI, 0.481.29), indicating similar rates of locoregional relapse after 40 Gy in 15 fractions compared with 50 Gy in 25 fractions. The residual imprecision indicated by the upper and lower 95% CI limits for the absolute difference between 40 Gy in 15 fractions and the control schedule in START B suggests that locoregional tumor relapse is unlikely to be more than 1% higher, and perhaps 1 or 2% lower, than after 50 Gy in 25 fractions.
The 5year rate of distant relapse was lower in the 40 Gy arm (7.6%) as compared to 50 Gy arm (10.2%), which contributed to higher rates of diseasefree survival and overall survival in the 40 Gy arm. If we consider that the impact on survival and distant metastasis obtained by the radiation treatment is explained by the avoidance of dissemination of micrometastasis from locoregional tumor nests left after surgery, these results remain unexplained because there was no significant difference in local tumor control. Furthermore, we know that the beneficial effect of RT on mortality is generally assessed after 10 years of followup. Thus, to avoid highly speculative hypotheses, such as the assumption that a shorter treatment time, 3 weeks, would mainly benefit more aggressive local disease, we should accept that this result could be a falsenegative that might change with longer followup and more events. From all the three trials we observed an interesting finding that a moderate change in fraction size from 3 to 3.3 Gy might have a large impact on local control. However, when the fraction size was 3.2 Gy or lower, results for local control were no different from those for the conventional schedule.
> Effect of hypofractionation on normal tissues   
The late effects on healthy tissues and breast cosmesis are an important issue in hypofractionated schedules. In RMH/GOC trial, primary endpoint was late change in breast appearance compared to postsurgical appearance scored from annual photographs blinded to treatment allocation. Secondary endpoints included palpable breast induration (fibrosis) and ipsilateral tumor recurrence. After a minimum 5year followup, the risk of scoring any change in breast appearance after 50 Gy/25 fraction, 39 Gy/13 fraction, and 42.9 Gy/13 fraction was 39.6, 30.3, and 45.7%, respectively, from which an α/β value of 3.6 Gy (95% CI 1.85.4) is estimated. The α/β value for palpable breast induration was 3.1 Gy (95% CI 1.84.4). The 3.3 Gy/fraction schedule showed the worst cosmetic results. ^{[8]}
In START A trial, photographic and patient self assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an hazard ratio (HR) for late change in breast appearance of 0.69 (95% CI 0.520.91, P = 0.01). A lower total dose in a smaller number of fractions could offer similar rates of tumor control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions. ^{[9]}
In Ontario trial, rates of breast cosmesis at a median follow up of >11 years were virtually identical in both treatment arms; whereas, the UK START B trial recorded a lower rate of change in breast appearance after 40 Gy/15fractions regimen (hazard ratio (HR) = 0.83; 95% CI, 0.661.04; P = 0.06).
Yarnold et al., ^{[12]} in their review highlighted a very important observation from START B trial. An HR of <1 for late adverse effects is likely to be real, since 40 Gy in 15 fractions is equivalent to 45.5 Gy in 2.0 Gy fractions if α/β ratio = 3.0 Gy. In other words, 40 Gy in 15 fractions is gentler on late reacting normal tissues than 50 Gy in 25 fractions. The important question is whether it is also gentler on breast cancer. If the α/β value for tumor control is 10 Gy, tumor control should be inferior after such a large reduction in total dose (from 50 to 40 Gy), unless there is a major effect of shortening overall time, but tumor control does not appear to be worse.
All four clinical trials provided photographic assessment of breast appearance and reported palpable breast induration. The most common change in breast appearance is shrinkage (atrophy); but edema, retraction, and telangiectasia also contribute. Late induration after RT usually signifies underlying fibrosis, but fat necrosis and breast edema contribute to induration scores in the early years. Neither photographic appearance nor induration records damage to underlying pectoral muscle or rib cage.
Olivot to et al., ^{[13]} showed similar results and found that short fractionation produces acceptable cosmetic results for majority of the women. Shelley et al., ^{[14]} used hypofractionated regimen of 40 Gy in 16 fractions and reported that in response to the cosmesis questionnaire, 77% of patients stated they were either extremely or very satisfied with the overall appearance of the breast, 19.5% moderately satisfied, and 3.5% either slightly or not at all satisfied.
There were no cases of brachial plexopathy recorded in 40 Gy/15 fraction arm in START B trial at a median followup of 6 years. The regimen is equivalent to 47 Gy in 2.0 Gy fractions if the α/β value for brachial plexus is 2.0 Gy or to 49 Gy in 2.0 Gy fractions, if α/β=1.0 Gy. Galecki et al., ^{[15]} in a review of their article found that the use of doses per fraction in the range 2.24.58 Gy with the total doses between 43.5 and 60 Gy caused a significant increase of the risk of brachial plexus injury from 1.7 to 73%. The risk of radiationinduced brachial plexopathy was smaller than 1% after administration of doses per fraction between 2.2 and 2.5 Gy with the total dose between 34 and 40 Gy. When biologically effective dose was above 55 Gy, the risk of radiationinduced brachial plexopathy increased rapidly.
Data on late lung and cardiac morbidity and survival rates is yet to emerge for the current hypofractionation schedules. Even with conventional fractionation, the Early Breast Cancer Trialists' Collaborative Group ^{[1]} reported that radiation therapy reduced the annual mortality from breast cancer by 13%, but increased the annual mortality rate from other causes by 21%, and that this increase was primarily due to an excess number of deaths from cardiovascular causes. Hypofractionation has the potential of making these figures worse. Furthermore, the cardiac adverse effects may not emerge until 15 years after treatment, and persist well beyond this period.
> Exclusively PostMastectomy Hypofractionated RT Trials   
All the aforementioned studies had been conducted in the setting of earlystage breast cancer patients, postBCS. As far as literature regarding postmastectomy hypofractionated RT regimens is concerned, two prospective randomized trials have provided data analyzing different hypofractionated schedules postmastectomy.
Bates ^{[16]} provided the 10year results of a prospective trial of 411 patients treated by mastectomy and postmastectomy RT (PMRT) given in either 2 or 3 fractions per week (i.e., a comparison of 6 fractions in 18 days with 12 fractions in 28 days). The early radiation effects on the normal tissues were similar and acceptable. The late skin changes in the chest wall (treated with 70 kV Xrays) were progressive and by 10 years were slightly more marked with 6 fractions. Late subcutaneous fibrosis in the axilla (treated with cobalt60 teletherapy), however, was much less in the 6fraction group. Twelve fractions resulted in greater restriction of shoulder movements and an increased incidence of lymphedema of the arm. The dose used to treat the axilla in the 6 fractions was 35 Gy. In this trial, the 6fraction technique showed an advantage over the 12fraction technique. It was equally effective in controlling local recurrence and had fewer late sequelae. It was also convenient for patients and economic in the usage of RT facilities.
Shahid et al., ^{[17]} from Pakistan compared three hypofractionated protocols in PMRT in terms of local control, toxicity, and work load. A total of 300 patients of breast cancer (T2T4, N any) were randomized into three arms after mastectomy, 27 Gy in 5 fractions (1 week) Arm A, 35 Gy in 10 fractions (2 weeks) Arm B, and 40 Gy in 15 fractions (3 weeks) Arm C. The locoregional relapses were 11, 12, and 10% in arms A, B, C, respectively. G3 and G4 skin toxicities were 37, 28, and 14%. G2 and G3 lymphedema was 21, 22, and 27%, respectively. Cardiac toxicity was 5, 6, and 5%; while pulmonary toxicity was 4, 5, and 5%, respectively. All the differences except skin toxicity were statistically insignificant.
Acceleration and hypofractionation a complex issue
Another approach, which has recently come into picture and is being studied all over the world, is to deliver high dose per fraction by accelerated partial breast irradiation (APBI). APBI is an approach that treats only the lumpectomy bed plus a 12 cm margin, rather than the whole breast. By increasing the radiation fraction size and decreasing the target volume, this technique allows the treatment to be accomplished in a shorter period.
Current protocols for accelerated hypofractionation to partial breast, using threedimensional (3D) conformal RT, include twice daily fractions separated by 6 h. Whatever the schedule, a twicedaily schedule will have a greater biological effect due to incomplete recovery. In the National Surgical Adjuvant Breast and Bowel Project B39 trial, ^{[18]} 38.5 Gy in 10 fractions delivered by external beam conformal RT in twicedaily fractions, MondayFriday of a single week, delivers the equivalent of 53 Gy in 2.0 Gy fractions, assuming complete repair and an α/β value of 3.4 Gy. If the recovery halftime for late effects is taken as 4.4 h estimated for subcutaneous fibrosis in the continuous hyperfractionated accelerated RT head and neck trial, the twicedaily schedule delivers the equivalent of 65 Gy in 2 Gy fractions. The satisfactory interim cosmetic results reported with this schedule suggest a significant volume effect in sparing late adverse effects.
Volume effect and hypofractionation
For a certain endpoint, the effect of same prescribed dose to different volumes of breast tissue has been tested. The volume effect varies according to the endpoint chosen. Though we do not have direct evidences; indirect measures of volume's effect for breast induration can be gained from few retrospective and prospective randomized trials. A study by Borger et al., ^{[19]} revealed low dose rate (LDR) iridium implantation given as boost after BCS followed by whole breast radiation was associated with fourfold increased risk of breast induration for each 100 cm ^{3} incrementin boost volume, suggesting a very steep volume response. On the contrary, European Organisation for Research and Treatment of Cancer (EORTC) study ^{[20]} of electron boost showed a shallower volume response. RMH/GOC fractionation trial ^{[8]} randomized 723 patients after wholebreast RT in to those who would not receive a tumor bed boost versus those who would receive a boost dose of 15.5 Gy (100%) in seven fractions via a direct electron field, typically 710 cm diameter and 812 MeVenergy. In this trial, 27.5% of patients randomized to the noboost group developed moderate or marked induration at 10 years compared to 44.5% of those randomized to receive boost therapy.
The scope for exploiting the dose volume effect in dose escalation is undergoing testing in UK IMPORT HIGH trial. ^{[21]} This trial is comparing sequential versus simultaneous integrated boost delivered to a standardized target volume. The results of the trial will be integrated with the results of the current phase 3 FASTForward trial, ^{[22]} testing a curative schedule of adjuvant RT delivered to whole breast/chest wall in 5 fractions over 1 week.
Current endeavors
The current endeavors include the FAST trial which compares two doses (5.7 and 6.0 Gy) in 5 fractions over 5 weeks with a control dose of 50 Gy in 25 fractions. Assuming α/β =4.0 Gy, the dose levels are equivalent to 46 and 50 Gy in 2.0 Gy fractions, respectively. An interim analysis of moderate/marked breast shrinkage (photographic assessment) generated aα/β of 2.4 Gy (95% CI, 1.03.9); consistent with estimates generated by the STARTA trial. A schedule of 30 Gy in 5 fractions over 15 days to the whole breast using 3D dosimetry reported very mild acute reactions and satisfactory 2year outcome in terms of change in breast appearance and induration compared to a matched sample of patients treated to 50 Gy in 25 fractions. This schedule is too intense to form the basis of a 5day schedule, given current estimates of α/β values derived from the FAST and START trials, but a 5day course of wholebreast RT that delivers 1 fraction per day can certainly be identified that is equivalent to standard fractionation in terms of late adverse effects in the breast (but not the lymphatic pathways). If the α/β value for late adverse effects is between 2 and 3 Gy and that for tumor control is between 4 and 5 Gy, a small loss of therapeutic gain might be compensated for by a time factor for tumor control when treatment times are compressed from 5 to 1 week.
To summarize, hypofractionation in breast cancer is an issue that can have widespread implications in breast cancer throughout the world. If found to have equivalent cosmesis, locoregional control, and survival to standard doses and schedules; it would be a revolutionary breakthrough for the future for breast cancer. Unfortunately, the demonstration of all of these would need followup data nearing 15 years. For now, the general acceptance of hypofractionation in breast cancer hangs in the balance. If hypofractionation works, it will be a major breakthrough as it will reduce the number of hospital visits and also the waiting list in several cancer centers in developing countries where patient burden is an alarming problem.
> References   
1.  Clarke M, Collins R, Darby S. For the Early Breast Cancer Trialists′ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15year survival: An overview of the randomized trials. Lancet 2005;366:2087106. 
2.  Withers HR, Thames HD Jr, Peters LJ. A new isoeffect curve for change in dose per fraction. Radiother Oncol 1983;1:18791. 
3.  Fowler JF. The linearquadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:67994. 
4.  Bentzen SM, Saunders MI, Dische S. Repair halftimes estimated from observations of treatmentrelated morbidity after CHART or conventional radiotherapy in head and neck cancer. Radiother Oncol 1999;53:21926. 
5.  Singh K. Two regimes with the same TDF but differing morbidity used in the treatment of stage III carcinoma of the cervix. Br J Radiol 1978;51:35762. 
6.  Thames HD Jr, Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: Implications for dosesurvival relationships. Int J Radiat Oncol Biol Phys 1982;8:21926. 
7.  Fowler JF. Review: Total doses in fractionated radiotherapyimplications of new radiobiological data. Int J Radiat Biol Relat Stud Phys Chem Med 1984;46:10320. 
8.  Owen JR, Ashton A, Bliss JM, Homewood J, Harper C, Hanson J, et al. Effect of radiotherapy fraction size on tumor control in patients with earlystage breast cancer after local tumor excision: Longterm results of a randomised trial. Lancet Oncol 2006;7:46771. 
9.  Bentzen SM, Agrawal RK, Aird EG, Barrett JM, BarrettLee PJ, Bliss JM, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomized trial. Lancet Oncol 2008;9:33141. 
10.  Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Longterm results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362:51320. 
11.  Bentzen SM, Agrawal RK, Aird EG, Barrett JM, BarrettLee PJ, Bentzen SM, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomized trial. Lancet 2008;371:1098107. 
12.  Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: Long term results of a randomised trial. Radiother Oncol 2005;75:917. 
13.  Olivotto IA, Weir LM, KimSing C, Bajdik CD, Trevisan CH, Doll CM, et al. Late cosmetic results of short fractionation for breast conservation. Radiother Oncol 1996;41:713. 
14.  Shelley W, Brundage M, Hayter C, Paszat L, Zhou S, Mackillop W. A shorter fractionation schedule for postlumpectomy breast cancer patients. Int J Radiat Oncol Biol Phys 2000;47:121928. 
15.  Galecki J, HicerGrzenkowicz J, GrudzienKowalska M, Michalska T, Za³ucki W. Radiationinduced brachial plexopathy and hypofractionated regimens in adjuvant irradiation of patients with breast cancer A review. Acta Oncol 2006;45:2804. 
16.  Bates TD. The 10year results of a prospective trial of postoperative radiotherapy delivered in 3 fractions per week versus 2 fractions per week in breast carcinoma. Br J Radiol 1988;61:62530. 
17.  Shahid A, Athar MA, Asghar S, Zubairi T, Murad S, Yunas N. Post mastectomy adjuvant radiotherapy in breast cancer: A comparision of three hypofractionated protocols. J Pak Med Assoc 2009;59:2827. 
18.  Radiation Therapy Oncology Group. National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B39. RTOG protocol 0413. A randomized phase III study of conventional wholebreast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. Available from: http://www.rtog.org. March 13, 2007 [Last accessed on 2014 Sep 10]. 
19.  Borger JH, Kemperman H, Smitt HS, Hart A, van Dongen J, Lebesque J, et al. Dose and volume effects on fibrosis after breast conservation therapy. Int J Radiat Oncol Biol Phys 1994;30:107381. 
20.  Vrieling C, Collette L, Fourquet A, Hoogenraad WJ, Horiot JH, Jager JJ, et al. The influence of patient, tumor and treatment factors on the cosmetic results after breastconserving therapy in the EORTC ′′boost vs. no boost′′ trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. Radiother Oncol 2000;55:21932. 
21.  Coles C, Yarnold J. IMPORT Trials Management Group. The IMPORT trials are launched (September 2006). Clin Oncol (R Coll Radiol) 2006;18:58790. 
22.  Brunt AM, Sydenham M, Bliss J, Coles C, Gothard M, Harnett A, et al. A 5fraction regimen of adjuvant radiotherapy for women with early breast cancer: First analysis of the randomised UK FAST trial (ISRCTN62488883, CRUKE/04/015). Eur J Cancer 2009;7 (Suppl):2. 
[Table 1]
