- Email: [email protected]
Dose and fractionation regimens for breast cancer
Reflection and Reaction
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Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328: 1581–86. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. Lancet 2000; 355: 528–33. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 2003; 362: 95–102. Solin LJ, Fourquet A, Vicini FA, et al. Salvage treatment for local or local-regional recurrence after initial breast conservation treatment with radiation for ductal carcinoma in situ. Eur J Cancer 2005; 41: 1715–23. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 2001; 28: 400–18.
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Allred D, Bryant J, Land S, et al. Estrogen receptor expression as a predictive marker of effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP B-24. Breast Cancer Res Treat 2002; 76 (suppl 1): 180 (abstr S29). Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: 1378–87. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997; 15: 963–68. Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network. Lancet Oncol 2006; 7: 652–56.
Dose and fractionation regimens for breast cancer Some aspects about a recent Article by Owen and colleagues1 merit attention. Although hypofractionation was used for breast radiotherapy in two of the three trial groups, boost doses were given by use of conventional fractionation (14 Gy in seven fractions of 2 Gy). This use of fractionation seems go against the hypothesis proposed in the Article, which postulates that use of higher radiotherapy doses per fraction is better than or at least equal to conventional fractionation. In breastcancer radiotherapy, the field size of a boost dose is usually reduced, and therefore hypofractionated regimens are used even after standard fractionated radiotherapy of the whole breast.2 Furthermore, why a quarter of patients were not given boost in the trial by Owen and co-workers is unclear. Data for late lung and cardiac morbidity and survival is yet to emerge for the current hypofractionation schedules. Even with conventional fractionation, the Early Breast Cancer Trialists’ Collaborative Group3 reported that yearly mortality from breast cancer fell by 13% after radiotherapy but increased by 21% from other causes (mainly because of an excess number of deaths from cardiovascular events). Furthermore, the data for long-term cardiac side-effects might not emerge for another 15 years and could remain unconfirmed beyond this period.3 Therefore, caution is recommended for leftsided tumours, before schedules with high doses per fraction are implemented. Finally, breast radiotherapy cannot be regarded as an isolated treatment of the breast. It affects a wide range of tissues that include the skin, subcutaneous tissue, fibroglandular tissue, pectoralis muscles, and ribs. http://oncology.thelancet.com Vol 7 August 2006
Every tissue type has a unique α/β ratio and radiation sensitivity profile.4 Tissues with a lower α/β ratio would be more sensitive to radiotherapy than other tissues. The tissue with lowest ratio, especially if it has a substantially large volume, would probably determine the critical fraction size that could be used. Anusheel Munshi Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai 400012, India [email protected] I declare no conflicts of interest. 1
2
3
4
Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006; 7: 467–71. Touboul E, Belkacemi Y, Lefranc JP, et al. Early breast cancer: influence of type of boost (electrons vs iridium-192) on local control and cosmesis after conservative surgery and radiation therapy. Radiother Oncol 1995; 34: 105–13. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757–70. Thames HD, Bentzen SM, Turesson I, et al. Time–dose factors in radiotherapy: a review of the human data. Radiother Oncol 1990; 19: 219–35.
In a randomised trial1 comparing the international standard of 50 Gy (25 fractions of 2 Gy) with 39 Gy (13 fractions of 3 Gy) or 42·9 Gy (13 fractions of 3·3 Gy) over 5 weeks, Owen and colleagues report reduced risks of local recurrence in women given breastconserving surgery and fewer, larger fractions of postoperative radiotherapy. The results were heralded by some sections of the press, stating that regimens with shorter, higher doses per fraction were more convenient for patients and were less demanding on 617
Astrid & Hanns-Frieder Michler/Science Photo Library
Reflection and Reaction
Use of fewer and higher doses of radiotherapy might affect rib morbidity
limited radiotherapy resources than were conventional regimens. However, the study needs to be interpreted with caution. First, no table was presented to show the distribution of clinical and pathological risk factors in the three fractionation groups of the trial population. Although these factors were probably balanced by randomisation, the completeness of data was needed for factors that affect prognosis, such as age, tumour size, grade, lymphovascular invasion, oestrogen-receptor status, and nodal status. Second, Owen and co-workers subrandomised the trial population further: 364 patients were assigned to a boost, 359 to no boost, and 687 to a non-randomised boost. An EORTC trial2 that compared boost with no boost showed an overall reduction of 40% in the risk of ipsilateral local relapse in patients with clear excision margins who received boost after whole-breast radiotherapy of 50 Gy in 25 fractions over 5 weeks. The greatest benefit was seen in women younger than 50 years. The subrandomisation was closed in July, 1997 (only 1 year before the end of the main trial), after which all patients were offered an elective boost. As a result, about three-quarters of patients in the trial received a boost. Therefore, the trial, in fact, is a comparison of wholebreast radiotherapy with three different fractionation 618
regimens supplemented by boost, rather than a comparison of whole-breast radiotherapy only with the same three regimens. Addition of a boost could have differentially favoured the shorter fractionation regimens, especially in younger women (in whom the EORTC boost trial showed the most benefit). It would be interesting to look at local control by fractionation regimen in the patients not receiving the boost, to see if the pattern of benefit in local control was the same. However, the numbers are probably too small to detect a significant difference from fractionation. Alternatively, some selection bias could have existed in those patients who refused to undergo subrandomisation. Thus, no conclusions can be drawn from the data for patients who were treated without a boost. The authors acknowledge that the trial1 was not powered for local control but for moderate or severe late radiation effects, and rightly encourage clinical oncologists to wait for the results of the adequately powered START A trial,3 in which 5-week regimens of 41·6 Gy (13 fractions of 3·2 Gy) and 39 Gy (13 fractions of 3 Gy) were compared with 50 Gy (25 fractions of 2 Gy). Decisions on the best dose and fractionation in breast-conserving treatment need to be based on studies that have comprehensive data for cosmesis and that are adequately powered for differences in local control, which are not available so far. A Canadian breast conservation trial4 has suggested equivalence in local breast control between the international standard of 50 Gy and the shorter fractionation regimen of 42·5 Gy (16 fractions of 2·66 Gy) over 22 days. However, as Owen and colleagues correctly acknowledge, the CIs of the local control data of this Canadian trial are wide and a comparison based on only 44 events is imprecise. The long life expectancy of patients undergoing breast-conserving surgery and postoperative radiotherapy mandates the need for very long-term followup of several decades to assess the effect of different dose and fractionation regimens on tumour control, morbidity, and cosmesis. In our department, fewer higher-dose fractions (42·5 Gy in ten fractions of 4·25 Gy) were compared with the regimen used currently (45 Gy in 20 fractions of 2·25 Gy) over 4 weeks,5 which showed a significant increase in acute skin morbidity (p<0·0001) and in late skin, subcutaneous, http://oncology.thelancet.com Vol 7 August 2006
Reflection and Reaction
and rib morbidity in patients given fewer fractions (p<0·0001). Although the 4·25 Gy dose is higher than the highest dose per fraction (3·3 Gy) reported by Owen and colleagues,1 these results5 are a salutary caution to the premature use of regimens with shorter and higher doses per fraction and to the importance of long-term follow-up in randomised trials of dose and fractionation. Ian Kunkler Department of Clinical Oncology, University of Edinburgh, Edinburgh EH42XU, UK [email protected] I declare no conflicts of interest. 1
2
3 4
5
Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006; 7: 467–71. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: 1378–87. START trial management group. Standardisation of Breast Radiotherapy (START) Trial. Clin Oncol 1999; 11: 145–47. Whelan T, MacKenzie R, Julian J, et al. Randomised trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002; 94: 1143–50. Rodger A, Jack WJL, Kerr G. A change in postmastectomy radiotherapy fractionation: an audit of tumour control, acute and late morbidity. The Breast 1996; 5: 244–50.
Authors’ reply Dr Kunkler is correct to assume that clinical and pathological risk factors tabulated in an earlier paper are balanced between randomised arms of the trial.1 With respect to radiotherapy boost allocation and regimen, Drs Munshi and Kunkler need not be concerned about interpretation of trial outcome. In the earlier article reporting late adverse effects, we stated that if the clinician felt it was appropriate and the patient consented, a subrandomisation to boost versus no boost was done in patients with complete microscopic tumour resection. Otherwise, an elective boost was given. Similar to surgical excision margins and adjuvant systemic therapy, the boost is a randomly
Crude hazard ratio (95% CI) Boost
No boost
50 Gy
1
1
42·9 Gy
0·88 (0·53–1·46)
0·80 (0·39–1·63)
39 Gy
1·38 (0·88–2·16)
1·24 (0·65–2·35)
Table 2: Survival analysis of local relapse according to fractionation schedule and breast boost
distributed variable. Stratification ensured that the distribution of patients in the boost categories was virtually identical in the three randomised groups (table 1). There was no evidence of an interaction between the effect of fractionation schedule and boost on the risk of local relapse (p=0·95), as shown by the results of Cox proportional hazards regression analysis stratified by boost (table 2). The 13-fraction regimen was delivered in the same overall treatment time (5 weeks) as the 25-fraction control schedule, so we can reassure Kunkler that there is no source of bias here. In addition, Munshi should understand that it is not possible to compute an equivalent schedule based on seven fraction sizes of 3·0 Gy or 3·3 Gy and α/β values of 1·8 Gy and 6·0 Gy. The size or number of fractions would have to change, and this would confound the randomisation. Kunkler argues for several decades of follow-up before judging the relative effects of different fractionation regimens, but relations between randomised schedules are unlikely to change qualitatively beyond the 10 years for adverse effects and the 16 years for tumour control that we reported. Where cardiac morbidity and mortality are concerned, the priority is to exclude the heart from the treatment volume altogether; this can usually be achieved by adjustments of arm position or breathing technique. As Munshi states, the breast is a compound tissue, but comprehensive clinical and photographic assessments yield a great many relevant dose-response data. Our report of late adverse effects
Randomised fractionation schedule 50 Gy (n=470)
42·9 Gy (n=466)
39 Gy (n=474)
Total (n=1410)
Randomly assigned to no boost
120 (26%)
118 (25%)
121 (26%)
359 (25%)
Randomly assigned to boost
122 (26%)
119 (26%)
123 (26%)
364 (26%)
Non-randomised boost
228 (49%)
229 (49%)
230 (49%)
687 (49%)
Table 1: Breast boost in 1410 patients according to randomised fractionation schedule
http://oncology.thelancet.com Vol 7 August 2006
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Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328: 1581–86. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. Lancet 2000; 355: 528–33. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 2003; 362: 95–102. Solin LJ, Fourquet A, Vicini FA, et al. Salvage treatment for local or local-regional recurrence after initial breast conservation treatment with radiation for ductal carcinoma in situ. Eur J Cancer 2005; 41: 1715–23. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 2001; 28: 400–18.
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Allred D, Bryant J, Land S, et al. Estrogen receptor expression as a predictive marker of effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP B-24. Breast Cancer Res Treat 2002; 76 (suppl 1): 180 (abstr S29). Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: 1378–87. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997; 15: 963–68. Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network. Lancet Oncol 2006; 7: 652–56.
Dose and fractionation regimens for breast cancer Some aspects about a recent Article by Owen and colleagues1 merit attention. Although hypofractionation was used for breast radiotherapy in two of the three trial groups, boost doses were given by use of conventional fractionation (14 Gy in seven fractions of 2 Gy). This use of fractionation seems go against the hypothesis proposed in the Article, which postulates that use of higher radiotherapy doses per fraction is better than or at least equal to conventional fractionation. In breastcancer radiotherapy, the field size of a boost dose is usually reduced, and therefore hypofractionated regimens are used even after standard fractionated radiotherapy of the whole breast.2 Furthermore, why a quarter of patients were not given boost in the trial by Owen and co-workers is unclear. Data for late lung and cardiac morbidity and survival is yet to emerge for the current hypofractionation schedules. Even with conventional fractionation, the Early Breast Cancer Trialists’ Collaborative Group3 reported that yearly mortality from breast cancer fell by 13% after radiotherapy but increased by 21% from other causes (mainly because of an excess number of deaths from cardiovascular events). Furthermore, the data for long-term cardiac side-effects might not emerge for another 15 years and could remain unconfirmed beyond this period.3 Therefore, caution is recommended for leftsided tumours, before schedules with high doses per fraction are implemented. Finally, breast radiotherapy cannot be regarded as an isolated treatment of the breast. It affects a wide range of tissues that include the skin, subcutaneous tissue, fibroglandular tissue, pectoralis muscles, and ribs. http://oncology.thelancet.com Vol 7 August 2006
Every tissue type has a unique α/β ratio and radiation sensitivity profile.4 Tissues with a lower α/β ratio would be more sensitive to radiotherapy than other tissues. The tissue with lowest ratio, especially if it has a substantially large volume, would probably determine the critical fraction size that could be used. Anusheel Munshi Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai 400012, India [email protected] I declare no conflicts of interest. 1
2
3
4
Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006; 7: 467–71. Touboul E, Belkacemi Y, Lefranc JP, et al. Early breast cancer: influence of type of boost (electrons vs iridium-192) on local control and cosmesis after conservative surgery and radiation therapy. Radiother Oncol 1995; 34: 105–13. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757–70. Thames HD, Bentzen SM, Turesson I, et al. Time–dose factors in radiotherapy: a review of the human data. Radiother Oncol 1990; 19: 219–35.
In a randomised trial1 comparing the international standard of 50 Gy (25 fractions of 2 Gy) with 39 Gy (13 fractions of 3 Gy) or 42·9 Gy (13 fractions of 3·3 Gy) over 5 weeks, Owen and colleagues report reduced risks of local recurrence in women given breastconserving surgery and fewer, larger fractions of postoperative radiotherapy. The results were heralded by some sections of the press, stating that regimens with shorter, higher doses per fraction were more convenient for patients and were less demanding on 617
Astrid & Hanns-Frieder Michler/Science Photo Library
Reflection and Reaction
Use of fewer and higher doses of radiotherapy might affect rib morbidity
limited radiotherapy resources than were conventional regimens. However, the study needs to be interpreted with caution. First, no table was presented to show the distribution of clinical and pathological risk factors in the three fractionation groups of the trial population. Although these factors were probably balanced by randomisation, the completeness of data was needed for factors that affect prognosis, such as age, tumour size, grade, lymphovascular invasion, oestrogen-receptor status, and nodal status. Second, Owen and co-workers subrandomised the trial population further: 364 patients were assigned to a boost, 359 to no boost, and 687 to a non-randomised boost. An EORTC trial2 that compared boost with no boost showed an overall reduction of 40% in the risk of ipsilateral local relapse in patients with clear excision margins who received boost after whole-breast radiotherapy of 50 Gy in 25 fractions over 5 weeks. The greatest benefit was seen in women younger than 50 years. The subrandomisation was closed in July, 1997 (only 1 year before the end of the main trial), after which all patients were offered an elective boost. As a result, about three-quarters of patients in the trial received a boost. Therefore, the trial, in fact, is a comparison of wholebreast radiotherapy with three different fractionation 618
regimens supplemented by boost, rather than a comparison of whole-breast radiotherapy only with the same three regimens. Addition of a boost could have differentially favoured the shorter fractionation regimens, especially in younger women (in whom the EORTC boost trial showed the most benefit). It would be interesting to look at local control by fractionation regimen in the patients not receiving the boost, to see if the pattern of benefit in local control was the same. However, the numbers are probably too small to detect a significant difference from fractionation. Alternatively, some selection bias could have existed in those patients who refused to undergo subrandomisation. Thus, no conclusions can be drawn from the data for patients who were treated without a boost. The authors acknowledge that the trial1 was not powered for local control but for moderate or severe late radiation effects, and rightly encourage clinical oncologists to wait for the results of the adequately powered START A trial,3 in which 5-week regimens of 41·6 Gy (13 fractions of 3·2 Gy) and 39 Gy (13 fractions of 3 Gy) were compared with 50 Gy (25 fractions of 2 Gy). Decisions on the best dose and fractionation in breast-conserving treatment need to be based on studies that have comprehensive data for cosmesis and that are adequately powered for differences in local control, which are not available so far. A Canadian breast conservation trial4 has suggested equivalence in local breast control between the international standard of 50 Gy and the shorter fractionation regimen of 42·5 Gy (16 fractions of 2·66 Gy) over 22 days. However, as Owen and colleagues correctly acknowledge, the CIs of the local control data of this Canadian trial are wide and a comparison based on only 44 events is imprecise. The long life expectancy of patients undergoing breast-conserving surgery and postoperative radiotherapy mandates the need for very long-term followup of several decades to assess the effect of different dose and fractionation regimens on tumour control, morbidity, and cosmesis. In our department, fewer higher-dose fractions (42·5 Gy in ten fractions of 4·25 Gy) were compared with the regimen used currently (45 Gy in 20 fractions of 2·25 Gy) over 4 weeks,5 which showed a significant increase in acute skin morbidity (p<0·0001) and in late skin, subcutaneous, http://oncology.thelancet.com Vol 7 August 2006
Reflection and Reaction
and rib morbidity in patients given fewer fractions (p<0·0001). Although the 4·25 Gy dose is higher than the highest dose per fraction (3·3 Gy) reported by Owen and colleagues,1 these results5 are a salutary caution to the premature use of regimens with shorter and higher doses per fraction and to the importance of long-term follow-up in randomised trials of dose and fractionation. Ian Kunkler Department of Clinical Oncology, University of Edinburgh, Edinburgh EH42XU, UK [email protected] I declare no conflicts of interest. 1
2
3 4
5
Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol 2006; 7: 467–71. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001; 345: 1378–87. START trial management group. Standardisation of Breast Radiotherapy (START) Trial. Clin Oncol 1999; 11: 145–47. Whelan T, MacKenzie R, Julian J, et al. Randomised trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002; 94: 1143–50. Rodger A, Jack WJL, Kerr G. A change in postmastectomy radiotherapy fractionation: an audit of tumour control, acute and late morbidity. The Breast 1996; 5: 244–50.
Authors’ reply Dr Kunkler is correct to assume that clinical and pathological risk factors tabulated in an earlier paper are balanced between randomised arms of the trial.1 With respect to radiotherapy boost allocation and regimen, Drs Munshi and Kunkler need not be concerned about interpretation of trial outcome. In the earlier article reporting late adverse effects, we stated that if the clinician felt it was appropriate and the patient consented, a subrandomisation to boost versus no boost was done in patients with complete microscopic tumour resection. Otherwise, an elective boost was given. Similar to surgical excision margins and adjuvant systemic therapy, the boost is a randomly
Crude hazard ratio (95% CI) Boost
No boost
50 Gy
1
1
42·9 Gy
0·88 (0·53–1·46)
0·80 (0·39–1·63)
39 Gy
1·38 (0·88–2·16)
1·24 (0·65–2·35)
Table 2: Survival analysis of local relapse according to fractionation schedule and breast boost
distributed variable. Stratification ensured that the distribution of patients in the boost categories was virtually identical in the three randomised groups (table 1). There was no evidence of an interaction between the effect of fractionation schedule and boost on the risk of local relapse (p=0·95), as shown by the results of Cox proportional hazards regression analysis stratified by boost (table 2). The 13-fraction regimen was delivered in the same overall treatment time (5 weeks) as the 25-fraction control schedule, so we can reassure Kunkler that there is no source of bias here. In addition, Munshi should understand that it is not possible to compute an equivalent schedule based on seven fraction sizes of 3·0 Gy or 3·3 Gy and α/β values of 1·8 Gy and 6·0 Gy. The size or number of fractions would have to change, and this would confound the randomisation. Kunkler argues for several decades of follow-up before judging the relative effects of different fractionation regimens, but relations between randomised schedules are unlikely to change qualitatively beyond the 10 years for adverse effects and the 16 years for tumour control that we reported. Where cardiac morbidity and mortality are concerned, the priority is to exclude the heart from the treatment volume altogether; this can usually be achieved by adjustments of arm position or breathing technique. As Munshi states, the breast is a compound tissue, but comprehensive clinical and photographic assessments yield a great many relevant dose-response data. Our report of late adverse effects
Randomised fractionation schedule 50 Gy (n=470)
42·9 Gy (n=466)
39 Gy (n=474)
Total (n=1410)
Randomly assigned to no boost
120 (26%)
118 (25%)
121 (26%)
359 (25%)
Randomly assigned to boost
122 (26%)
119 (26%)
123 (26%)
364 (26%)
Non-randomised boost
228 (49%)
229 (49%)
230 (49%)
687 (49%)
Table 1: Breast boost in 1410 patients according to randomised fractionation schedule
http://oncology.thelancet.com Vol 7 August 2006
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