- Email: [email protected]
Can older women with early breast cancer avoid radiation?
Comment
2 3
4
5
6
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371: 2167–77. Agwa ES, Ma PC. Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: emerging role of tivantinib. Cancer Manag Res 2014; 6: 397. Scagliotti GV, Novello S, Schiller JH, et al. Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non small-cell lung cancer. Clin Lung Cancer 2012; 13: 391–95. Domingues D, Turner A, Silva MD, et al. Immunotherapy and lung cancer: current developments and novel targeted therapies. Immunotherapy 2014; 6: 1221–35.
7
8
9
10
Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-smallcell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013; 24: 75–83. Rivzi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; published online Feb 20. http://dx.doi.org/10.1016/S1470-2045(15)70054-9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 2013; 15: 3936–43.
In The Lancet Oncology, Ian Kunkler and colleagues report findings of PRIME II,1 a randomised controlled trial in older women with early breast cancer who have had breast-conserving surgery, to assess whether omission of radiotherapy has any effect on local recurrence. This report is welcomed, as it shows once again that addition of radiotherapy to adjuvant endocrine treatment in this population of older women with small oestrogen receptor-positive cancers produces a statistically significant, albeit minimal, reduction in ipsilateral breast tumour recurrence at 5 years (1·3% [95% CI 0·2–2·3] with radiotherapy vs 4·1% [2·4–5·7] without radiotherapy; p=0·0002), while showing no differences between treatment groups with respect to regional recurrence, distant metastases, contralateral tumours, or new breast cancers. Furthermore, PRIME II confirms that the vast majority of deaths in older women with early breast cancer are from other causes (n=77 of 89), not breast cancer. In view of the low risk of ipsilateral breast tumour recurrence at 5 years, Kunkler and colleagues suggest that omission of postoperative radiotherapy could be considered in some patients meeting the eligibility criteria for the trial. We not only wholeheartedly agree, but would go a step further to suggest that not only should omission of radiotherapy be considered, it should actually be omitted in all women who meet the eligibility requirements of this trial. It is interesting that a criticism of PRIME II, the Cancer and Leukemia Group B (CALGB) 9343 trial,2 and other similar studies has been that the rate of ipsilateral breast tumour recurrence without radiation is relatively high when compared with women who have radiotherapy www.thelancet.com/oncology Vol 16 March 2015
and, thus, justifies radiation. This relativistic argument is designed to perpetuate the use of radiation under almost any circumstances, as radiation will always decrease local recurrence to some degree. We would suggest that considering absolute risk might be more useful. Nijenhuis and Rutjers suggest,3 while referring to EUSOMA guidelines (in terms of locoregional recurrence),4 that for early breast cancer, locoregional recurrence should be within the limit of 1% per year (or within 10% at 10 years). We thus feel very comfortable recommending lumpectomy with radiation for women aged 50 years and younger, whose risk of ipsilateral breast tumour recurrence increases by 1% per year (or about 10% at 10 years).5 We have no qualms about telling our patients in this age group that lumpectomy is safe and equivalent to mastectomy. We reassure them that the rate of ipsilateral breast tumour recurrence is acceptable, mindful of the fact that future local recurrence will lead to mastectomy. No clinician would recommend mastectomy plus chestwall radiation in all women younger than 50 years to avoid a 1% per year increase in local recurrence. On the other hand, patients who meet the eligibility requirements for PRIME II or CALGB 9343 are often made to fear this same rate of ipsilateral breast tumour recurrence (about 9% at 10 years) if they do not receive radiation. Kunkler and colleagues mention the possibility of using a lower dose of radiation,1 as have others with respect to CALGB 9343, which is a fascinating suggestion when we look at the data. Patients who met the eligibility requirements for PRIME II will be told that, without radiation, their risk of ipsilateral breast tumour recurrence
Nancy Kedersha/Science Photo Library
Can older women with early breast cancer avoid radiation?
Published Online January 28, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70014-8 See Articles page 266
235
Comment
will be 4·1% at 5 years, but with radiation that risk can be reduced to 1·3%, saving them a 2·8% risk of ipsilateral breast tumour recurrence. Even the promise of this small reduction is often enough to sway older women into agreeing to radiotherapy. Once hooked, the conversation changes. We now explain that we can radiate part of the breast, instead of using whole-breast radiation, with a technique called accelerated partial breast irradiation, which is faster and more convenient. We state that the risk of ipsilateral breast tumour recurrence requiring mastectomy is only 4·0% with accelerated partial breast irradiation, which is only 1·8% more than the 2·2% with whole-breast radiation.6 Alternatively, we offer targeted intraoperative radiotherapy7 or electron intraoperative radiotherapy,8 either of which can be accomplished while the patient is under anaesthesia for lumpectomy. We state that with intraoperative therapy, the risk of ipsilateral breast tumour recurrence is only 3·3–4·4% at 5 years, which is only 2–4% more than the 0·4–1·3% risk with whole-breast radiation. Another way to discredit the results of these randomised trials is by damning with faint praise, suggesting that we can avoid radiation only in subgroups of patients who were eligible for the trial. Using underpowered, unplanned subgroup analyses, or by intuition, we try to say that not everyone who was eligible for the trial is really eligible for the management approach proven by the trial. Kunkler and colleagues concluded that patients should be assessed individually, and although this general statement is certainly true, it is not supported by, and it undermines the results of, their randomised trial. The PRIME II investigators did an underpowered, unplanned, hypothesis-generating subgroup analysis and ascertained that their results might not apply to patients who are oestrogen receptor-positive at a low level. This idea is interesting and worth testing, but, in the meantime, the results of the trial stand and these patients fall into the group that do not need radiation. The authors also imply that healthier women might need radiation, even though they meet the eligibility requirements of the randomised trial which showed minimal benefit. CALGB 9343 and PRIME II apply to all healthy older women who meet the eligibility requirements, not just the infirm. In CALGB 9343,2 we showed that women in the study had a longer life expectancy than did an age-matched population. 236
This finding would be expected, because women who are well enough to understand and participate in a clinical trial are likely to be healthier than those not included in trials. We would submit this statement is also true for the PRIME II participants. In fact, the study’s inclusion criteria excluded less healthy women in the eligible age group by requiring axillary assessment, something that is not always done in older and infirm individuals. More explicitly, all patients had to be “fit for all treatment and follow-up”.1 After publication in 2004 of the initial results of CALGB 9343, and the resulting change in National Comprehensive Cancer Network (NCCN) guidelines,9 it is unclear why the recommendation to omit radiation treatment in older women has not been adopted widely. Soulos and colleagues suggested, in a 2012 review of Surveillance, Epidemiology, and End Results Program data,10 that clinicians had concerns about the length of follow-up and patients viewed omission of radiation as substandard treatment. McCormick and colleagues11 reported variability in the use of breast radiation in older women among NCCN institutions, implying clinician bias or an absence of uniform dissemination and acceptance of the data. It is time to face reality. We are no longer able to afford expensive treatments unless definite benefit is evident. In the new zero sum world of health care, money spent on breast radiation for older women who do not really need it is money taken away from other aspects of their care. In the CALGB 9343 study,2 only 21 (6%) of 313 deaths were due to breast cancer, and in PRIME II, only 12 (13%) of 89 deaths were caused by the disease.1 Many older women have more complex and life-threatening problems than their breast cancer. We should treat breast cancer in the most effective and least costly way possible and use the money saved to manage other major health-care issues. If we are objective, it is fairly clear that if patients are selected properly, we can use lumpectomy with radiation in younger women and omit radiation as women get older, with acceptable rates of ipsilateral breast tumour recurrence. PRIME II adds to the growing body of knowledge that radiation has minimal real benefit for women aged 65 years and older with oestrogen receptor-positive tumours of 3 cm or smaller. It is time to stop radiating these older women. www.thelancet.com/oncology Vol 16 March 2015
Comment
*Kevin S Hughes, Lauren A Schnaper
6
Avon Comprehensive Breast Evaluation Center, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA (KSH); and Greater Baltimore Medical Center, Baltimore, MD, USA (LAS) [email protected]
7
We declare no competing interests.
8
1
2
3 4 5
Kunkler IH, Williams LJ, Jack WJL, Cameron DA, Dixon JM, on behalf of the PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015; published online Jan 28. http://dx.doi.org/10.1016/S1470-2045(14)71221-5. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382–87. Nijenhuis MV, Rutgers EJ. Who should not undergo breast conservation? Breast 2013; 22 (suppl 2): S110–14. Rutgers EJ, for the EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer 2001; 37: 447–53. Bartelink H, Maingon P, Poortmans P, et al, on behalf of the European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 2015; 16: 47–56.
9
10
11
Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. Cancer Res 2011; 71 (24 suppl): abstr S2-1. Vaidya JS, Wenz F, Bulsara M et al, on behalf of the TARGIT trialists’ group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014; 383: 603–13. Veronesi U, Oreccia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013; 14: 1269–77. National Comprehensive Cancer Network. NCCN guidelines for treatment of cancer by site: breast cancer. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp#site (accessed Jan 8, 2015). Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the Medicare population. J Clin Oncol 2012; 30: 1601–07. McCormick B, Ottesen RA, Hughes ME, et al. Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: practice patterns at National Comprehensive Cancer Network institutions. J Am Coll Surg 2014; 219: 796–802.
External beam radiotherapy is one of the standard treatment options for patients with intermediaterisk or high-risk localised prostate cancer, and more than 10 000 men are treated using this modality every year in the UK.1 Dose escalation by use of conformal radiotherapy has become a standard of care.2 Intensity modulated and image-guided contemporary radiotherapy techniques have reduced treatment-related complications3,4 and good disease control is achieved in most men with appropriate use of neoadjuvant and adjuvant androgen deprivation.5 In the past decade there has been much speculation that prostate cancer might have high radiationfraction sensitivity, suggesting a therapeutic advantage of hypofractionated treatment.6,7 Many retrospective reviews of patient cohorts8 have supported the hypothesis that the α/β ratio is low, and a recent systematic review of six small phase 3 trials concluded that hypofractionation seemed safe but that further data were needed to establish clinical effectiveness.9 If hypofractionation was shown to be beneficial in larger studies, this would have a major effect on the use of radiotherapy as a resource—currently 28% of radiotherapy in the UK is for the radical treatment of prostate cancer—as well as www.thelancet.com/oncology Vol 16 March 2015
improving the convenience of treatment for patients. Three large phase 3 trials of modest hypofractionation with fraction sizes of 3·0 Gy–3·4 Gy have been completed. A Dutch group are comparing 64·6 Gy in 19 fractions (hypofractionation) with 78 Gy in 39 fractions (standard fractionation) in 820 patients (HYPRO study; ISRCTN 85138529); in the UK, a threegroup study has completed recruitment of 3200 men comparing 60 Gy in 20, 57 Gy in 19 with 74 Gy in 37 fractions (CHHiP study; ISRCTN 97182923); and in Canada, investigators are comparing 60 Gy in 20 fractions with 78 Gy in 39 fractions in a planned cohort of 1204 patients (ISRCTN 43853433). The preliminary results of the HYPRO study are now reported in The Lancet Oncology by Aluwini and colleagues.10 Acute toxic effects have been measured until 3 months after radiotherapy completion with both physician and patient-completed instruments. Although non-inferiority for genitourinary toxicity was statistically unproven, peak toxicity grade 2 or worse was similar (57·8% [95% CI 52·9–62·7] for standard fractionation and 60·5% [55·8–65·3] for hypofractionation; difference 2·7%, 90% CI –2·99 to 8·48, p=0·43), and 3 months after treatment levels decreased back to baseline levels (about 23% in both
Antonia Reeve/Science Photo Library
Hypofractionated radiotherapy in prostate cancer
Published Online February 3, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70021-5 This online publication has been corrected. The corrected version first appeared at thelancet.com/ oncology on March 2, 2015 See Articles page 274
237
2 3
4
5
6
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371: 2167–77. Agwa ES, Ma PC. Targeting the MET receptor tyrosine kinase in non-small cell lung cancer: emerging role of tivantinib. Cancer Manag Res 2014; 6: 397. Scagliotti GV, Novello S, Schiller JH, et al. Rationale and design of MARQUEE: a phase III, randomized, double-blind study of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients with locally advanced or metastatic, nonsquamous, non small-cell lung cancer. Clin Lung Cancer 2012; 13: 391–95. Domingues D, Turner A, Silva MD, et al. Immunotherapy and lung cancer: current developments and novel targeted therapies. Immunotherapy 2014; 6: 1221–35.
7
8
9
10
Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-smallcell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013; 24: 75–83. Rivzi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 2015; published online Feb 20. http://dx.doi.org/10.1016/S1470-2045(15)70054-9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 2013; 15: 3936–43.
In The Lancet Oncology, Ian Kunkler and colleagues report findings of PRIME II,1 a randomised controlled trial in older women with early breast cancer who have had breast-conserving surgery, to assess whether omission of radiotherapy has any effect on local recurrence. This report is welcomed, as it shows once again that addition of radiotherapy to adjuvant endocrine treatment in this population of older women with small oestrogen receptor-positive cancers produces a statistically significant, albeit minimal, reduction in ipsilateral breast tumour recurrence at 5 years (1·3% [95% CI 0·2–2·3] with radiotherapy vs 4·1% [2·4–5·7] without radiotherapy; p=0·0002), while showing no differences between treatment groups with respect to regional recurrence, distant metastases, contralateral tumours, or new breast cancers. Furthermore, PRIME II confirms that the vast majority of deaths in older women with early breast cancer are from other causes (n=77 of 89), not breast cancer. In view of the low risk of ipsilateral breast tumour recurrence at 5 years, Kunkler and colleagues suggest that omission of postoperative radiotherapy could be considered in some patients meeting the eligibility criteria for the trial. We not only wholeheartedly agree, but would go a step further to suggest that not only should omission of radiotherapy be considered, it should actually be omitted in all women who meet the eligibility requirements of this trial. It is interesting that a criticism of PRIME II, the Cancer and Leukemia Group B (CALGB) 9343 trial,2 and other similar studies has been that the rate of ipsilateral breast tumour recurrence without radiation is relatively high when compared with women who have radiotherapy www.thelancet.com/oncology Vol 16 March 2015
and, thus, justifies radiation. This relativistic argument is designed to perpetuate the use of radiation under almost any circumstances, as radiation will always decrease local recurrence to some degree. We would suggest that considering absolute risk might be more useful. Nijenhuis and Rutjers suggest,3 while referring to EUSOMA guidelines (in terms of locoregional recurrence),4 that for early breast cancer, locoregional recurrence should be within the limit of 1% per year (or within 10% at 10 years). We thus feel very comfortable recommending lumpectomy with radiation for women aged 50 years and younger, whose risk of ipsilateral breast tumour recurrence increases by 1% per year (or about 10% at 10 years).5 We have no qualms about telling our patients in this age group that lumpectomy is safe and equivalent to mastectomy. We reassure them that the rate of ipsilateral breast tumour recurrence is acceptable, mindful of the fact that future local recurrence will lead to mastectomy. No clinician would recommend mastectomy plus chestwall radiation in all women younger than 50 years to avoid a 1% per year increase in local recurrence. On the other hand, patients who meet the eligibility requirements for PRIME II or CALGB 9343 are often made to fear this same rate of ipsilateral breast tumour recurrence (about 9% at 10 years) if they do not receive radiation. Kunkler and colleagues mention the possibility of using a lower dose of radiation,1 as have others with respect to CALGB 9343, which is a fascinating suggestion when we look at the data. Patients who met the eligibility requirements for PRIME II will be told that, without radiation, their risk of ipsilateral breast tumour recurrence
Nancy Kedersha/Science Photo Library
Can older women with early breast cancer avoid radiation?
Published Online January 28, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70014-8 See Articles page 266
235
Comment
will be 4·1% at 5 years, but with radiation that risk can be reduced to 1·3%, saving them a 2·8% risk of ipsilateral breast tumour recurrence. Even the promise of this small reduction is often enough to sway older women into agreeing to radiotherapy. Once hooked, the conversation changes. We now explain that we can radiate part of the breast, instead of using whole-breast radiation, with a technique called accelerated partial breast irradiation, which is faster and more convenient. We state that the risk of ipsilateral breast tumour recurrence requiring mastectomy is only 4·0% with accelerated partial breast irradiation, which is only 1·8% more than the 2·2% with whole-breast radiation.6 Alternatively, we offer targeted intraoperative radiotherapy7 or electron intraoperative radiotherapy,8 either of which can be accomplished while the patient is under anaesthesia for lumpectomy. We state that with intraoperative therapy, the risk of ipsilateral breast tumour recurrence is only 3·3–4·4% at 5 years, which is only 2–4% more than the 0·4–1·3% risk with whole-breast radiation. Another way to discredit the results of these randomised trials is by damning with faint praise, suggesting that we can avoid radiation only in subgroups of patients who were eligible for the trial. Using underpowered, unplanned subgroup analyses, or by intuition, we try to say that not everyone who was eligible for the trial is really eligible for the management approach proven by the trial. Kunkler and colleagues concluded that patients should be assessed individually, and although this general statement is certainly true, it is not supported by, and it undermines the results of, their randomised trial. The PRIME II investigators did an underpowered, unplanned, hypothesis-generating subgroup analysis and ascertained that their results might not apply to patients who are oestrogen receptor-positive at a low level. This idea is interesting and worth testing, but, in the meantime, the results of the trial stand and these patients fall into the group that do not need radiation. The authors also imply that healthier women might need radiation, even though they meet the eligibility requirements of the randomised trial which showed minimal benefit. CALGB 9343 and PRIME II apply to all healthy older women who meet the eligibility requirements, not just the infirm. In CALGB 9343,2 we showed that women in the study had a longer life expectancy than did an age-matched population. 236
This finding would be expected, because women who are well enough to understand and participate in a clinical trial are likely to be healthier than those not included in trials. We would submit this statement is also true for the PRIME II participants. In fact, the study’s inclusion criteria excluded less healthy women in the eligible age group by requiring axillary assessment, something that is not always done in older and infirm individuals. More explicitly, all patients had to be “fit for all treatment and follow-up”.1 After publication in 2004 of the initial results of CALGB 9343, and the resulting change in National Comprehensive Cancer Network (NCCN) guidelines,9 it is unclear why the recommendation to omit radiation treatment in older women has not been adopted widely. Soulos and colleagues suggested, in a 2012 review of Surveillance, Epidemiology, and End Results Program data,10 that clinicians had concerns about the length of follow-up and patients viewed omission of radiation as substandard treatment. McCormick and colleagues11 reported variability in the use of breast radiation in older women among NCCN institutions, implying clinician bias or an absence of uniform dissemination and acceptance of the data. It is time to face reality. We are no longer able to afford expensive treatments unless definite benefit is evident. In the new zero sum world of health care, money spent on breast radiation for older women who do not really need it is money taken away from other aspects of their care. In the CALGB 9343 study,2 only 21 (6%) of 313 deaths were due to breast cancer, and in PRIME II, only 12 (13%) of 89 deaths were caused by the disease.1 Many older women have more complex and life-threatening problems than their breast cancer. We should treat breast cancer in the most effective and least costly way possible and use the money saved to manage other major health-care issues. If we are objective, it is fairly clear that if patients are selected properly, we can use lumpectomy with radiation in younger women and omit radiation as women get older, with acceptable rates of ipsilateral breast tumour recurrence. PRIME II adds to the growing body of knowledge that radiation has minimal real benefit for women aged 65 years and older with oestrogen receptor-positive tumours of 3 cm or smaller. It is time to stop radiating these older women. www.thelancet.com/oncology Vol 16 March 2015
Comment
*Kevin S Hughes, Lauren A Schnaper
6
Avon Comprehensive Breast Evaluation Center, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA (KSH); and Greater Baltimore Medical Center, Baltimore, MD, USA (LAS) [email protected]
7
We declare no competing interests.
8
1
2
3 4 5
Kunkler IH, Williams LJ, Jack WJL, Cameron DA, Dixon JM, on behalf of the PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015; published online Jan 28. http://dx.doi.org/10.1016/S1470-2045(14)71221-5. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382–87. Nijenhuis MV, Rutgers EJ. Who should not undergo breast conservation? Breast 2013; 22 (suppl 2): S110–14. Rutgers EJ, for the EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer 2001; 37: 447–53. Bartelink H, Maingon P, Poortmans P, et al, on behalf of the European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 2015; 16: 47–56.
9
10
11
Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. Cancer Res 2011; 71 (24 suppl): abstr S2-1. Vaidya JS, Wenz F, Bulsara M et al, on behalf of the TARGIT trialists’ group. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014; 383: 603–13. Veronesi U, Oreccia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013; 14: 1269–77. National Comprehensive Cancer Network. NCCN guidelines for treatment of cancer by site: breast cancer. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp#site (accessed Jan 8, 2015). Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the Medicare population. J Clin Oncol 2012; 30: 1601–07. McCormick B, Ottesen RA, Hughes ME, et al. Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: practice patterns at National Comprehensive Cancer Network institutions. J Am Coll Surg 2014; 219: 796–802.
External beam radiotherapy is one of the standard treatment options for patients with intermediaterisk or high-risk localised prostate cancer, and more than 10 000 men are treated using this modality every year in the UK.1 Dose escalation by use of conformal radiotherapy has become a standard of care.2 Intensity modulated and image-guided contemporary radiotherapy techniques have reduced treatment-related complications3,4 and good disease control is achieved in most men with appropriate use of neoadjuvant and adjuvant androgen deprivation.5 In the past decade there has been much speculation that prostate cancer might have high radiationfraction sensitivity, suggesting a therapeutic advantage of hypofractionated treatment.6,7 Many retrospective reviews of patient cohorts8 have supported the hypothesis that the α/β ratio is low, and a recent systematic review of six small phase 3 trials concluded that hypofractionation seemed safe but that further data were needed to establish clinical effectiveness.9 If hypofractionation was shown to be beneficial in larger studies, this would have a major effect on the use of radiotherapy as a resource—currently 28% of radiotherapy in the UK is for the radical treatment of prostate cancer—as well as www.thelancet.com/oncology Vol 16 March 2015
improving the convenience of treatment for patients. Three large phase 3 trials of modest hypofractionation with fraction sizes of 3·0 Gy–3·4 Gy have been completed. A Dutch group are comparing 64·6 Gy in 19 fractions (hypofractionation) with 78 Gy in 39 fractions (standard fractionation) in 820 patients (HYPRO study; ISRCTN 85138529); in the UK, a threegroup study has completed recruitment of 3200 men comparing 60 Gy in 20, 57 Gy in 19 with 74 Gy in 37 fractions (CHHiP study; ISRCTN 97182923); and in Canada, investigators are comparing 60 Gy in 20 fractions with 78 Gy in 39 fractions in a planned cohort of 1204 patients (ISRCTN 43853433). The preliminary results of the HYPRO study are now reported in The Lancet Oncology by Aluwini and colleagues.10 Acute toxic effects have been measured until 3 months after radiotherapy completion with both physician and patient-completed instruments. Although non-inferiority for genitourinary toxicity was statistically unproven, peak toxicity grade 2 or worse was similar (57·8% [95% CI 52·9–62·7] for standard fractionation and 60·5% [55·8–65·3] for hypofractionation; difference 2·7%, 90% CI –2·99 to 8·48, p=0·43), and 3 months after treatment levels decreased back to baseline levels (about 23% in both
Antonia Reeve/Science Photo Library
Hypofractionated radiotherapy in prostate cancer
Published Online February 3, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70021-5 This online publication has been corrected. The corrected version first appeared at thelancet.com/ oncology on March 2, 2015 See Articles page 274
237