- Email: [email protected]
Is radiotherapy boost needed in young patients with ductal carcinoma-in-situ?
Reflection and Reaction
was used is unclear, but two patients in the transhiatal group and four in the thoracoabdominal group had histologically positive proximal margins. The chance of an anastomotic recurrence is related to the length of the proximal oesophageal margin obtained.2 Skip lesions do occur in the oesophagus and, therefore, a clear frozen section at the time of operation might not guarantee against recurrence. The incidence of anastomotic recurrence in the two groups are unfortunately not stated. The results of this study show that an abdominal approach should be the preferred method, if very strict criteria for the selection of patients are used. Equivalent survival can be obtained with less pulmonary
morbidity by use of this rather than a thoracoabdominal approach. However, surgeons must be prepared to do a thoracotomy when a clear proximal margin is difficult to obtain. John Wong, Simon Law Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China [email protected] We declare no conflicts of interest. 1
2
Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 2006; 7: 644–51. Law S, Arcilla C, Chu KM, Wong J. The significance of histologically infiltrated resection margin after esophagectomy for esophageal cancer. Am J Surg 1998; 176: 286–90.
Is radiotherapy boost needed in young patients with ductal carcinoma-in-situ? The diagnosis and management of ductal carcinoma in situ (DCIS) is challenging to clinicians. Partly because of increased awareness of the importance of screening and improved mammographic technique, DCIS is diagnosed with increasing frequency. However, the optimum local treatment is unclear and complicated by the heterogeneity of the disease. In rare cases, DCIS involves large areas of the breast and requires mastectomy. However, most patients have localised DCIS and are candidates for breast-conserving surgery, commonly followed by radiotherapy. A subset of patients for whom radiotherapy can be safely omitted has yet to be defined.1 Large randomised trials consistently have shown a reduction of about half in local recurrence with the use of radiotherapy after breast-conserving surgery.2–4 The importance of local control is worth emphasising, as about half of recurrences are invasive and have a prognosis similar to that of a primary invasive breast cancer.5 In the National Surgical Adjuvant Breast and Bowel Project (NSABP B-24), the use of tamoxifen further improved local control in patients with DCIS who received radiotherapy.6 The number of patients who had invasive recurrence in the ipsilateral breast was 27 (2·6%) at 7 years for those assigned radiotherapy and tamoxifen, and 49 (5·3%) for those assigned radiotherapy and placebo.6 A subsequent http://oncology.thelancet.com Vol 7 August 2006
analysis showed that the benefit of tamoxifen is limited to patients with oestrogen-receptor-positive DCIS lesions.7 Given these data, radiotherapy, commonly with tamoxifen, is a standard treatment option in the management of DCIS. The use of radiotherapy in DCIS was developed along the lines of the use of breast-conserving surgery and radiotherapy in early-stage invasive breast cancer. The radiotherapy technique therefore is similar to that used to treat invasive cancer. Many centres have used wholebreast irradiation, with or without a boost, in early-stage invasive disease. The NSABP used 50 Gy to the whole breast, without a boost, as their standard in breastirradiation trials (both for invasive disease and for DCIS). Until recently, whether the use of a boost was of value was unclear. The usefulness of a boost has been assessed in invasive disease, notably by the European Organisation for the Research and Treatment of Cancer.8 In this trial of 5569 patients randomly assigned to receive either boost or no boost after whole-breast irradiation of 50 Gy, the 5-year hazard ratio for local recurrence was 0·59 (99% CI 0·43–0·81) in patients receiving a boost of 16 Gy compared with patients receiving no boost; this reduction in recurrence was seen in all subsets. Because the highest rate of local recurrence was in younger patients, the largest absolute difference in
See Articles page 652
615
Reflection and Reaction
Detlev Van Ravenswaay/Science Photo Library
local recurrence between the two treatment groups was in the younger patients. Patients younger than age 40 years had a 5-year local recurrence of 19·5% (95% CI 16·5–22·5) without a boost compared with 10·2% (7·9–12·5) with a boost. A smaller trial from Lyon, France, with early follow-up has also shown a similar reduction in local recurrence with the use of a boost.9 These trials support the notion that a boost further reduces local recurrence in invasive breast cancer treated with whole-breast irradiation. Whether the use of a boost similarly reduces local recurrence in patients with DCIS is unresolved. In this issue of The Lancet Oncology, Omlin and colleagues10 report the results of a carefully done, multiinstitutional, retrospective study assessing the effect of a boost in patients with DCIS. This is the only study specifically addressing the use of a boost in patients with DCIS. 373 patients age 45 years or younger were managed with excision alone (15%), excision followed by whole breast radiotherapy (45%), or excision followed by whole-breast radiotherapy with a boost (40%); no one received tamoxifen. The median follow up was 72 months. The primary outcomes assessed were local recurrence and local-recurrence-free survival. The 10-year local-recurrence-free survival rates were 46%, 72%, and 86%, respectively (p<0·0001). The hazard ratio for whole-breast radiotherapy compared with no radiotherapy was 0·33 (95% CI 0·16–0·71); for
radiotherapy with a boost, the hazard ratio was 0·15 (0·06–0·36). The investigators conclude that a boost is useful in the management of DCIS. Although retrospective, these results, showing a reduction in local recurrence with the addition of a boost in patients with DCIS, are consistent with the findings seen in the trials of boost for invasive cancer. Of note, however, is that the specifics of the detection methods and pathological assessment were not standardised. Central pathological review was not done, and a substantial proportion of patients had unknown margins, grade, and size. Selection bias by treating clinicians is also a possibility. Therefore, while certainly promising, these retrospective data should be interpreted with caution. Modern practice typically includes thorough mammographic and pathological assessment with detailed margin assessment; these differences may limit the ability to generalise the data presented by Omlin and colleagues. In addition, the increasing use of tamoxifen in DCIS may also affect the ultimate risk of local recurrence in patients who receive radiotherapy (with or without a boost). However, I agree with the investigators that, in light of the absence of data from prospective randomised trials on the usefulness of a boost in DCIS, the established benefit of a boost in patients with invasive cancer, and these retrospective results, the use of a boost in patients with DCIS should be encouraged, particularly in young patients. Our current practice is to use detailed mammography including magnification views and often postexcision mammograms if the adequacy of the excision is in question. Careful attention is likewise paid to pathological review, especially of margins, and hormone-receptor status is routinely assessed. Radiotherapy at our institution consists of wholebreast irradiation to 44–45 Gy followed by a 16 Gy boost, and tamoxifen is considered for patients with oestrogen-receptor positive DCIS, especially young patients. Julia S Wong Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [email protected] I declare no conflicts of interest. 1
An encouraging boost for DCIS management?
616
Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 2006; 24: 1031–36.
http://oncology.thelancet.com Vol 7 August 2006
Reflection and Reaction
2
3
4
5
6
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.
7
8
9
10
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
was used is unclear, but two patients in the transhiatal group and four in the thoracoabdominal group had histologically positive proximal margins. The chance of an anastomotic recurrence is related to the length of the proximal oesophageal margin obtained.2 Skip lesions do occur in the oesophagus and, therefore, a clear frozen section at the time of operation might not guarantee against recurrence. The incidence of anastomotic recurrence in the two groups are unfortunately not stated. The results of this study show that an abdominal approach should be the preferred method, if very strict criteria for the selection of patients are used. Equivalent survival can be obtained with less pulmonary
morbidity by use of this rather than a thoracoabdominal approach. However, surgeons must be prepared to do a thoracotomy when a clear proximal margin is difficult to obtain. John Wong, Simon Law Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China [email protected] We declare no conflicts of interest. 1
2
Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial. Lancet Oncol 2006; 7: 644–51. Law S, Arcilla C, Chu KM, Wong J. The significance of histologically infiltrated resection margin after esophagectomy for esophageal cancer. Am J Surg 1998; 176: 286–90.
Is radiotherapy boost needed in young patients with ductal carcinoma-in-situ? The diagnosis and management of ductal carcinoma in situ (DCIS) is challenging to clinicians. Partly because of increased awareness of the importance of screening and improved mammographic technique, DCIS is diagnosed with increasing frequency. However, the optimum local treatment is unclear and complicated by the heterogeneity of the disease. In rare cases, DCIS involves large areas of the breast and requires mastectomy. However, most patients have localised DCIS and are candidates for breast-conserving surgery, commonly followed by radiotherapy. A subset of patients for whom radiotherapy can be safely omitted has yet to be defined.1 Large randomised trials consistently have shown a reduction of about half in local recurrence with the use of radiotherapy after breast-conserving surgery.2–4 The importance of local control is worth emphasising, as about half of recurrences are invasive and have a prognosis similar to that of a primary invasive breast cancer.5 In the National Surgical Adjuvant Breast and Bowel Project (NSABP B-24), the use of tamoxifen further improved local control in patients with DCIS who received radiotherapy.6 The number of patients who had invasive recurrence in the ipsilateral breast was 27 (2·6%) at 7 years for those assigned radiotherapy and tamoxifen, and 49 (5·3%) for those assigned radiotherapy and placebo.6 A subsequent http://oncology.thelancet.com Vol 7 August 2006
analysis showed that the benefit of tamoxifen is limited to patients with oestrogen-receptor-positive DCIS lesions.7 Given these data, radiotherapy, commonly with tamoxifen, is a standard treatment option in the management of DCIS. The use of radiotherapy in DCIS was developed along the lines of the use of breast-conserving surgery and radiotherapy in early-stage invasive breast cancer. The radiotherapy technique therefore is similar to that used to treat invasive cancer. Many centres have used wholebreast irradiation, with or without a boost, in early-stage invasive disease. The NSABP used 50 Gy to the whole breast, without a boost, as their standard in breastirradiation trials (both for invasive disease and for DCIS). Until recently, whether the use of a boost was of value was unclear. The usefulness of a boost has been assessed in invasive disease, notably by the European Organisation for the Research and Treatment of Cancer.8 In this trial of 5569 patients randomly assigned to receive either boost or no boost after whole-breast irradiation of 50 Gy, the 5-year hazard ratio for local recurrence was 0·59 (99% CI 0·43–0·81) in patients receiving a boost of 16 Gy compared with patients receiving no boost; this reduction in recurrence was seen in all subsets. Because the highest rate of local recurrence was in younger patients, the largest absolute difference in
See Articles page 652
615
Reflection and Reaction
Detlev Van Ravenswaay/Science Photo Library
local recurrence between the two treatment groups was in the younger patients. Patients younger than age 40 years had a 5-year local recurrence of 19·5% (95% CI 16·5–22·5) without a boost compared with 10·2% (7·9–12·5) with a boost. A smaller trial from Lyon, France, with early follow-up has also shown a similar reduction in local recurrence with the use of a boost.9 These trials support the notion that a boost further reduces local recurrence in invasive breast cancer treated with whole-breast irradiation. Whether the use of a boost similarly reduces local recurrence in patients with DCIS is unresolved. In this issue of The Lancet Oncology, Omlin and colleagues10 report the results of a carefully done, multiinstitutional, retrospective study assessing the effect of a boost in patients with DCIS. This is the only study specifically addressing the use of a boost in patients with DCIS. 373 patients age 45 years or younger were managed with excision alone (15%), excision followed by whole breast radiotherapy (45%), or excision followed by whole-breast radiotherapy with a boost (40%); no one received tamoxifen. The median follow up was 72 months. The primary outcomes assessed were local recurrence and local-recurrence-free survival. The 10-year local-recurrence-free survival rates were 46%, 72%, and 86%, respectively (p<0·0001). The hazard ratio for whole-breast radiotherapy compared with no radiotherapy was 0·33 (95% CI 0·16–0·71); for
radiotherapy with a boost, the hazard ratio was 0·15 (0·06–0·36). The investigators conclude that a boost is useful in the management of DCIS. Although retrospective, these results, showing a reduction in local recurrence with the addition of a boost in patients with DCIS, are consistent with the findings seen in the trials of boost for invasive cancer. Of note, however, is that the specifics of the detection methods and pathological assessment were not standardised. Central pathological review was not done, and a substantial proportion of patients had unknown margins, grade, and size. Selection bias by treating clinicians is also a possibility. Therefore, while certainly promising, these retrospective data should be interpreted with caution. Modern practice typically includes thorough mammographic and pathological assessment with detailed margin assessment; these differences may limit the ability to generalise the data presented by Omlin and colleagues. In addition, the increasing use of tamoxifen in DCIS may also affect the ultimate risk of local recurrence in patients who receive radiotherapy (with or without a boost). However, I agree with the investigators that, in light of the absence of data from prospective randomised trials on the usefulness of a boost in DCIS, the established benefit of a boost in patients with invasive cancer, and these retrospective results, the use of a boost in patients with DCIS should be encouraged, particularly in young patients. Our current practice is to use detailed mammography including magnification views and often postexcision mammograms if the adequacy of the excision is in question. Careful attention is likewise paid to pathological review, especially of margins, and hormone-receptor status is routinely assessed. Radiotherapy at our institution consists of wholebreast irradiation to 44–45 Gy followed by a 16 Gy boost, and tamoxifen is considered for patients with oestrogen-receptor positive DCIS, especially young patients. Julia S Wong Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [email protected] I declare no conflicts of interest. 1
An encouraging boost for DCIS management?
616
Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 2006; 24: 1031–36.
http://oncology.thelancet.com Vol 7 August 2006
Reflection and Reaction
2
3
4
5
6
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.
7
8
9
10
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