- Email: [email protected]
Effects of radiotherapy and surgery for early breast cancer
radiotherapy patients was excluded from that report.3 Several of the nine trials in the “mastectomy with axillary clearance and node-negative” early cancers group seem to have been inappropriately placed. For example, patients in the Metaxas Athens trial4 had stage III disease (T3, T4a-b, any N, M0), and the node-negative patients in the Dana-Farber Cancer Institute trial5 had tumours larger than 5 cm; that trial also included patients with T4 disease. These locally advanced cases can hardly be conceived as “early” breast cancer. One might note that patients who had “mastectomy with axillary clearance and node-negative disease” treated with radiotherapy had significantly higher breast cancer mortality (log-rank p=0·01) despite a low recurrence rate.1 Patients in the Stockholm A trial were randomly assigned preoperative, postoperative, or no radiotherapy before surgery—ie, before knowledge of pathological nodal status. Hence, classification of these patients as node-negative or node-positive before randomisation seems incorrect. Trials of “mastectomy alone” per definition had no axillary pathological assessment, so to classify patients in such trials into nodenegative or node-positive alongside pathologically assessed patients is pointless. The EBCTCG overview argues that local control and long-term breast cancer mortality are correlated. Its argument hinges on partitioning data according to type of surgery and nodal status. Although its conclusions are supportive of our beliefs and daily practice, the question of whether or not collaborative metaanalyses of individual patients’ data could account for all of the abovementioned possible contradictions remains to be answered, and the lack of transparency in the partitioning of the data can also result in some scepticism. www.thelancet.com Vol 367 May 20, 2006
I declare that I have no conflict of interest.
Gábor Cserni [email protected] Bács-Kiskun County Teaching Hospital, Nyíri út 38, H-6000 Kecskemét, Hungary 1
2
3
4
5
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Fisher B, Slack NH, Cavanaugh PJ, Gardner B, Ravdin RG. Postoperative radiotherapy in the treatment of breast cancer: results of the NSABP clinical trial. Ann Surg 1970; 172: 711–32. Fisher B, Slack NH, Bross IDJ. Cancer of the breast: size of neoplasm and prognosis. Cancer 1969; 24: 1071–80. Papaioannou A, Lissaios B, Vasilaros S, et al. Pre- and postoperative chemoendocrine treatment with or without postoperative radiotherapy for locally advanced breast cancer. Cancer 1983; 51: 1284–90. Griem KL, Henderson IC, Gelman R, et al. The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. J Clin Oncol 1987; 5: 1546–55.
The EBCTCG overview of postoperative radiotherapy in early breast cancer1 shows a survival advantage for breastconserving surgery irrespective of nodal status. We would encourage a note of caution over the survival advantage in the older age-group. Only 600 of the 19 582 included in the 2000 EBCTCG overview2 were older than 70 years. Such patients have a competing risk of non-breast-cancer mortality.3 Many of these older patients were excluded from randomised trials on the basis of their age. The PRIME II trial4 has recruited 580 of its target 1000 patients internationally in the group consisting of patients aged 65 years or older with node-negative, hormone-receptorpositive disease and tumours 3 cm in diameter or smaller after breastconserving surgery and adjuvant endocrine therapy. Patients are being randomly assigned breast radiotherapy or no breast radiotherapy. Local recurrence is the primary endpoint but we will in time have data on survival. The 2005 overview also shows a survival advantage with postoperative
radiotherapy in women with nodepositive disease who underwent mastectomy and axillary clearance. The absolute reduction of all-cause mortality at 15 years is both substantial (4·4%) and highly significant (logrank p=0·0009). Curiously, subgroup analyses show an insignificant 1·6% reduction of all-cause mortality at 15 years in the lower-risk group of women with one to three involved lymph nodes (webfigure 2, d1) and the same insignificant 1·6% reduction of all-cause mortality at 15 years in the higher-risk group of women with four or more involved lymph nodes (webfigure 2, e1). This reversed Will Rogers phenomenon5—whereby an effect is shown in the overall analysis but in none of the subgroups–– highlights that clinical practice and decisions on therapy ideally should not be based on post-hoc subgroup analyses. The trade-off among locoregional control, survival, and toxicity of postmastectomy radiation therapy for lower-risk breast cancer patients with one to three involved axillary lymph nodes needs to be examined by use of contemporary radiotherapy and systemic therapy in the context of a large randomised phase III trial. The international SUPREMO trial (Selective Use of Postoperative Radiotherapy after Mastectomy, ISRCTN61145589) will address this issue.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
We declare that we have no conflict of interest.
*Ian H Kunkler, Linda Williams, Robin Prescott, Celia King [email protected] Department of Clinical Oncology, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK 1
2
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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.
1653
Science Photo Library
Correspondence
Correspondence
3
4 5
Kunkler I, Williams L, Prescott R, King C. Re: Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 1255–57. Kunkler I. PRIME II breast cancer trial. Clin Oncol (R Coll Radiol) 2004; 16: 447–48. Stephens R. The dangers of subgroup analysis. Lancet Oncol 2001; 2: 9.
Ratio breast cancer deaths
Every overview from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has represented a milestone. The latest overview of post-surgery radiotherapy in breast cancer1 meets the high expectations to which we have been accustomed. It confirms the insight of our late colleague Jan Van de Steene who observed years ago that the survival benefit of radiotherapy became increasingly significant with longer follow-up and with improved maturity of the trials.2 This is important, because the overview’s confirmation challenges the common perception that radiation toxicity is delayed. Make no mistake: radiation is a harmful environmental hazard. But what Jan and the overview show is that the radiation hazard from controlled clinical trials is constant over time and hence reasonably predictable, and not an increasingly overwhelming hazard like that of accidental exposures or from nuclear devastations. The 2005 overview incorrectly cites our pooled analysis3 as a review of just the published results of radiotherapy trials after breast-conserving therapy. First, our pooled analysis identified more trials than any previously. Second, it ascertained whether or not the trials were still active. And third, contrary to 1·4
We declare that we have no conflict of interest.
1·2
Claire Verschraegen, *Vincent Vinh-Hung
1·0
[email protected]
0·8
University of New Mexico, Cancer Research and Treatment Center, Albuquerque, NM, USA (CV); and Oncology Center, AZ-VUB, 1090 Jette, Belgium (VV-H)
0·6 0·4 0·1
0·2
0·3
0·4
0·5
Ratio recurrence rates
Figure: Breast conserving surgery: lack of correlation between breast cancer mortality and isolated recurrences
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the overview’s affirmation, we also used unpublished data. Our pooled analysis concerned the overall survival benefit, or lack thereof, that could be expected from radiation treatment. We provided a conservative estimate of an 8·6% relative gain in reduction of mortality. A previous EBCTCG report indicated a 6% proportional reduction in any-cause mortality.4 The 2005 overview provides no updated overall mortality figure and hence is uninformative for treatment decisions. There is also no mention of the major difference between the overview and our pooled analysis. Whereas we considered that the reduction in recurrences did not explain the mortality reduction,3 the 2005 overview equates four local recurrences avoided with one breast cancer death avoided. This is not supported by the overview itself: the plot of the overview’s ratios of breast cancer deaths as a function of recurrences shows no correlation, and there is even a suggestion that the two trials with the most recurrence reductions are associated with an increased risk of breast cancer death (figure). In keeping with our modelling of population data,4 our pooled analysis cautions against any Halstedian interpretation of results and argues for conservative local management in early breast cancer. The overview’s interpretation forces aggressive local treatment, since radical mastectomy in node-negative patients is associated with the lowest risk of local recurrence.5 This is a critical issue that should be openly debated.
1
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106.
2
3
4
5
Van de Steene J, Vinh-Hung V, Cutuli B, Storme G. Adjuvant radiotherapy for breast cancer: effects of longer follow-up. Radiother Oncol 2004; 72: 35–43. Vinh-Hung V, Verschraegen C, The Breast Conserving Surgery Project. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 115–21. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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. Verschraegen C, Vinh-Hung V, Cserni G, et al. Modeling the effect of tumor size in early breast cancer. Ann Surg 2005; 241: 309–18.
Authors’ reply The EBCTCG report presented metaanalyses of the randomised trials of local treatments in early breast cancer that began by 1995. Individual patients’ data were obtained on 7000 women in 10 trials of radiotherapy versus no radiotherapy after breast-conserving surgery (BCS), 10 000 women in 25 trials of radiotherapy versus no radiotherapy after mastectomy and axillary clearance, and 25 000 women in trials of various other local treatment comparisons. The main finding was that improvements in the initial treatment of local disease (by radiotherapy or by more extensive surgery) can eventually reduce breast cancer mortality. In aggregate, the treatment comparisons that involved a substantial reduction in the 5-year risk of local recurrence also involved a moderate reduction in the 15-year risk of death from breast cancer. The figure shows the combined evidence from all treatment comparisons that produced an absolute reduction of 10% or more in the 5-year local recurrence risk. (The other comparisons involved, on average, little difference in local recurrence or in breast cancer mortality.) These results suggest that, for every four local recurrences avoided by differences in local treatment, about one breast cancer death will eventually be avoided. This does not, as some correspondents suggest, assume a causal relation www.thelancet.com Vol 367 May 20, 2006
I declare that I have no conflict of interest.
Gábor Cserni [email protected] Bács-Kiskun County Teaching Hospital, Nyíri út 38, H-6000 Kecskemét, Hungary 1
2
3
4
5
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Fisher B, Slack NH, Cavanaugh PJ, Gardner B, Ravdin RG. Postoperative radiotherapy in the treatment of breast cancer: results of the NSABP clinical trial. Ann Surg 1970; 172: 711–32. Fisher B, Slack NH, Bross IDJ. Cancer of the breast: size of neoplasm and prognosis. Cancer 1969; 24: 1071–80. Papaioannou A, Lissaios B, Vasilaros S, et al. Pre- and postoperative chemoendocrine treatment with or without postoperative radiotherapy for locally advanced breast cancer. Cancer 1983; 51: 1284–90. Griem KL, Henderson IC, Gelman R, et al. The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. J Clin Oncol 1987; 5: 1546–55.
The EBCTCG overview of postoperative radiotherapy in early breast cancer1 shows a survival advantage for breastconserving surgery irrespective of nodal status. We would encourage a note of caution over the survival advantage in the older age-group. Only 600 of the 19 582 included in the 2000 EBCTCG overview2 were older than 70 years. Such patients have a competing risk of non-breast-cancer mortality.3 Many of these older patients were excluded from randomised trials on the basis of their age. The PRIME II trial4 has recruited 580 of its target 1000 patients internationally in the group consisting of patients aged 65 years or older with node-negative, hormone-receptorpositive disease and tumours 3 cm in diameter or smaller after breastconserving surgery and adjuvant endocrine therapy. Patients are being randomly assigned breast radiotherapy or no breast radiotherapy. Local recurrence is the primary endpoint but we will in time have data on survival. The 2005 overview also shows a survival advantage with postoperative
radiotherapy in women with nodepositive disease who underwent mastectomy and axillary clearance. The absolute reduction of all-cause mortality at 15 years is both substantial (4·4%) and highly significant (logrank p=0·0009). Curiously, subgroup analyses show an insignificant 1·6% reduction of all-cause mortality at 15 years in the lower-risk group of women with one to three involved lymph nodes (webfigure 2, d1) and the same insignificant 1·6% reduction of all-cause mortality at 15 years in the higher-risk group of women with four or more involved lymph nodes (webfigure 2, e1). This reversed Will Rogers phenomenon5—whereby an effect is shown in the overall analysis but in none of the subgroups–– highlights that clinical practice and decisions on therapy ideally should not be based on post-hoc subgroup analyses. The trade-off among locoregional control, survival, and toxicity of postmastectomy radiation therapy for lower-risk breast cancer patients with one to three involved axillary lymph nodes needs to be examined by use of contemporary radiotherapy and systemic therapy in the context of a large randomised phase III trial. The international SUPREMO trial (Selective Use of Postoperative Radiotherapy after Mastectomy, ISRCTN61145589) will address this issue.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
We declare that we have no conflict of interest.
*Ian H Kunkler, Linda Williams, Robin Prescott, Celia King [email protected] Department of Clinical Oncology, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK 1
2
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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.
1653
Science Photo Library
Correspondence
Correspondence
3
4 5
Kunkler I, Williams L, Prescott R, King C. Re: Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 1255–57. Kunkler I. PRIME II breast cancer trial. Clin Oncol (R Coll Radiol) 2004; 16: 447–48. Stephens R. The dangers of subgroup analysis. Lancet Oncol 2001; 2: 9.
Ratio breast cancer deaths
Every overview from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has represented a milestone. The latest overview of post-surgery radiotherapy in breast cancer1 meets the high expectations to which we have been accustomed. It confirms the insight of our late colleague Jan Van de Steene who observed years ago that the survival benefit of radiotherapy became increasingly significant with longer follow-up and with improved maturity of the trials.2 This is important, because the overview’s confirmation challenges the common perception that radiation toxicity is delayed. Make no mistake: radiation is a harmful environmental hazard. But what Jan and the overview show is that the radiation hazard from controlled clinical trials is constant over time and hence reasonably predictable, and not an increasingly overwhelming hazard like that of accidental exposures or from nuclear devastations. The 2005 overview incorrectly cites our pooled analysis3 as a review of just the published results of radiotherapy trials after breast-conserving therapy. First, our pooled analysis identified more trials than any previously. Second, it ascertained whether or not the trials were still active. And third, contrary to 1·4
We declare that we have no conflict of interest.
1·2
Claire Verschraegen, *Vincent Vinh-Hung
1·0
[email protected]
0·8
University of New Mexico, Cancer Research and Treatment Center, Albuquerque, NM, USA (CV); and Oncology Center, AZ-VUB, 1090 Jette, Belgium (VV-H)
0·6 0·4 0·1
0·2
0·3
0·4
0·5
Ratio recurrence rates
Figure: Breast conserving surgery: lack of correlation between breast cancer mortality and isolated recurrences
1654
the overview’s affirmation, we also used unpublished data. Our pooled analysis concerned the overall survival benefit, or lack thereof, that could be expected from radiation treatment. We provided a conservative estimate of an 8·6% relative gain in reduction of mortality. A previous EBCTCG report indicated a 6% proportional reduction in any-cause mortality.4 The 2005 overview provides no updated overall mortality figure and hence is uninformative for treatment decisions. There is also no mention of the major difference between the overview and our pooled analysis. Whereas we considered that the reduction in recurrences did not explain the mortality reduction,3 the 2005 overview equates four local recurrences avoided with one breast cancer death avoided. This is not supported by the overview itself: the plot of the overview’s ratios of breast cancer deaths as a function of recurrences shows no correlation, and there is even a suggestion that the two trials with the most recurrence reductions are associated with an increased risk of breast cancer death (figure). In keeping with our modelling of population data,4 our pooled analysis cautions against any Halstedian interpretation of results and argues for conservative local management in early breast cancer. The overview’s interpretation forces aggressive local treatment, since radical mastectomy in node-negative patients is associated with the lowest risk of local recurrence.5 This is a critical issue that should be openly debated.
1
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 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–106.
2
3
4
5
Van de Steene J, Vinh-Hung V, Cutuli B, Storme G. Adjuvant radiotherapy for breast cancer: effects of longer follow-up. Radiother Oncol 2004; 72: 35–43. Vinh-Hung V, Verschraegen C, The Breast Conserving Surgery Project. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004; 96: 115–21. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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. Verschraegen C, Vinh-Hung V, Cserni G, et al. Modeling the effect of tumor size in early breast cancer. Ann Surg 2005; 241: 309–18.
Authors’ reply The EBCTCG report presented metaanalyses of the randomised trials of local treatments in early breast cancer that began by 1995. Individual patients’ data were obtained on 7000 women in 10 trials of radiotherapy versus no radiotherapy after breast-conserving surgery (BCS), 10 000 women in 25 trials of radiotherapy versus no radiotherapy after mastectomy and axillary clearance, and 25 000 women in trials of various other local treatment comparisons. The main finding was that improvements in the initial treatment of local disease (by radiotherapy or by more extensive surgery) can eventually reduce breast cancer mortality. In aggregate, the treatment comparisons that involved a substantial reduction in the 5-year risk of local recurrence also involved a moderate reduction in the 15-year risk of death from breast cancer. The figure shows the combined evidence from all treatment comparisons that produced an absolute reduction of 10% or more in the 5-year local recurrence risk. (The other comparisons involved, on average, little difference in local recurrence or in breast cancer mortality.) These results suggest that, for every four local recurrences avoided by differences in local treatment, about one breast cancer death will eventually be avoided. This does not, as some correspondents suggest, assume a causal relation www.thelancet.com Vol 367 May 20, 2006