Adjuvant Treatment of Breast Cancer with Exemestane
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Coombes et al. (March 11 issue)1 report an important advantage in terms of disease-free survival with the use of adjuvant exemestane after initial treatment with tamoxifen. Adjuvant postmastectomy radiotherapy might have influenced the risk of locoregional recurrence. Adjuvant radiotherapy reduces the annual odds of locoregional failure by 75 percent.2 However, the policy on the use of postmastectomy radiotherapy in the trial is not stated. More than half the patients (1222 in the exemestane group and 1235 in the tamoxifen-only group) underwent mastectomy. Whereas postmastectomy radiotherapy would be standard practice3 for patients with four or more nodes (321 patients in the exemestane group and 330 in the tamoxifen-only group), practice varies4 for patients with one to three positive nodes (715 patients in the exemestane group and 706 in the tamoxifen-only group). A Danish trial involving postmenopausal, predominantly node-positive women showed a 9 percent advantage in terms of 10-year overall survival with postmastectomy radiotherapy given in addition to tamoxifen.5 An imbalance in the use of postmastectomy radiotherapy between the two groups in the trial reported by Coombes et al. could have influenced both disease-free survival and long-term overall survival.
Ian H. Kunkler, F.R.C.P.E.
Western General Hospital
Edinburgh EH4 2XU, United Kingdom
i.kunkler@ed.ac.uk
References
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092.
Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220-1229.
Taghian A, Ceilley E, Goldberg S, Grignon L, Kachnic L, Powell S. The radiotherapeutic management of breast cancer: a comparison between different European countries. Radiother Oncol 2002;64:Suppl 1:S135-S135. abstract.
Recht A, Bartelink H, Fourquet A, et al. Postmastectomy radiotherapy: questions for the twenty-first century. J Clin Oncol 1998;16:2886-2889.
Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-1648.
To the Editor: We are concerned about the P values that are presented in Table 4 in the article by Coombes et al. In comparable tables in a report on letrozole1 and a report from the Arimidex and Tamoxifen Alone or in Combination trial,2 adverse events were compared with the use of Fisher's exact test. In the article by Coombes et al., "P values were determined by trend tests." We question whether a trend test is appropriate in this context. As presented, the results could lead to erroneous conclusions about the safety of exemestane. We recalculated the data with the use of Fisher's exact test and found significantly worse effects in the exemestane group after the recalculation in terms of cardiovascular disease, pain, headaches, visual disturbances, arthralgia, depression, and diarrhea.
Luc A.M.L. Vakaet, M.D., Ph.D.
Wilfried De Neve, M.D., Ph.D.
Ghent University Hospital
9000 Ghent, Belgium
vakaet@krtkg1.ugent.be
References
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-2139.
To the Editor: I disagree with the statement by Coombes and colleagues that "all third-generation aromatase inhibitors or inactivators increase bone resorption." Although nonsteroidal third-generation aromatase inhibitors may accelerate bone loss, exemestane, a steroidal aromatase inhibitor, has never been associated with clinical osteoporosis. Theoretically, the androgenic effect of steroidal agents may lessen this problem. In fact, preclinical data suggest that exemestane prevents bone loss after oophorectomy.1,2,3
Moreover, for a meaningful comparison of the incidence of osteoporosis among patients continuing to receive tamoxifen and those switching to exemestane, one needs to know whether any differences in baseline bone mineral density exist between the two groups. Unlike tamoxifen, which may be associated with thromboembolic events, osteoporosis is frequently asymptomatic, making clinical evidence of severe osteoporosis unreliable. Therefore, measurement of bone mineral density at intervals is necessary to understand the difference in the incidence of osteoporosis between the two groups. In the study by Coombes et al., the reported prevalence of osteoporosis among the patients taking exemestane was, in fact, similar to that among postmenopausal women in general.4 Finally, it is unclear whether the reported fractures were osteoporotic fractures, such as spine or hip fractures.
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
References
Goss PE, Qi S, Josse RG, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 2004;34:384-392.
Goss PE, Grynpas MD, Qi S, Hu H. The effects of exemestane on bone and lipids in the ovariectomized rat. Breast Cancer Res Treat 2001;69:224-224. abstract.
Goss PE, Cheung AM, Lowery C, Hu H, Qi S. Comparison of the effects of exemestane, 17-hydroexemestane and letrozole on bone and lipid metabolism in the ovariectomized rat. Breast Cancer Res Treat 2002;76:Suppl 1:S107-S107.
Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA 2001;286:2815-2822.
The authors reply: In response to Dr. Kunkler: overall, 65 percent of the patients in the Intergroup Exemestane Study received radiotherapy to the breast. The protocol did not specify a policy for use of postmastectomy radiotherapy, and its use was thus according to local practice. Rates of postmastectomy radiotherapy were as follows: all patients who underwent mastectomy, 35 percent; those with node-negative disease, 22 percent; those with one to three positive nodes, 37 percent; and those with four or more positive nodes, 64 percent. There is no evidence that use of postmastectomy radiotherapy differed according to the randomized treatment assignment, nor is there any reason to suspect that it would have differed, since the decision whether or not to use postmastectomy radiotherapy was made before randomization.
Drs. Vakaet and De Neve present an alternative analysis of our data on the incidence of side effects, using Fisher's exact test. The statistical test that we chose1 makes use of the ordering of the data (in this case, the severity of the incident) and is appropriate when more than two categories of the variable are available (in this case, grade 0, grade 1 or 2, and grade 3 or 4) and when differences between groups are expected to be related to the ordering — that is, when most of the variation is expected to be due to a trend. Conclusions were similar when a nonparametric test was used, rather than a chi-square test for trend. The analytic method was predefined and was not influenced by the observed results.
Because of multiple testing, we focused our interpretation of the safety results on differences in the rates of side effects that were significant at the 1 percent level. According to these criteria, side effects that were significantly worse in the exemestane group (by Fisher's exact test) were pain or aches (P=0.005), diarrhea (P<0.001), and arthralgia (P=0.005), whereas side effects that were worse in the tamoxifen group were gynecologic symptoms (P<0.001), cramps (P=0.008), and thromboembolic disease (P=0.008). The alternative analysis thus suggests that pain or aches, in addition to the effects discussed in our article, may be a significant adverse effect of adjuvant exemestane. Although this idea is plausible, particularly given the increase in the rate of arthralgia, we caution against overinterpretation of these data. As stated in the footnote to Table 4, the data on side effects — especially pain and aches, arthralgia, depression, diarrhea, and cramps — are preliminary; we are currently reviewing and systematically coding all adverse events. When this process and follow-up are complete, we will be able to assess the risk–benefit ratio for adjuvant exemestane.
In response to Dr. Tanvetyanon: 18 of the 72 reported fractures in the exemestane group and 14 of 53 in the tamoxifen group were labeled by the treating clinician as osteoporotic. Data on all fractures are being systematically reviewed and continually updated.
R. Charles Coombes, M.D.
Imperial College London
London W12 0NN, United Kingdom
c.coombes@imperial.ac.uk
Judith M. Bliss, M.Sc.
Emma Hall, Ph.D.
Institute of Cancer Research
Sutton SM2 5NG, United Kingdom
References
Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.
Ian H. Kunkler, F.R.C.P.E.
Western General Hospital
Edinburgh EH4 2XU, United Kingdom
i.kunkler@ed.ac.uk
References
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092.
Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220-1229.
Taghian A, Ceilley E, Goldberg S, Grignon L, Kachnic L, Powell S. The radiotherapeutic management of breast cancer: a comparison between different European countries. Radiother Oncol 2002;64:Suppl 1:S135-S135. abstract.
Recht A, Bartelink H, Fourquet A, et al. Postmastectomy radiotherapy: questions for the twenty-first century. J Clin Oncol 1998;16:2886-2889.
Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-1648.
To the Editor: We are concerned about the P values that are presented in Table 4 in the article by Coombes et al. In comparable tables in a report on letrozole1 and a report from the Arimidex and Tamoxifen Alone or in Combination trial,2 adverse events were compared with the use of Fisher's exact test. In the article by Coombes et al., "P values were determined by trend tests." We question whether a trend test is appropriate in this context. As presented, the results could lead to erroneous conclusions about the safety of exemestane. We recalculated the data with the use of Fisher's exact test and found significantly worse effects in the exemestane group after the recalculation in terms of cardiovascular disease, pain, headaches, visual disturbances, arthralgia, depression, and diarrhea.
Luc A.M.L. Vakaet, M.D., Ph.D.
Wilfried De Neve, M.D., Ph.D.
Ghent University Hospital
9000 Ghent, Belgium
vakaet@krtkg1.ugent.be
References
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-2139.
To the Editor: I disagree with the statement by Coombes and colleagues that "all third-generation aromatase inhibitors or inactivators increase bone resorption." Although nonsteroidal third-generation aromatase inhibitors may accelerate bone loss, exemestane, a steroidal aromatase inhibitor, has never been associated with clinical osteoporosis. Theoretically, the androgenic effect of steroidal agents may lessen this problem. In fact, preclinical data suggest that exemestane prevents bone loss after oophorectomy.1,2,3
Moreover, for a meaningful comparison of the incidence of osteoporosis among patients continuing to receive tamoxifen and those switching to exemestane, one needs to know whether any differences in baseline bone mineral density exist between the two groups. Unlike tamoxifen, which may be associated with thromboembolic events, osteoporosis is frequently asymptomatic, making clinical evidence of severe osteoporosis unreliable. Therefore, measurement of bone mineral density at intervals is necessary to understand the difference in the incidence of osteoporosis between the two groups. In the study by Coombes et al., the reported prevalence of osteoporosis among the patients taking exemestane was, in fact, similar to that among postmenopausal women in general.4 Finally, it is unclear whether the reported fractures were osteoporotic fractures, such as spine or hip fractures.
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
References
Goss PE, Qi S, Josse RG, et al. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 2004;34:384-392.
Goss PE, Grynpas MD, Qi S, Hu H. The effects of exemestane on bone and lipids in the ovariectomized rat. Breast Cancer Res Treat 2001;69:224-224. abstract.
Goss PE, Cheung AM, Lowery C, Hu H, Qi S. Comparison of the effects of exemestane, 17-hydroexemestane and letrozole on bone and lipid metabolism in the ovariectomized rat. Breast Cancer Res Treat 2002;76:Suppl 1:S107-S107.
Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA 2001;286:2815-2822.
The authors reply: In response to Dr. Kunkler: overall, 65 percent of the patients in the Intergroup Exemestane Study received radiotherapy to the breast. The protocol did not specify a policy for use of postmastectomy radiotherapy, and its use was thus according to local practice. Rates of postmastectomy radiotherapy were as follows: all patients who underwent mastectomy, 35 percent; those with node-negative disease, 22 percent; those with one to three positive nodes, 37 percent; and those with four or more positive nodes, 64 percent. There is no evidence that use of postmastectomy radiotherapy differed according to the randomized treatment assignment, nor is there any reason to suspect that it would have differed, since the decision whether or not to use postmastectomy radiotherapy was made before randomization.
Drs. Vakaet and De Neve present an alternative analysis of our data on the incidence of side effects, using Fisher's exact test. The statistical test that we chose1 makes use of the ordering of the data (in this case, the severity of the incident) and is appropriate when more than two categories of the variable are available (in this case, grade 0, grade 1 or 2, and grade 3 or 4) and when differences between groups are expected to be related to the ordering — that is, when most of the variation is expected to be due to a trend. Conclusions were similar when a nonparametric test was used, rather than a chi-square test for trend. The analytic method was predefined and was not influenced by the observed results.
Because of multiple testing, we focused our interpretation of the safety results on differences in the rates of side effects that were significant at the 1 percent level. According to these criteria, side effects that were significantly worse in the exemestane group (by Fisher's exact test) were pain or aches (P=0.005), diarrhea (P<0.001), and arthralgia (P=0.005), whereas side effects that were worse in the tamoxifen group were gynecologic symptoms (P<0.001), cramps (P=0.008), and thromboembolic disease (P=0.008). The alternative analysis thus suggests that pain or aches, in addition to the effects discussed in our article, may be a significant adverse effect of adjuvant exemestane. Although this idea is plausible, particularly given the increase in the rate of arthralgia, we caution against overinterpretation of these data. As stated in the footnote to Table 4, the data on side effects — especially pain and aches, arthralgia, depression, diarrhea, and cramps — are preliminary; we are currently reviewing and systematically coding all adverse events. When this process and follow-up are complete, we will be able to assess the risk–benefit ratio for adjuvant exemestane.
In response to Dr. Tanvetyanon: 18 of the 72 reported fractures in the exemestane group and 14 of 53 in the tamoxifen group were labeled by the treating clinician as osteoporotic. Data on all fractures are being systematically reviewed and continually updated.
R. Charles Coombes, M.D.
Imperial College London
London W12 0NN, United Kingdom
c.coombes@imperial.ac.uk
Judith M. Bliss, M.Sc.
Emma Hall, Ph.D.
Institute of Cancer Research
Sutton SM2 5NG, United Kingdom
References
Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.