- Email: [email protected]
Inappropriate ATAC on tamoxifen
Reflection and Reaction
programme at least 12 months before the full report appears in print. The articles by NICE will complement NICE’s other publications (ie, full appraisal, quick reference guide, and information for the public) that are issued when a final appraisal is announced, and will provide oncologists with an overview of the decision-making processes that have gone into issuing the appraisal as well as a discussion of the pertinent clinical evidence and economic considerations that influenced the decision. Since its establishment in 1999, NICE has published 35 appraisals of drugs for treating cancer, 33 of which are discussed in a recent Keynote Comment by Michael Rawlins, Chairman of NICE.2 NICE’s decisions can sometimes be controversial, taking up many column inches in the popular media, both in the UK and internationally, so further detail of the thought processes underlying the decisions could help doctors explain NICE’s final recommendations to their patients. Furthermore, NICE’s recommendations are not just relevant to the UK (the issue of paying for modern cancer care is of global concern),3 thus NICE’s decisions and reasoning are of interest to health-care authorities and drug-funding organisations across the world. NICE currently works with other medical journals to provide summaries to doctors of new clinical guidelines.4 As yet, however, no formal collaboration exists between NICE and a journal to highlight when a decision on a technology is made—a decision that is fundamental to subsequent guidelines. Thus, this new collaboration will provide a record of NICE’s oncology-related appraisals (and reappraisals where a change to existing recommendations
is made) in the medical literature, and will make knowledge of and details of their recommendations more accessible to worldwide audiences. Commenting on this collaboration, Carole Longson, Director of the Centre for Health Technology Evaluation at NICE, said: “This is an exciting opportunity for NICE to work with a prominent medical journal and highlight our recommendations to their readers. Developments in cancer therapy are ever increasing and it is important these new technologies are assessed by an independent organisation to assess their value to the NHS. We hope the readers of The Lancet Oncology find this Special Report a useful aid to understanding how we make our assessments and decisions”. The oncology drug pipeline is a busy one, and NICE has many technology appraisals in development for drugs against cancer. We hope our collaboration with NICE will provide a useful aid for understanding the complex processes involved in deciding which oncology drugs are approved for use in the NHS. Lidia Siemaszkiewicz The Lancet Oncology, London, UK 1
2 3 4
Gajraj E, Chung H, Longson C, Stevens A. Rituximab for follicular nonHodgkin lymphoma. Lancet Oncol 2008; published online Feb 27. DOI:10.1016/S1470-2045(08)70036-6. Rawlings M. Paying for modern cancer care—a global perspective. Lancet Oncol 2007; 8: 749–51. Schwartsmann G, Picon PD. When drugs are worth more than gold! Lancet Oncol 2007; 8: 1049–50. Norton C, Thomas L, Hill J. Management of faecal incontinence in adults: summary of NICE guidance. BMJ 2007; 334: 1370–71.
Inappropriate ATAC on tamoxifen The 100-month findings in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) update trial,1 confirm that postmenopausal patients with early-stage breast cancer treated with tamoxifen or anastrazole have the same overall survival (OS) even after prolonged follow-up. This finding is explained by competing causes of death that might have occurred in this group of patients and by a non-significant, otherwise unexplained higher number of deaths due to non-breast cancer in the anastrazole group. An alternative explanation might be that the advantage of anastrazole is restricted to a small subgroup of patients who cannot be distinguished in the 314
present conditions, while most patients still benefit from treatment with tamoxifen. The effect of genetic polymorphism of the cytochrome P450 CYP2D6 on tamoxifen metabolism might support this view.2 Patients homozygous for the wild-type gene (almost 80%) metabolise tamoxifen to the active form endoxifen more efficiently, and therefore, have the greatest advantage compared with those who are heterozygous or homozygous for the mutated gene (intermediate or poor metabolisers). Punglia and co-workers3 used a mathematical model to extrapolate this hypothesis to the findings of the Breast International Group (BIG) 1-98 trial http://oncology.thelancet.com Vol 9 April 2008
Reflection and Reaction
1
2
AJ Photo/HOP Americain/Science Photo Library
3
4
5
Considering adjuvant treatment options for patients with breast cancer
and noted that only intermediate and poor metabolisers benefited from the substitution of tamoxifen with letrozole. Several attempts to identify predictive factors of differential response to adjuvant endocrine treatment are underway,4,5 but no practical criteria have been agreed for choosing between tamoxifen and aromatase inhibitors. Nonetheless, the advantage of aromatase inhibitors over tamoxifen is overemphasised in clinical practice, although no ongoing trials have shown a substantial advantage in OS, even with extended follow-up. Consequently, adjuvant tamoxifen might be abandoned by clinicians with the justification that frontline aromatase inhibitors are more effective. Analogously, sequential combined treatment, which improved OS compared with tamoxifen alone,6,7 is supposed to be detrimental, because it will not prevent early systemic relapse: this will not be proved unless ongoing trials (ie, BIG 1-98 trial) do not show that aromatase inhibitors alone are any better than the sequential schedule, which seemed more effective by mathematical modelling.8 Furthermore, tamoxifen is cheap and has beneficial effects (eg, on bone metabolism and the cardiovascular system) that might affect OS. An Italian saying warns mothers in a hurry not to throw the baby out with the bathwater: tamoxifen should not be discarded, it might still be important in the adjuvant treatment of early-stage breast cancer. Giovanni Ucci Oncology Department, SC Oncologia Medica, Azienda Ospedale di Lecco, Lecco, Italy [email protected]
http://oncology.thelancet.com Vol 9 April 2008
6
7
8
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45–53. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005; 23: 9312–18. Punglia RS, Winer EP, Weeks JC, Burstein HJ. Could treatment with tamoxifen be superior to aromatase inhibitors in early-stage breast cancer after pharmacogenomic testing? A modeling analysis. J Clin Oncol 2007; 25: 18S (20 suppl): 502. Viale G, Giobbie-Hurder A. BIG 1-98 Collaborative Group and IBCSG: value of centrally-assessed Ki-67 labeling index as a marker of prognosis and predictor of response to adjuvant endocrine therapy in the BIG 1-98 trial of postmenopausal women with estrogen receptor-positive breast cancer. 30th San Antonio Breast Cancer Symposium; 2007: (abstr 64). Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 2008; 9: 23–28. Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 2006; 7: 991–96. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559–70. Punglia RS, Kuntz KM, Winer EP, Weeks JC, Burstein HJ. Optimizing adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer: a decision analysis. J Clin Oncol 2005; 23: 5178–87.
We welcome the updated, 100-month findings from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.1 However, the cross-study comparisons of cardiovascular adverse events that are discussed in the paper are flawed, and could more appropriately be subtitled: “if you do not look, you do not find”. As previously described,2 adverse events, including cardiovascular events, were reported by checking specific boxes on the case report forms in the Breast International Group (BIG) 1-98 trial, compared with a nonspecific request to report adverse events in the ATAC trial. We therefore believe this is a misleading comparison. Readers should be alerted to the invalidity of cross-study comparisons, especially when methodology is so disparate, and should reject any premature conclusions until direct evidence from headto-head randomised trials is available.3 Alan Coates*, Henning Mouridsen, Beat Thürlimann, for the BIG 1-98 Collaborative Group International Breast Cancer Study Group, Bern, Switzerland (AC), Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark (HM), Senology Centre of Eastern Switzerland, Kantonsspital, St Gallen, Switzerland (BT) [email protected] AC has received travel grants from Novartis for presenting findings of the BIG 1-98 trial at academic and educational meetings. HM has received honoraria from Pfizer and Novartis for advisory boards and teaching lectures. BT holds Novartis stock and has received travel grants from Novartis and AstraZeneca during the BIG 1-98 trial (1998–2008).
315
programme at least 12 months before the full report appears in print. The articles by NICE will complement NICE’s other publications (ie, full appraisal, quick reference guide, and information for the public) that are issued when a final appraisal is announced, and will provide oncologists with an overview of the decision-making processes that have gone into issuing the appraisal as well as a discussion of the pertinent clinical evidence and economic considerations that influenced the decision. Since its establishment in 1999, NICE has published 35 appraisals of drugs for treating cancer, 33 of which are discussed in a recent Keynote Comment by Michael Rawlins, Chairman of NICE.2 NICE’s decisions can sometimes be controversial, taking up many column inches in the popular media, both in the UK and internationally, so further detail of the thought processes underlying the decisions could help doctors explain NICE’s final recommendations to their patients. Furthermore, NICE’s recommendations are not just relevant to the UK (the issue of paying for modern cancer care is of global concern),3 thus NICE’s decisions and reasoning are of interest to health-care authorities and drug-funding organisations across the world. NICE currently works with other medical journals to provide summaries to doctors of new clinical guidelines.4 As yet, however, no formal collaboration exists between NICE and a journal to highlight when a decision on a technology is made—a decision that is fundamental to subsequent guidelines. Thus, this new collaboration will provide a record of NICE’s oncology-related appraisals (and reappraisals where a change to existing recommendations
is made) in the medical literature, and will make knowledge of and details of their recommendations more accessible to worldwide audiences. Commenting on this collaboration, Carole Longson, Director of the Centre for Health Technology Evaluation at NICE, said: “This is an exciting opportunity for NICE to work with a prominent medical journal and highlight our recommendations to their readers. Developments in cancer therapy are ever increasing and it is important these new technologies are assessed by an independent organisation to assess their value to the NHS. We hope the readers of The Lancet Oncology find this Special Report a useful aid to understanding how we make our assessments and decisions”. The oncology drug pipeline is a busy one, and NICE has many technology appraisals in development for drugs against cancer. We hope our collaboration with NICE will provide a useful aid for understanding the complex processes involved in deciding which oncology drugs are approved for use in the NHS. Lidia Siemaszkiewicz The Lancet Oncology, London, UK 1
2 3 4
Gajraj E, Chung H, Longson C, Stevens A. Rituximab for follicular nonHodgkin lymphoma. Lancet Oncol 2008; published online Feb 27. DOI:10.1016/S1470-2045(08)70036-6. Rawlings M. Paying for modern cancer care—a global perspective. Lancet Oncol 2007; 8: 749–51. Schwartsmann G, Picon PD. When drugs are worth more than gold! Lancet Oncol 2007; 8: 1049–50. Norton C, Thomas L, Hill J. Management of faecal incontinence in adults: summary of NICE guidance. BMJ 2007; 334: 1370–71.
Inappropriate ATAC on tamoxifen The 100-month findings in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) update trial,1 confirm that postmenopausal patients with early-stage breast cancer treated with tamoxifen or anastrazole have the same overall survival (OS) even after prolonged follow-up. This finding is explained by competing causes of death that might have occurred in this group of patients and by a non-significant, otherwise unexplained higher number of deaths due to non-breast cancer in the anastrazole group. An alternative explanation might be that the advantage of anastrazole is restricted to a small subgroup of patients who cannot be distinguished in the 314
present conditions, while most patients still benefit from treatment with tamoxifen. The effect of genetic polymorphism of the cytochrome P450 CYP2D6 on tamoxifen metabolism might support this view.2 Patients homozygous for the wild-type gene (almost 80%) metabolise tamoxifen to the active form endoxifen more efficiently, and therefore, have the greatest advantage compared with those who are heterozygous or homozygous for the mutated gene (intermediate or poor metabolisers). Punglia and co-workers3 used a mathematical model to extrapolate this hypothesis to the findings of the Breast International Group (BIG) 1-98 trial http://oncology.thelancet.com Vol 9 April 2008
Reflection and Reaction
1
2
AJ Photo/HOP Americain/Science Photo Library
3
4
5
Considering adjuvant treatment options for patients with breast cancer
and noted that only intermediate and poor metabolisers benefited from the substitution of tamoxifen with letrozole. Several attempts to identify predictive factors of differential response to adjuvant endocrine treatment are underway,4,5 but no practical criteria have been agreed for choosing between tamoxifen and aromatase inhibitors. Nonetheless, the advantage of aromatase inhibitors over tamoxifen is overemphasised in clinical practice, although no ongoing trials have shown a substantial advantage in OS, even with extended follow-up. Consequently, adjuvant tamoxifen might be abandoned by clinicians with the justification that frontline aromatase inhibitors are more effective. Analogously, sequential combined treatment, which improved OS compared with tamoxifen alone,6,7 is supposed to be detrimental, because it will not prevent early systemic relapse: this will not be proved unless ongoing trials (ie, BIG 1-98 trial) do not show that aromatase inhibitors alone are any better than the sequential schedule, which seemed more effective by mathematical modelling.8 Furthermore, tamoxifen is cheap and has beneficial effects (eg, on bone metabolism and the cardiovascular system) that might affect OS. An Italian saying warns mothers in a hurry not to throw the baby out with the bathwater: tamoxifen should not be discarded, it might still be important in the adjuvant treatment of early-stage breast cancer. Giovanni Ucci Oncology Department, SC Oncologia Medica, Azienda Ospedale di Lecco, Lecco, Italy [email protected]
http://oncology.thelancet.com Vol 9 April 2008
6
7
8
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45–53. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005; 23: 9312–18. Punglia RS, Winer EP, Weeks JC, Burstein HJ. Could treatment with tamoxifen be superior to aromatase inhibitors in early-stage breast cancer after pharmacogenomic testing? A modeling analysis. J Clin Oncol 2007; 25: 18S (20 suppl): 502. Viale G, Giobbie-Hurder A. BIG 1-98 Collaborative Group and IBCSG: value of centrally-assessed Ki-67 labeling index as a marker of prognosis and predictor of response to adjuvant endocrine therapy in the BIG 1-98 trial of postmenopausal women with estrogen receptor-positive breast cancer. 30th San Antonio Breast Cancer Symposium; 2007: (abstr 64). Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 2008; 9: 23–28. Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 2006; 7: 991–96. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007; 369: 559–70. Punglia RS, Kuntz KM, Winer EP, Weeks JC, Burstein HJ. Optimizing adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer: a decision analysis. J Clin Oncol 2005; 23: 5178–87.
We welcome the updated, 100-month findings from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial.1 However, the cross-study comparisons of cardiovascular adverse events that are discussed in the paper are flawed, and could more appropriately be subtitled: “if you do not look, you do not find”. As previously described,2 adverse events, including cardiovascular events, were reported by checking specific boxes on the case report forms in the Breast International Group (BIG) 1-98 trial, compared with a nonspecific request to report adverse events in the ATAC trial. We therefore believe this is a misleading comparison. Readers should be alerted to the invalidity of cross-study comparisons, especially when methodology is so disparate, and should reject any premature conclusions until direct evidence from headto-head randomised trials is available.3 Alan Coates*, Henning Mouridsen, Beat Thürlimann, for the BIG 1-98 Collaborative Group International Breast Cancer Study Group, Bern, Switzerland (AC), Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen, Denmark (HM), Senology Centre of Eastern Switzerland, Kantonsspital, St Gallen, Switzerland (BT) [email protected] AC has received travel grants from Novartis for presenting findings of the BIG 1-98 trial at academic and educational meetings. HM has received honoraria from Pfizer and Novartis for advisory boards and teaching lectures. BT holds Novartis stock and has received travel grants from Novartis and AstraZeneca during the BIG 1-98 trial (1998–2008).
315