- Email: [email protected]
Breast screening in women aged 40–49 years
Accepting survival statistics from the two published studies,2,3 both of which originated between 1978 and 1981, as an indicator of the appropriateness of a screening procedure at the present time may be inappropriate. Current and future treatments may improve the future statistics for long-term survival of patients currently detected by mammographic screening. The issue should not be the suggestion that any segment of the population be excluded, but rather a rational discussion of who should pay for screening under what circumstances. As noted by Gail and Rimer,4 any woman aged 40–49 years who shared the same risk for developing breast cancer as a woman aged 50 or greater would certainly qualify for screening. One would then have to quantify risk on an individual basis for those at increased risk. It would then have to be determined, should controversy continue, who should pay for mammography in women at low or no increased risk of breast cancer. We should not address all women in a particular decade of life with the implication that they share equal risk. *Murray H Seltzer, Janette H McDermott Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey College of Medicine, Newark, NJ; Department of Surgery, St Barnabas Medical Center, Livingston, NJ; and *Practice Limited to Surgical Diseases of the Breast, PO Box 1845, Livingston, NJ 07039, USA 1
Dickersin K. Breast screening in women aged 40–49 years: what next? Lancet 1999; 353: 1896–97. 2 Alexander FE, Anderson TJ, Brown HK, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–08. 3 UK Trial of Early Detection of Breast Cancer group. 16-year mortality from breast cancer in the UK Trial of Early Detection of Breast Cancer. Lancet 1999; 353: 1909–14. 4 Gail M, Rimer B. Risk-based recommendations for mammographic screening for women in their forties. J Clin Oncol 1998; 16: 3105–14.
Author’s reply Sir—D W van Bekkum takes issue with the fact that I am from the USA and commented on UK studies. I fail to see the problem. If research evidence applied only to the country in which it was generated, patients and their doctors would have little to guide them in selecting the right care. Furthermore, I am not sure what is “widely” different between the USA and Europe. Irrespective of who pays for health care, women are afraid of breast cancer and currently depend on mammography as the only available means to detect it early.
THE LANCET • Vol 354 • September 11, 1999
I did not discuss the NCI recommendations or the results of the other randomised trials of mammography for women aged 40–49, mainly because that territory has been well covered in the literature. It is unlikely that either he or I or others who have been thinking about these issues for a long time would be swayed in our opinions by yet another critical review of the existing trials. My point was that the issue of screening women aged 40–49 is no longer just scientific, it is also political. Van Bekkum states that the best way to decrease the risks associated with a diagnosis of breast cancer is through early detection by mammography. One of the main difficulties with screening younger women is the low prevalence of breast cancer in this age group resulting in a rather large number of women who have false-positive results and must return for further testing, including biopsies. In addition, mammography frequently detects ductal carcinoma in situ (DCIS), a breast condition that progresses in some but not all women to invasive cancer. Because it is not possible to predict when DCIS will progress, women with DCIS are commonly treated as if they have invasive breast cancer, for example with mastectomy. Daniel Kopans is correct that discussion of the efficacy of mammographic screening seems to imply inappropriately a special significance to age 50. Age groups originally constructed for the purpose of statistical analysis have perhaps become firmly entrenched because age 50 is seen as a surrogate for menopause, when the risk of breast cancer and the sensitivity of mammography do in fact increase. What we all really want to know is: at what age should women begin mammographic screening? Unfortunately, no trial has addressed this question so far. And with the exception of the Canadian trial,1 none of the available data are from randomised trials specifically designed to address the efficacy of screening women in their forties. The Canadian trial showed no benefit to screening in this age group. The benefit shown by F Alexander and colleagues’ Edinburgh trial,2 was not apparent while the participating women were still in their forties, but only when they had reached their fifties. Kopans’ major criticism centres on combining results in a systematic review and meta-analysis, yet he has not specified how such an analysis might “skew” interpretation. Indeed, the objective of a systematic review is to apply scientific principles to reviewing
research. Thus, it is correct to take all available high-quality evidence into consideration when making a treatment decision or setting policy. Would Kopans prefer instead that a nonsystematic method of combining data or just selected individual studies be used to inform decision making? In describing the distribution of age at diagnosis of breast cancer, I did not intend to trivialise a breast cancer diagnosis at any age. I agree that the importance of DCIS to the issue of mammographic screening in women 40–49 is not trivial, but I known of no evidence that the mortality reduction that accrued more than 10 years after the start of the Edinburgh or Swedish trials is the result of an intervention in women with DCIS. Kay Dickersin Department of Community Health, School of Medicine, Brown University, Providence, RI 02912, USA (e-mail: [email protected]) 1
2
Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: In: Beast cancer detection and death rates among women aged 40 to 49 years. Can Med Assoc J 1992; 147: 1459–76. Alexander FE, Alderson TJ, Forrest APM, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–08.
Sir—In the summary of their report on the Edinburgh study of breast cancer screening, F E Alexander and colleagues (June 5, p 1903),1 conclude that “the results for younger women suggest benefit from introduction of screening before 50 years of age”. However, earlier in the summary they note that “no breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years”. Although screening was associated with a (non-significant) reduction in breast cancer mortality for women who entered the trial at ages 45–49, all the benefit these women experienced was derived from cancers detected by screening that occurred after they turned 50, which would seem to argue against screening before age 50. *Virginia L Ernster, Karla Kerlikowske Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA (e-mail: [email protected]) 1
Alexander FE, Anderson TJ, Brown HK, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–09.
Author’s reply Sir—Interpretation of the analysis that Virginia Ernster and Karla Kerlikowske cite has to be made very carefully, as we noted in our report, because the
947
subgroup analysis involves selection by values of a variable (age at diagnosis) that is influenced by trial group. We have found no evidence that breast cancer mortality from cancers diagnosed under the age of 50 was lower in women offered screening. This lack of evidence certainly suggests that no benefit was derived from screening for women whose cancers would, in the absence of screening, have been diagnosed while under 50. It is, however, false to conclude that, for younger entrants, “all the benefit these women experienced was derived from cancers detected by screening after they turned 50”. This conclusion ignores the potential for reduced mortality from cancers that were detected by screening under the age of 50 but would not have become symptomatic until after the 50th birthday. This sentence in our summary possibly oversimplifies data we present at the end of the results section and subsequently discuss. Freda Alexander Public Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, UK (e-mail: [email protected])
Immunisation with gp160 in HIV-1 infection Sir—When The Lancet grants a large amount of space to a single study (22 May, p 1735),1 its readership can hardly doubt the over-riding importance of the results. Eric Sanström and colleagues report that, in combination with HAART and no denial of best available treatment, this trial of a highly regarded vaccine shows “no clinical benefit”. There are a few indications of possible benefit in a rise in some CD4 cell counts, fewer deaths in treated patients than in controls after 2 years but not after 3 years, a substantial increase in gp160specific T-cell proliferation (immune activation?) in 64 vaccinees compared with 59 placebo recipients who were given the same number of injections of an inorganic, much less antigenic adjuvant (aluminium phosphate). No details are given about viral replication, usually regarded as an essential measurement of therapeutic effect. In all 14 primary clinical endpoints, including deaths, there was no difference between the vaccine and placebo groups in the 124 out of 835 patients who completed the trial. Although input variables for treated and control groups are scrupulously balanced, intervening variables affecting clinical endpoints are not. For instance, no detail was given about drop-out or recidivation, and no
948
reference to the pattern, interrupting, or continuation of risk behaviour in the 642 homosexual men, nor to use of recreational drugs by the 78 patients who admitted drug injecting. Anal intercourse with or without such drugs, relapse to risk behaviour, and drugs by themselves considerably increase the risk of progression to AIDS, sometimes substantially, 2 because of sharing of opportunistic infections3 and for other reasons. 4 Sandström and colleagues are by no means unique in ignoring these decisive variables. In a retrieval of 90 clinical trials listed in EMBASE and MEDLINE, in almost 50 0 0 0 references to (clinical) AIDS in 1988–99, no data relate to continuation or interruption of risk behaviour during trials, despite 4847 references to drugs and 315 to the combination of drugs and sexual activity as risk factors in non-trial situations. In 95 trials between 1995 and 1999 summarised by experts at the US National Institutes of Health, 5 none give information about risk behaviour during the trials and only ten assess clinical end points, withdrawals, and toxicity. In all the others, results are assessed by CD4 cell counts and PCR RNA load. We agree that this commerciallysponsored study of a new vaccine, along with HAART, and best clinical practice, contains important messages for vaccine development and cinical trials in the future. Christian Fiala, *Gordon T Stewart Krankenhaus Korneuburg, 2100 Korneuburg, Austria; Department of Public Health, University of Glasgow, Glasgow, UK; and *Glenavon, Clifton Down, Bristol BS8 3HT, UK (e-mail: [email protected]) 1
Sandströn E, Wahren B, Nordic VAC-04 Study Group. Therapeutic immunisation with recombinant gp160 in HIV-1 infection. Lancet 1999; 353: 1735–42. 2 Stewart GT. Scientific surveillance and the control of AIDS. Health Care Anal 1994; 2: 279–88. 3 Jones JL, Hanson DL, Dworkin MS, Kaplan JE, Ward JW. Trends in AIDS-related opportunistic infections in men who have sex with men and drug users, 1991–1996. J Infect Dis 1998; 178: 114–20. 4 Fiala C. Lieben win gefährlich? WienMünchen: Deuticke, 1997. 5 Tavel JA, Miller KD, Masur H. Guide to major clinical trials of antiretroviral therapy in HIV-infected patients: protease inhibitors, non-nucleoside reversetranscriptase inhibitors, and nucleoside reverse-transcriptase inhibitors. Clin Infect Dis 1999; 228: 643–76.
Sir—Eric Sandström and Britta Wahren’s report 1 of post-exposure immunisation with recombinant gp160 in HIV-1-infected patients has further ignited the idea of combining
highly active antiretroviral therapy (HAART) and immunisation to, as these investigators state, improve the total effect. We suggest that the correct interpretation should be that any form of immunisation in HIV-1 infection should be done in the presence of HAART. To expect a summation of effects, a clear benefit of immunisation should be shown. In our study of immunisation with gp160 (the same used by Sandström and Wahren) alone or in combination with zidovudine monotherapy,2 the benefit of associated antiretroviral therapy in inducing accelerated responses to gp160 was evident. 3 However, that did not result in a better long-term outcome than with antiretroviral therapy alone. The Nordic 04 study1 shows a discrepancy between the lack of effect on clinical endpoints and a slower decline of CD4 T-cell numbers. Unfortunately in such a large study no viral load data were analysed and a multivariate analysis to assess the impact of associated antiretroviral therapy was not undertaken. To save the idea of post-exposure immunisation in HIV-1 infection, which has not yet been exhaustively tested for modalities other than envelope subunits, the chance to interpret the vast amount of data from several trials seems to have been missed. Although it is now clear that the detection of lymphoproliferative responses to HIV-1 proteins (mainly p24) in the absence of deliberate immunisation is associated with better outcome, 4 post-exposure immunisation trials suggest that the induction of similarly detectable responses does not greatly modify the course of infection. Furthermore, disproving Rosenberg’s hypothesis,4 no apparent deletion of HIV-1-specific CD4 T cells takes place. We think it is important to emphasise that even after repeated immunisations with an HIV-1 protein in the absence of virus suppression, lymphoproliferative responses are increasingly detected rather than disappearing. HAART provides the opportunity to test rationally designed immunisations in conditions of safety and optimum immune reactivity, possibly leading to virus control after HAART discontinuation. This opportunity, however, should not be used to merely repeat strategies, such as envelope subunits, which failed also in association with suboptimum treatment. On the contrary, recombinant subunits, such as Tat, 5 that are proven to induce protective immunity in animals, or other forms
THE LANCET • Vol 354 • September 11, 1999
Dickersin K. Breast screening in women aged 40–49 years: what next? Lancet 1999; 353: 1896–97. 2 Alexander FE, Anderson TJ, Brown HK, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–08. 3 UK Trial of Early Detection of Breast Cancer group. 16-year mortality from breast cancer in the UK Trial of Early Detection of Breast Cancer. Lancet 1999; 353: 1909–14. 4 Gail M, Rimer B. Risk-based recommendations for mammographic screening for women in their forties. J Clin Oncol 1998; 16: 3105–14.
Author’s reply Sir—D W van Bekkum takes issue with the fact that I am from the USA and commented on UK studies. I fail to see the problem. If research evidence applied only to the country in which it was generated, patients and their doctors would have little to guide them in selecting the right care. Furthermore, I am not sure what is “widely” different between the USA and Europe. Irrespective of who pays for health care, women are afraid of breast cancer and currently depend on mammography as the only available means to detect it early.
THE LANCET • Vol 354 • September 11, 1999
I did not discuss the NCI recommendations or the results of the other randomised trials of mammography for women aged 40–49, mainly because that territory has been well covered in the literature. It is unlikely that either he or I or others who have been thinking about these issues for a long time would be swayed in our opinions by yet another critical review of the existing trials. My point was that the issue of screening women aged 40–49 is no longer just scientific, it is also political. Van Bekkum states that the best way to decrease the risks associated with a diagnosis of breast cancer is through early detection by mammography. One of the main difficulties with screening younger women is the low prevalence of breast cancer in this age group resulting in a rather large number of women who have false-positive results and must return for further testing, including biopsies. In addition, mammography frequently detects ductal carcinoma in situ (DCIS), a breast condition that progresses in some but not all women to invasive cancer. Because it is not possible to predict when DCIS will progress, women with DCIS are commonly treated as if they have invasive breast cancer, for example with mastectomy. Daniel Kopans is correct that discussion of the efficacy of mammographic screening seems to imply inappropriately a special significance to age 50. Age groups originally constructed for the purpose of statistical analysis have perhaps become firmly entrenched because age 50 is seen as a surrogate for menopause, when the risk of breast cancer and the sensitivity of mammography do in fact increase. What we all really want to know is: at what age should women begin mammographic screening? Unfortunately, no trial has addressed this question so far. And with the exception of the Canadian trial,1 none of the available data are from randomised trials specifically designed to address the efficacy of screening women in their forties. The Canadian trial showed no benefit to screening in this age group. The benefit shown by F Alexander and colleagues’ Edinburgh trial,2 was not apparent while the participating women were still in their forties, but only when they had reached their fifties. Kopans’ major criticism centres on combining results in a systematic review and meta-analysis, yet he has not specified how such an analysis might “skew” interpretation. Indeed, the objective of a systematic review is to apply scientific principles to reviewing
research. Thus, it is correct to take all available high-quality evidence into consideration when making a treatment decision or setting policy. Would Kopans prefer instead that a nonsystematic method of combining data or just selected individual studies be used to inform decision making? In describing the distribution of age at diagnosis of breast cancer, I did not intend to trivialise a breast cancer diagnosis at any age. I agree that the importance of DCIS to the issue of mammographic screening in women 40–49 is not trivial, but I known of no evidence that the mortality reduction that accrued more than 10 years after the start of the Edinburgh or Swedish trials is the result of an intervention in women with DCIS. Kay Dickersin Department of Community Health, School of Medicine, Brown University, Providence, RI 02912, USA (e-mail: [email protected]) 1
2
Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: In: Beast cancer detection and death rates among women aged 40 to 49 years. Can Med Assoc J 1992; 147: 1459–76. Alexander FE, Alderson TJ, Forrest APM, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–08.
Sir—In the summary of their report on the Edinburgh study of breast cancer screening, F E Alexander and colleagues (June 5, p 1903),1 conclude that “the results for younger women suggest benefit from introduction of screening before 50 years of age”. However, earlier in the summary they note that “no breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years”. Although screening was associated with a (non-significant) reduction in breast cancer mortality for women who entered the trial at ages 45–49, all the benefit these women experienced was derived from cancers detected by screening that occurred after they turned 50, which would seem to argue against screening before age 50. *Virginia L Ernster, Karla Kerlikowske Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA (e-mail: [email protected]) 1
Alexander FE, Anderson TJ, Brown HK, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999; 353: 1903–09.
Author’s reply Sir—Interpretation of the analysis that Virginia Ernster and Karla Kerlikowske cite has to be made very carefully, as we noted in our report, because the
947
subgroup analysis involves selection by values of a variable (age at diagnosis) that is influenced by trial group. We have found no evidence that breast cancer mortality from cancers diagnosed under the age of 50 was lower in women offered screening. This lack of evidence certainly suggests that no benefit was derived from screening for women whose cancers would, in the absence of screening, have been diagnosed while under 50. It is, however, false to conclude that, for younger entrants, “all the benefit these women experienced was derived from cancers detected by screening after they turned 50”. This conclusion ignores the potential for reduced mortality from cancers that were detected by screening under the age of 50 but would not have become symptomatic until after the 50th birthday. This sentence in our summary possibly oversimplifies data we present at the end of the results section and subsequently discuss. Freda Alexander Public Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, UK (e-mail: [email protected])
Immunisation with gp160 in HIV-1 infection Sir—When The Lancet grants a large amount of space to a single study (22 May, p 1735),1 its readership can hardly doubt the over-riding importance of the results. Eric Sanström and colleagues report that, in combination with HAART and no denial of best available treatment, this trial of a highly regarded vaccine shows “no clinical benefit”. There are a few indications of possible benefit in a rise in some CD4 cell counts, fewer deaths in treated patients than in controls after 2 years but not after 3 years, a substantial increase in gp160specific T-cell proliferation (immune activation?) in 64 vaccinees compared with 59 placebo recipients who were given the same number of injections of an inorganic, much less antigenic adjuvant (aluminium phosphate). No details are given about viral replication, usually regarded as an essential measurement of therapeutic effect. In all 14 primary clinical endpoints, including deaths, there was no difference between the vaccine and placebo groups in the 124 out of 835 patients who completed the trial. Although input variables for treated and control groups are scrupulously balanced, intervening variables affecting clinical endpoints are not. For instance, no detail was given about drop-out or recidivation, and no
948
reference to the pattern, interrupting, or continuation of risk behaviour in the 642 homosexual men, nor to use of recreational drugs by the 78 patients who admitted drug injecting. Anal intercourse with or without such drugs, relapse to risk behaviour, and drugs by themselves considerably increase the risk of progression to AIDS, sometimes substantially, 2 because of sharing of opportunistic infections3 and for other reasons. 4 Sandström and colleagues are by no means unique in ignoring these decisive variables. In a retrieval of 90 clinical trials listed in EMBASE and MEDLINE, in almost 50 0 0 0 references to (clinical) AIDS in 1988–99, no data relate to continuation or interruption of risk behaviour during trials, despite 4847 references to drugs and 315 to the combination of drugs and sexual activity as risk factors in non-trial situations. In 95 trials between 1995 and 1999 summarised by experts at the US National Institutes of Health, 5 none give information about risk behaviour during the trials and only ten assess clinical end points, withdrawals, and toxicity. In all the others, results are assessed by CD4 cell counts and PCR RNA load. We agree that this commerciallysponsored study of a new vaccine, along with HAART, and best clinical practice, contains important messages for vaccine development and cinical trials in the future. Christian Fiala, *Gordon T Stewart Krankenhaus Korneuburg, 2100 Korneuburg, Austria; Department of Public Health, University of Glasgow, Glasgow, UK; and *Glenavon, Clifton Down, Bristol BS8 3HT, UK (e-mail: [email protected]) 1
Sandströn E, Wahren B, Nordic VAC-04 Study Group. Therapeutic immunisation with recombinant gp160 in HIV-1 infection. Lancet 1999; 353: 1735–42. 2 Stewart GT. Scientific surveillance and the control of AIDS. Health Care Anal 1994; 2: 279–88. 3 Jones JL, Hanson DL, Dworkin MS, Kaplan JE, Ward JW. Trends in AIDS-related opportunistic infections in men who have sex with men and drug users, 1991–1996. J Infect Dis 1998; 178: 114–20. 4 Fiala C. Lieben win gefährlich? WienMünchen: Deuticke, 1997. 5 Tavel JA, Miller KD, Masur H. Guide to major clinical trials of antiretroviral therapy in HIV-infected patients: protease inhibitors, non-nucleoside reversetranscriptase inhibitors, and nucleoside reverse-transcriptase inhibitors. Clin Infect Dis 1999; 228: 643–76.
Sir—Eric Sandström and Britta Wahren’s report 1 of post-exposure immunisation with recombinant gp160 in HIV-1-infected patients has further ignited the idea of combining
highly active antiretroviral therapy (HAART) and immunisation to, as these investigators state, improve the total effect. We suggest that the correct interpretation should be that any form of immunisation in HIV-1 infection should be done in the presence of HAART. To expect a summation of effects, a clear benefit of immunisation should be shown. In our study of immunisation with gp160 (the same used by Sandström and Wahren) alone or in combination with zidovudine monotherapy,2 the benefit of associated antiretroviral therapy in inducing accelerated responses to gp160 was evident. 3 However, that did not result in a better long-term outcome than with antiretroviral therapy alone. The Nordic 04 study1 shows a discrepancy between the lack of effect on clinical endpoints and a slower decline of CD4 T-cell numbers. Unfortunately in such a large study no viral load data were analysed and a multivariate analysis to assess the impact of associated antiretroviral therapy was not undertaken. To save the idea of post-exposure immunisation in HIV-1 infection, which has not yet been exhaustively tested for modalities other than envelope subunits, the chance to interpret the vast amount of data from several trials seems to have been missed. Although it is now clear that the detection of lymphoproliferative responses to HIV-1 proteins (mainly p24) in the absence of deliberate immunisation is associated with better outcome, 4 post-exposure immunisation trials suggest that the induction of similarly detectable responses does not greatly modify the course of infection. Furthermore, disproving Rosenberg’s hypothesis,4 no apparent deletion of HIV-1-specific CD4 T cells takes place. We think it is important to emphasise that even after repeated immunisations with an HIV-1 protein in the absence of virus suppression, lymphoproliferative responses are increasingly detected rather than disappearing. HAART provides the opportunity to test rationally designed immunisations in conditions of safety and optimum immune reactivity, possibly leading to virus control after HAART discontinuation. This opportunity, however, should not be used to merely repeat strategies, such as envelope subunits, which failed also in association with suboptimum treatment. On the contrary, recombinant subunits, such as Tat, 5 that are proven to induce protective immunity in animals, or other forms
THE LANCET • Vol 354 • September 11, 1999