The solution to the debate (and equipoise) will come from a randomised trial
Thus the benefit was largely due to the very presence of a well-oiled screening infrastructure in these regions, i.e., more resources, better equipment, more accountability, quality assurance, doctors, nurses and radiographers with highly practised skills, etc., rather than the detection and treatment of mammographically detected lesions.
Could these resources, skills and awareness be retained, without the mammograms? That being questionable, there should be a proper informed consent in place- which would in turn create an equipoise- an ideal situation to conduct a randomised trial for which the current evidence provides ethical support.
The existence of overdiagnosis(1,2,3) by screening (5-15 per 2500/10 years) makes one wonder how the host maintains the dormancy of even invasive cancers. This is vividly demonstrated in the peaks of incidence of invasive breast cancer during a 3-yearly screening round that is not followed by troughs(4), even after several rounds of screening running up to current times.
The answer to this puzzle could be provided by a randomised trial that should be performed within national screening programmes to test the value of treating screen-detected lesions within the context of modern multidisciplinary therapeutic approach. In such a trial, standard care would be compared with the experimental group in which mammogram results are not disclosed unless there is radiological evidence of progression or development of a clinical lump. A translational component is important for understanding host mechanisms that maintain dormancy. Not performing a biopsy of suspicious lesions would avoid any inducement of growth that may theoretically occur due to the trauma and consequent local release of growth factors(5). While halving overdiagnosis, such a trial could lead to novel host-based therapies.
There is a precedence of even greater hereticism in the PROTECT trial for prostate cancer in which men with confirmed prostate cancer (including the trauma of core biospy) are randomised to a no-treatment arm, surgery or radiotherapy.6
However, if such a trial is found impossible to approve, another design is possible to test the hypothesis that only hormone resistant tumours are dangerous. The trial would be limited to postmenopausal women with a mammographically suspicious lesions who would be consented and randomly allocated to the experimental arm or further standard investigations and treatment. Those in the experimental arm would receive a short course (until tumour changes size or 6 months whichever is earlier) of an aromatase inhibitor (e.g., letrozole) and carefully monitored by ultrasound every 2 months and a mammogram repeated at 6 months.
If the drug continued for 5 years - it would be similar to the IBIS-2 trial. However, to test the hypothesis that 'only hormone resistant tumours are dangerous' the following would need to be done: If the lesion shrinks, or remains stable, the drug is stopped and watchful wait continued. If the lesion grows in size then the patient is investigated by a biopsy and given standard treatment. The trial would be powered to test for non-inferiority of 5 and 10-year survival from the date of randomisation and the secondary end points would be lowering the risk of diagnosis and treatment of cancer in the experimental arm, along with translational and psychological sub studies.
Jayant S Vaidya
1. Kalager M, Zelen M, Langmark F, Adami HO. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med 2010;363(13):1203-10.
2. Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2009(4):CD001877.
3. Jorgensen KJ, Gotzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BMJ 2009;339:b2587.
4. Vaidya JS. Women undergoing screening mammography experience a higher incidence of invasive breast cancer, without a corresponding reduction in symptomatic breast cancer. BMJ 20 Jul 2009 http://www.bmj.com/content/339/bmj.b2587/reply#
5. Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res 2008;14(5):1325-32.
6. Pashayan N, Duffy SW, Pharoah P, Greenberg D, Donovan J, Martin RM, et al. Mean sojourn time, overdiagnosis, and reduction in advanced stage prostate cancer due to screening with PSA: implications of sojourn time on screening. Br J Cancer 2009;100(7):1198-204.
Competing interests: No competing interests