Overestimated lead times in cancer screening has led to substantial underestimation of overdiagnosis.

BACKGROUND: Published lead time estimates in breast cancer screening vary from 1 to 7 years and the percentages of overdiagnosis vary from 0 to 75%. The differences are usually explained as random variations. We study how much can be explained by using different definitions and methods. METHODS: We estimated the clinically relevant lead time based on the observed incidence reduction after attending the last screening round in the Norwegian mammography screening programme. We compared this estimate with estimates based on models that do not take overdiagnosis into account (model-based lead times), for varying levels of overdiagnosis. Finally, we calculated overdiagnosis adjusted for clinical and model-based lead times and compared results. RESULTS: Clinical lead time was about one year based on the reduction in incidence in women previously offered screening. When overdiagnosed tumours were included, the estimates increased to 4-9 years, depending on the age at which screening begins and the level of overdiagnosis. Including all breast cancers detected in women long after the end of the screening programme dilutes the level of overdiagnosis by a factor of 2-3. CONCLUSION: When overdiagnosis is not taken into account, lead time is substantially overestimated. Overdiagnosis adjusted for model-based lead time is a function tending to zero, with no simple interpretation. Furthermore, the estimates are not in general comparable, because they depend on both the duration of screening and duration of follow-up. In contrast, overdiagnosis adjusted for clinically relevant tumours is a point estimate (and interpreted as percentage), which we find is the most reasonable method.

Informed choice requires information about both benefits and harms.

A study found that women participating in mammography screening were content with the programme and the paternalistic invitations that directly encourage participation and include a pre-specified time of appointment. We argue that this merely reflects that the information presented to the invited women is seriously biased in favour of participation. Women are not informed about the major harms of screening, and the decision to attend has already been made for them by a public authority. This short-circuits informed decision-making and the legislation on informed consent, and violates the autonomy of the women. Screening invitations must present both benefits and harms in a balanced fashion, and should offer, not encourage, participation. It should be stated clearly that the choice not to participate is as sensible as the choice to do so. To allow this to happen, the responsibility for the screening programmes must be separated from the responsibility for the information material.

Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

Voriconazole versus amphotericin B in cancer patients with neutropenia.

BACKGROUND: Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy are used both empirically and therapeutically in these patients. OBJECTIVES: To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. SEARCH STRATEGY: MEDLINE and the Cochrane Library (May 2005). Letters, abstracts and unpublished trials were accepted. Contact to authors and industry. SELECTION CRITERIA: Randomised trials comparing voriconazole with amphotericin B or fluconazole. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by two authors independently. MAIN RESULTS: Two trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infections) in neutropenic cancer patients (849 patients, 58 deaths). The other trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from analysis by the authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication and substitution with electrolytes and salt water to avoid handicapping this drug. This choice of comparator resulted in a marked difference in the duration of treatment on trial drugs (77 days with voriconazole versus 10 days with amphotericin B), and precludes meaningful comparisons of the benefits and harms of the two drugs. AUTHORS' CONCLUSIONS: Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions.