Correspondence
of falls prevention is inconsistent, and significant effects on other nonskeletal endpoints are unlikely.4 Our meta-analysis suggested that lower doses of vitamin D were more effective than higher doses on BMD, refuting the suggestion that more aggressive dosing might produce better outcomes. Non-compliance is an issue with any intervention, more so in clinical practice than in clinical trials. Thus, if vitamin D is ineffective in a trial context, it is even less likely to be effective in clinical practice. Our review suggests that vitamin concentrations higher than 40 nmol/L are adequate for bone health and, as a result, that vitamin D deficiency is rather less common than previously suggested. We declare that we have no competing interests.
*Ian R Reid, Mark J Bolland, Andrew Grey [email protected] Faculty of Medical and Health Sciences, University of Auckland, PB 92019, Auckland, New Zealand (IRR, MJB, AG); and Department of Endocrinology, Auckland District Health Board, Auckland, New Zealand (IRR) 1
2
3
4
Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55. Iuliano-Burns S, Ayton J, Hillam S, et al. Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners. Osteoporos Int 2012; 23: 2461–67. Wamberg L, Pedersen SB, Richelsen B, Rejnmark L. The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study. Calcif Tissue Int 2013; 93: 69–77. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http://dx.doi. org/10.1016/S2213-8587(13)70212-2.
number of invasive cervical cancers detected in the human papillomavirus (HPV)-based screening group was slightly lower than in the cytologybased screening group only at the first screening round. This result suggests that HPV testing is not as effective as cytology in early detection of invasive cervical cancers;2 and this is plausible from both epidemiological and biological points of view. In western countries the incidence of invasive cervical cancers is very low; after the first round of screening, clearance of cervical intraepithelial neoplasia grade 3 (CIN3) following HPV testing is high, and the efficacy of early detection of invasive cancer by cytology is masked. The lesser sensitivity of HPV testing for invasive cervical cancers could be explained because invasive cervical cancers are shedding cells with major molecular rearrangement and the viral DNA load could be in some instances under the sensitivity of the test.3 Ronco and colleagues’ study infers two different roles for cytology and HPVbased testing: the first is best directed for the identification of precursors, the second is best for early diagnosis of cervical cancer and to a lesser extent to CIN3 detection. These two different performances should be acknowledged to choose cytology or HPV-based testing on the basis of disease prevalence and screening aims, cancer prevention, or early cancer diagnosis. The European Institute of Oncology receives fundings for the activity of MS from Sanofi Pasteur, GSK, Qiagen, Roche Molecular Systems, and Becton Dickinsons. SI declares that she has no competing interests.
Mario Sideri, *Sarah Igidbashian [email protected] Preventive Gynaecology Unit, European Institute of Oncology, 20141 Milano, Italy
HPV-based screening for prevention of invasive cervical cancer
1
2
We read with interest Guglielmo Ronco and colleagues’ Article (Feb 8, p 524).1 It is important to note that the 1294
Ronco G, Dillner J, Elfström KM, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383: 524–32. Zucchetto A, Ronco G, Giorgi Rossi P, et al. IMPATTO CERVICE Working Group. Screening patterns within organized programs and survival of Italian women with invasive cervical cancer. Prev Med 2013; 57: 220–26.
3
Sundström K, Ploner A, Dahlström LA, et al. Prospective study of HPV16 viral load and risk of in situ and invasive squamous cervical cancer. Cancer Epidemiol Biomarkers Prev 2013; 22: 150–58.
The landmark follow-up study by Guglielmo Ronco and colleagues 1 clearly demonstrates that high grade cervical intraepithelial neoplasia (CIN) is an excellent surrogate marker for invasive cervical cancer, strengthening the findings of the initial screening studies conducted in the four European countries (Sweden [Swedescreen], the Netherlands [POBASCAM], England [ARTISTIC], and Italy [NTCC]). Non-believers now lose another argument often used against prophylactic HPV vaccination programmes. Furthermore, the pooled analysis proves again that HPV testing is superior to regular cytologic screening, as has been repeatedly proven in multiple trials over the years. However, it is disappointing that even with HPV screening so many women still developed cervical cancer in both groups, especially the 19 patients diagnosed during the long-term follow-up raise concern. The rates in the Italian NTCC trial were much lower than in the other three trials. Can this be explained by a more stringent triage, a more careful follow-up of test-positive women, or because of other reasons? We feel the authors should really provide a more thorough analysis of all such breakthrough cases, including compliance issues, demographics, history, stage, proportion of adenocarcinomas, just to name a few potential key variables. While there is evidence that HPV testing is the best screening test, it appears that further improvement is needed. We must identify the best triage, including colposcopy and follow-up protocols to ensure that women who comply do not develop cervical cancer. Another important point is the fact that in some countries the first cohorts of HPV-vaccinated women are already in their thirties thus entering the www.thelancet.com Vol 383 April 12, 2014
of falls prevention is inconsistent, and significant effects on other nonskeletal endpoints are unlikely.4 Our meta-analysis suggested that lower doses of vitamin D were more effective than higher doses on BMD, refuting the suggestion that more aggressive dosing might produce better outcomes. Non-compliance is an issue with any intervention, more so in clinical practice than in clinical trials. Thus, if vitamin D is ineffective in a trial context, it is even less likely to be effective in clinical practice. Our review suggests that vitamin concentrations higher than 40 nmol/L are adequate for bone health and, as a result, that vitamin D deficiency is rather less common than previously suggested. We declare that we have no competing interests.
*Ian R Reid, Mark J Bolland, Andrew Grey [email protected] Faculty of Medical and Health Sciences, University of Auckland, PB 92019, Auckland, New Zealand (IRR, MJB, AG); and Department of Endocrinology, Auckland District Health Board, Auckland, New Zealand (IRR) 1
2
3
4
Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet 2014; 383: 146–55. Iuliano-Burns S, Ayton J, Hillam S, et al. Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners. Osteoporos Int 2012; 23: 2461–67. Wamberg L, Pedersen SB, Richelsen B, Rejnmark L. The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study. Calcif Tissue Int 2013; 93: 69–77. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014; published online Jan 24. http://dx.doi. org/10.1016/S2213-8587(13)70212-2.
number of invasive cervical cancers detected in the human papillomavirus (HPV)-based screening group was slightly lower than in the cytologybased screening group only at the first screening round. This result suggests that HPV testing is not as effective as cytology in early detection of invasive cervical cancers;2 and this is plausible from both epidemiological and biological points of view. In western countries the incidence of invasive cervical cancers is very low; after the first round of screening, clearance of cervical intraepithelial neoplasia grade 3 (CIN3) following HPV testing is high, and the efficacy of early detection of invasive cancer by cytology is masked. The lesser sensitivity of HPV testing for invasive cervical cancers could be explained because invasive cervical cancers are shedding cells with major molecular rearrangement and the viral DNA load could be in some instances under the sensitivity of the test.3 Ronco and colleagues’ study infers two different roles for cytology and HPVbased testing: the first is best directed for the identification of precursors, the second is best for early diagnosis of cervical cancer and to a lesser extent to CIN3 detection. These two different performances should be acknowledged to choose cytology or HPV-based testing on the basis of disease prevalence and screening aims, cancer prevention, or early cancer diagnosis. The European Institute of Oncology receives fundings for the activity of MS from Sanofi Pasteur, GSK, Qiagen, Roche Molecular Systems, and Becton Dickinsons. SI declares that she has no competing interests.
Mario Sideri, *Sarah Igidbashian [email protected] Preventive Gynaecology Unit, European Institute of Oncology, 20141 Milano, Italy
HPV-based screening for prevention of invasive cervical cancer
1
2
We read with interest Guglielmo Ronco and colleagues’ Article (Feb 8, p 524).1 It is important to note that the 1294
Ronco G, Dillner J, Elfström KM, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383: 524–32. Zucchetto A, Ronco G, Giorgi Rossi P, et al. IMPATTO CERVICE Working Group. Screening patterns within organized programs and survival of Italian women with invasive cervical cancer. Prev Med 2013; 57: 220–26.
3
Sundström K, Ploner A, Dahlström LA, et al. Prospective study of HPV16 viral load and risk of in situ and invasive squamous cervical cancer. Cancer Epidemiol Biomarkers Prev 2013; 22: 150–58.
The landmark follow-up study by Guglielmo Ronco and colleagues 1 clearly demonstrates that high grade cervical intraepithelial neoplasia (CIN) is an excellent surrogate marker for invasive cervical cancer, strengthening the findings of the initial screening studies conducted in the four European countries (Sweden [Swedescreen], the Netherlands [POBASCAM], England [ARTISTIC], and Italy [NTCC]). Non-believers now lose another argument often used against prophylactic HPV vaccination programmes. Furthermore, the pooled analysis proves again that HPV testing is superior to regular cytologic screening, as has been repeatedly proven in multiple trials over the years. However, it is disappointing that even with HPV screening so many women still developed cervical cancer in both groups, especially the 19 patients diagnosed during the long-term follow-up raise concern. The rates in the Italian NTCC trial were much lower than in the other three trials. Can this be explained by a more stringent triage, a more careful follow-up of test-positive women, or because of other reasons? We feel the authors should really provide a more thorough analysis of all such breakthrough cases, including compliance issues, demographics, history, stage, proportion of adenocarcinomas, just to name a few potential key variables. While there is evidence that HPV testing is the best screening test, it appears that further improvement is needed. We must identify the best triage, including colposcopy and follow-up protocols to ensure that women who comply do not develop cervical cancer. Another important point is the fact that in some countries the first cohorts of HPV-vaccinated women are already in their thirties thus entering the www.thelancet.com Vol 383 April 12, 2014
