Ethics of “standard care” in randomised trials of screening for cervical cancer should not ignore scientific evidence and ground realities
C S Pramesh, Surendra Shastri, Indraneel Mittra, Rajendra A Badwe
We read with interest the recent editorial (1) in the IJME on the ethics of standard care in screening trials for cervical cancer in India. The author takes exception to the fact that three cervical cancer screening studies in India used no screening as the control arm, in spite of evidence that the Pap smear is an effective screening tool. The author argues that the Pap smear should have been the standard arm in these trials, and that it was unethical to “withhold” this screening method from participants in the control arm of the trial. At the outset, we wish to declare a conflict of interest in our response by virtue of being investigators of one of the aforesaid trials, but feel it necessary to clarify certain facts that have been overlooked. First, during the consent process, all women in the Mumbai trial (control and intervention arms) were counseled on Pap smear testing, given information on the centres nearby that offered the Pap smear and assured that they were free to get themselves screened if they so wished. Second, the author’s assertion that visual inspection with acetic acid (VIA) had already been proven to be effective on the basis of crosssectional studies, and that there was no need to perform randomised trials to prove that it was effective, lacks scientific credibility. The hierarchy of medical evidence places the randomised trial at level 1, or providing the highest level of evidence, whereas that yielded by cross-sectional studies is considered to be level 4 evidence, ie evidence that is unreliable. Major national public health policy decisions are always made on the basis of randomised level 1 evidence. Prior to our study, there had been no randomised evidence that VIA performed by trained primary health workers (who are the only healthcare providers available for the vast majority of the poor in rural and urban areas) leads to cervical cancer mortality reduction. In fact, an earlier study had shown that neither the Pap smear nor VIA had led to a decrease in mortality due to cervical cancer in India (2). Should we not obtain robust level 1 evidence before making a major public health decision to offer VIA as a routine screening method to all women in India?
Before commencing with the trial, the choice of no screening for the control arm was discussed with several experts at the national level. Three points are noteworthy. First, the Indian Council of Medical Research (ICMR) and the Ministry of Health and Family Welfare, Government of India had concluded that there was a dearth of facilities for nationwide screening for cervical cancer using the Pap smear, and had made a projection that even with a twelve-fold increase in staff trained in Pap smear, only a quarter of the eligible women in India could be screened (3). The report emphasised the urgent need for alternative methods of screening and suggested that visual examination of the cervix be evaluated (3). Second, a WHO– Government of India committee reiterated the points made in the ICMR report and, in view of the fact that the infrastructure and resources did not permit a nationwide Pap smear-based screening programme, stressed the need for the identification of an alternative method that was “scientifically correct, ethical and feasible” in India (4). Finally, a report from the Center for Risk Analysis, Department of health policy and management, Harvard School of Public Health affirmed that the Pap smear was difficult to implement in developing countries and suggested that alternative strategies be considered (5). Using mathematical modelling techniques, the report went on to compare the cost-effectiveness of the Pap smear, direct visual inspection of the cervix and human papilloma virus (HPV) DNA testing. The efficacy of once-in-a-lifetime screening with HPV DNA and direct inspection was almost identical (27% and 26% reduction in the incidence of cancer, respectively), and was superior to that of the Pap smear, which was 19%. The incremental cost-effectiveness ratio of the three techniques, when implemented three-yearly, was $460 per year of life saved (YLS) for visual inspection, while that of HPV DNA testing was 25 times higher, at $11,500 per YLS, and that of the Pap smear was even higher. The paper concluded that the Pap smear was the least effective and the most expensive amongst the techniques tested.
It becomes clear from the expert reports that the Pap smear cannot be considered the standard of care in India, not only because of the lack of infrastructure and trained manpower, but also because it is not cost-effective. The results of our study showed that VIA screening reduced the death rate from cervical cancer by 31%, ie 1 in 3 deaths were prevented. In addition, the study detected a very large number of pre-invasive cancers, which were easily treated by outpatient procedures. The latter suggests that in addition to a reduction in mortality, VIA screening promises to markedly bring down even the incidence of cervical cancer in this group in the future. Thus, the results of our study, if implemented widely, would save thousands of lives globally in the developing countries. In fact, the Wall Street Journal, while covering the plenary presentation of our study (6) at the annual American Society of Clinical Oncology (ASCO) meeting, quoted experts as saying: “(VIA) … can save lives, and could even be useful in low-income areas of the US with relatively high cervical cancer rates and low use of Pap tests” (7). An international expert estimated the number of lives saved by VIA screening globally to be of the order of 270,000 per year (8).
There has always existed a healthy tension between ethics and the scientific process, but a show of moral outrage only helps to vitiate this healthy relationship.
- Srinivasan S. Ethics of ‘standard care’ in randomised controlled trials of screening for cervical cancer. Indian J Med Ethics. 2013 Jul– Sep;10(3):147–9.
- Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, Hingmire S, Malvi SG, Thorat R, Kothari A, Chinoy R, Kelkar R, Kane S, Desai S, Keskar VR, Rajeshwarkar R, Panse N, Dinshaw KA. HPV screening for cervical cancer in rural India. N Engl J Med. 2009 Apr 2;360(14):1385– 94. doi: 10.1056/NEJMoa0808516.
- Singh V, Sehgal A, Luthra UK. Screening for cervical cancer by direct inspection. BMJ. 1992;304:534–5.
- Government of India – World Health Organization Collaborative Programme (2004–2005). Guidelines for cervical cancer screening programme [Internet]. Chandigarh: GoI-WHO; 2006 Jun [cited 2013 Aug 28]. Available from: http://www.rho.org/files/WHO_India_CCSP_guidelines_2005.pdf.
- Goldie SJ, Kuhn L, Denny L, Pollack A, Wright TC. Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness. JAMA. 2001 Jun 27;285 (24):3107–15. Erratum in: JAMA. 2001 Sep 5;286(9):1026.
- Shastri SS, Mittra I, Mishra G, Gupta S, Dikshit R, Badwe RA; Tata Memorial Centre, Mumbai, India. Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India [Internet]. Presentation, American Society for Clinical Oncology annual meeting 2013 [cited 2013 Aug 28]. Available from: http://www.meetinglibrary.asco.org/content/112133-132.
- Loftus P. Vinegar gets high marks in cervical cancer study. The Wall Street Journal [Internet]. 2012 June 2 [cited 2013 Aug 13]. Available from: http://www.online.wsj.com/article/SB10001424127887323469804578521201691094128.html.
- Lederman L. “Bridges built” at the 2013 ASCO annual meeting [Internet]. OBR green. 2013 June [cited 2013 Aug 13];7(6). Available from: http://www.obroncology.com/obrgreen/article/Bridges-Built-at-the-2013-ASCO-Annual-Meeting.