Published 28 July 2009, doi:10.1136/bmj.b3014
Cite this as: BMJ 2009;339:b3014

Editorials

Managing low grade and borderline cervical abnormalities

The dilemma of choosing between conservative and aggressive policies remains

Broadly speaking, the goal of cancer screening is to shift disease detection to the furthest point upstream in the course of the neoplastic process at which treatment can prevent a precancerous lesion from becoming invasive, thus averting cancer, or prevent an early cancerous lesion from spreading, thus averting death from cancer. The challenges go beyond defining end points and choosing tests and procedures: not all precancerous lesions progress to invasive disease, and not all early invasive cancers progress to causedeath. The more upstream the lesion end point targeted for intervention, the greater the probability of overtreatment and harm to patients. Conversely, acting conservatively by shifting the trigger for treatment to downstream end points risks missing lesions that should have been treated earlier.

Anyone concerned with the challenges of screening for cancer, particularly from anatomical sites that are relatively inaccessible, must view the linked articles (doi:10.1136/bmj.b2546; doi:10.1136/bmj.b2548; doi:10.1136/bmj.b2549) from the trial of management of borderline and other low grade abnormal smears (TOMBOLA) as an embarrassment of riches.^{1 2 3} More is known about the course of cervical neoplasia than for any other cancer. Thus, to an outsider, it might seem that identifying precancerous cervical lesions and establishing the threshold for management and treatment should no longer be a matter of debate. The TOMBOLA articles, however, remind us that this is clearly not the case.^{1 2 3}

TOMBOLA examined the merits of conservative versus aggressive management and treatment of women with equivocal cytological findings or low grade abnormalities on Papanicolaou smears. Despite the differences in cytopathological nomenclature between North American and British or European systems, these two types of abnormalities serve as the earliest screening trigger for decisions on diagnostic management and treatment. The best course of action for women with these abnormalities is still unclear. Should they be immediately referred for colposcopy, or is close cytological surveillance safe enough? The ALTS trial in the United States concluded that women with low grade smears should be managed mostly by immediate colposcopy,^{4 5} whereas for women with borderline smears, surveillance with repeat cytology or human papillomavirus (HPV) testing are equally acceptable options.^{5 6} The findings of the ALTS trial have set the boundaries for professional guidelines in the US and have influenced clinical practice internationally.⁵ What the ALTS trial did not do, but TOMBOLA did, was to evaluate the merit of aggressive colposcopic management. In a secondary randomisation, TOMBOLA compared the policy of biopsy with selective recall with that of immediate large loop excision during colposcopy.²

The main findings from TOMBOLA have been eagerly awaited but are hardly surprising. The comparison of Papanicolaou surveillance with immediate colposcopy, the primary objective, showed that 37% more high grade cervical intraepithelial neoplasia lesions were found in the colposcopy arm than in the cytology arm. However, this benefit was offset by the harm of overtreatment,¹ which can lead to fertility problems, particularly in young women, in whom cervical intraepithelial neoplasia tends to regress more often than in older ones. Reassuringly, the extra detection of high grade lesions in the colposcopy arm of the trial was restricted to women younger than 40. Also expected was the finding that the difference in detection of high grade cervical intraepithelial neoplasia occurred mostly in women with low grade smear abnormalities, which suggests that a policy of immediate colposcopy for women with equivocal atypical cytology (borderline abnormalities in the United Kingdom and ASCUS (atypical cells of undetermined significance) smears in North America) would be excessive, unless a triage option for risk stratification can be adopted, such as HPV testing. Such stratification was supported by the ALTS trial,⁶ and it is also discussed in another editorial (doi:10.1136/bmj.b3005) and a further linked article in the BMJ (doi:10.1136/bmj.b2569).^{7 8}

It is worth noting that the findings of enhanced detection of high grade cervical intraepithelial neoplasia in the colposcopy arm of TOMBOLA represent the net effect from a combination of policies: the usual policy of biopsy and recall, together with an aggressive policy of immediate large loop excision if lesions were present. The comparison between these two policies was the second objective of TOMBOLA.² Again, the more aggressive approach resulted in more disease detection, but this happened exclusively at the initial examination. Over time, the proportions of women with high grade lesions were similar, as the "biopsy and recall" arm caught up with the "see and treat" arm in detecting prevalent and early incident lesions, offsetting the lead time bias. The more aggressive policy resulted in more overtreatment and adverse health events than the conservative option.²

An economic analysis based on the true costs, actual outcomes, and trajectory of care of TOMBOLA participants concluded that none of the three policies represented a clearly more cost effective option for managing women with equivocal or low grade smears.³ Unfortunately, given the fast pace of technological advances in cervical cancer screening, what happened to TOMBOLA participants is no longer applicable in the UK, particularly for those in the smear surveillance arm. Liquid based cytology has become the favoured technique in the UK, replacing the conventional smear test. Further analyses and secondary economic evaluations of the TOMBOLA data may help policy makers fully appreciate the evidence from this landmark study.

Cite this as: BMJ 2009;339:b3014

¹ Departments of Oncology and Epidemiology, McGill University, Montreal, QC, Canada H2W1S6

Research, doi:10.1136/bmj.b2546; Research, doi:10.1136/bmj.b2548; Research, doi:10.1136/bmj.b2549; Research, doi:10.1136/bmj.b2569; Editorial, doi:10.1136/bmj.b3005

---

Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. TOMBOLA Group. Cytological surveillance compared with immediate referral for colposcopy in management of women with low grade cervical abnormalities: multicentre randomised controlled trial. BMJ 2009;339:b2546.[Abstract/Free Full Text]
2. TOMBOLA Group. Biopsy and selective recall compared with immediate large loop excision in management of women with low grade cervical cytology referred for colposcopy: multicentre randomised controlled trial. BMJ 2009;339:b2548.[Abstract/Free Full Text]
3. TOMBOLA Group. Options for managing low grade cervical abnormalities detected at screening: cost effectiveness study. BMJ 2009;339:b2549.[Abstract/Free Full Text]
4. Anonymous. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 2000;92:397-402.[Abstract/Free Full Text]
5. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346-55.[CrossRef][Web of Science][Medline]
6. .Solomon D, Schiffman M, Tarone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-9.[Abstract/Free Full Text]
7. Ronco G, Arbyn M, Segnan N. Influence of HPV infection and age on the effectiveness of cervical screening. BMJ 2009;339:b3005.[Free Full Text]
8. Castle PE, Rodrìguez AC, Burk RD, Herrero R, Wacholder S, Alfaro M, et al. Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study. BMJ 2009;339:b2569.[Abstract/Free Full Text]

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