Confusion Over Differences in Registration and Randomization Criteria for the LORIS (Low-Risk DCIS) Trial

See response to this letter here.


Letter to the Editor

By Daniel Rea, Adele Francis, Jeremy Thomas, John Bartlett, Sarah Bowden, David Dodwell, Lesley Fallowfield, Claire, Gaunt, Andrew Hanby, Valerie Jenkins, Lucy Matthews, Sarah Pinder, Sarah Pirrie, Malcom Reed, Matthew Wallis, Maggie Wilcox, and Jennie Young on behalf of the LORIS Trial Management Group

To the Editors:

We read with interest and concern the article by Pilewskie et al.[1] The author's study claims to match a series of patients whom they have interpreted as fulfilling the eligibility for inclusion in the LORIS trial from retrospective cases diagnosed with DCIS and treated with surgery. Their stated aim was to explore the safety of an observation approach as an alternative management strategy for DCIS outside the context of a clinical trial. They report an upgrade from DCIS to invasive cancer in 20% (58 of 296) cases examined.

The authors have unfortunately used the inclusion criteria for the initial qualification to be registered for the LORIS study and not the eligibility criteria for randomization in to this study. In the LORIS trial, all diagnostic samples from women with DCIS who fulfil the criteria for registration are submitted for real-time central pathology review. Only those patients with centrally confirmed low grade DCIS or low intermediate grade DCIS features (i.e. absence of comedo-type necrosis or intermediate to high grade nuclei) are eligible for randomization; this is most definitely not equivalent to all 'non-high-grade DCIS,' which has been included in Pilewskie et al's analysis. We would note that the referenced source the authors provide for the LORIS trial design and the LORIS trial protocol (which is openly and easily accessible online [2]), both describe the rationale, processes and features assessed for eligibility in the central pathology review. For LORIS, diagnostic biopsies must be taken using large gauge vacuum-assisted biopsy (i.e., minimum of 12 gauge). The criteria used for determining eligibility at central pathology review are then as follows:

Eligible

  • Lesions which are low cytonuclear grade, or in the lower half of the intermediate
  • grade category, and where low grade has been considered in the diagnostic categorization;
  • No comedo-type necrosis;
  • No more than occasional mitoses - no more than 1 per 3 duct cross section;
  • Nuclei to show minimal pleomorphism and must not be more than 2.5 red blood cells in diameter.

Ineligible

  • Where differential for classification lies between intermediate and high grade disease;
  • Presence of comedo-type necrosis;
  • Frequent mitoses;
  • Nuclei more than 2.5 red blood cells in diameter;
  • Section quality does not permit confident assessment of these criteria.

Variability in the histopathological grading and categorization of DCIS is a longstanding issue and agreement between pathologists about breast cancer diagnosis in general and DCIS in particular is far from ideal in both Europe and North America.[4] [5] [6] Accurate grading and identification of invasive foci are also dependent on the quantity of material available for examination and invasion is more likely to be missed in smaller bore core biopsy samples than the vacuum-assisted wide bore specimens required in LORIS.[7]

In designing the feasibility phase of LORIS, we acknowledged the problems of grading consistency and use central pathology review to ensure consistency of final pathological assessment of eligibility and to exclude patients that are not low grade or low intermediate grade. All the sections from each case are reviewed by a minimum of two (of three) specialist breast pathologists (JT, SEP, AH), with arbitration by the third if there is initial disagreement.

The data presented by Pilewskie et al are therefore unrepresentative of the patients entering the randomization phase of the LORIS trial of standard treatment including surgery vs active monitoring through annual mammography. To date in LORIS, as we had anticipated, about two thirds of the cases submitted for central pathology review were found to be ineligible by the above criteria.

As a consequence, Pilewskie et al have seriously misrepresented the LORIS trial design and we wish to correct any impression that all cases meeting the registration criteria are candidates for randomization. In LORIS, half of the eligible patients are randomized to surgery and any upgrades to invasive disease at surgery would be reported directly to the Data and Safety Monitoring Committee.

Because DCIS has always been treated by primary surgery, the natural history of DCIS is poorly studied and is incompletely understood. We seek to determine whether there is a group of women with DCIS where active monitoring is safe. In agreement with the authors we believe it is currently premature to recommend active surveillance as an appropriate off-study option in any case of DCIS, including those meeting the eligibility for randomization in LORIS. The current standard management of DCIS is surgery with consideration of postoperative adjuvant therapy. Active monitoring of screen-detected and asymptomatic DCIS should be confined to women participating in well-conducted clinical trials.

In summary, the data presented are not those of patients who would be randomized into the UK LORIS trial and it is not even possible to conclude that the patients assessed would have been eligible to be registered to the LORIS trial for central pathology review from the information given. It is of concern for clinicians and women of screening age seeking to make an informed choice that this article will mislead the readers regarding the eligibility criteria for randomization into LORIS.

References

1. Pilewskie M, Stemple M, Rosenfeld H, et al. Do LORIS Trial Eligibility Criteria Identify a Ductal Carcinoma In Situ Patient Population at Low Risk of Upgrade to Invasive carcinoma. Ann Surg Oncol. 2016;23:3487-3493

2. http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0006/136986/PRO-11-36-16.pdf

3. Francis A, Thomas J, Fallowfield L, et al: Addressing overtreatment of screen detected DCIS; the LORIS trial. Eur J Cancer. 2015;51:2296-2303.

4. Wells WA, Carney PA, Eliasson MS, Grove MR, Tosteson ANA. Pathologists' agreement with experts and reproducibility of breast ductal carcinoma in situ classification schemes. Am J Surg Pathol. 2000; 24: 651-659.

5. Schuh F, Biazus JV, Resetkova E, Benfica CZ, Edelweiss MIA. Reproducibility of three classification systems of ductal carcinoma in situ of the breast using a web-based survey. Pathol Res Pract. 2010; 206:705-711.

6. Douglas-Jones A, Morgan JM, Appleton MAC et al Consistency in the observation of features used to classify duct carcinoma in situ (DCIS) of the breast. J Clin Pathol. 2000;53:596-602.

7. Kim J, Han W, Lee JW, et al. Factors associated with upstaging from ductal carcinoma in situ following core needle biopsy to invasive cancer in subsequent surgical excision. Breast. 2012; 21:641-645.


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