January 2011

Editor:
Fredrick L. Kiechle, MD, PhD

Q. Our pharmacist colleagues have raised a question about a supposed FDA requirement that creatinine testing be converted to an “IDMS” method in a relatively short period. Does the CAP have knowledge of this, and can you provide guidance?

A. The FDA in October 2010 notified the oncology community of a potential safety issue related to the dosing of carboplatin,¹ a chemothe-rapeutic agent used to treat advanced ovarian and other cancers. The FDA advisory was based on a National Cancer Institute letter advising investigators in NCI-funded clinical trials. Among the most common methods of calculating dosage for this drug is the use of the Calvert equation, for which the prescribing physician chooses a target “area under the concentration versus time curve” (AUC) and multiplies it by the patient’s glomerular filtration rate (GFR) to get a total dose:

Total dose (mg) = (target AUC) × (GFR (mL/min) + 25)

Of note, GFR values used to generate this equation were based on ⁵¹Cr-EDTA clearance.

Since the original dosing guidelines were promulgated, creatinine methods have been recalibrated so that values on patient samples match values generated with the reference method (isotope dilution mass spectrometry, or IDMS). The net effect of this change was to lower serum creatinines by anywhere from four percent to 34 percent, depending on the method used.² As a result of lowering the serum creatinine, of course, the estimated GFR, no matter which method is used, is correspondingly higher.

Based on oral comments at the July 2010 Manufacturers’ Forum of the Laboratory Working Group of the National Kidney Disease Education Program, all major global IVD manufacturers of creatinine methods, with one exception,³ now sell in the United States only creatinine methods with calibration traceable to the IDMS reference method. (There are also a number of smaller manufacturers of creatinine methods, and the current status of their calibration traceability is not known. It is always a good idea for the laboratory to check with the manufacturer of its specific creatinine method to determine its calibration status.) Laboratories should be proactive in communicating this information to the appropriate people (in this case, oncologists and pharmacists at their institutions).

The key point of the FDA advisory is this: When using the Calvert equation to calculate carboplatin dose with current IDMS-traceable creatinine methods, one should use an estimated GFR no greater than 125 mL/min, irrespective of the equation used to calculate the estimated GFR. This limit value for eGFR is intended to prevent excessive doses for people with relatively normal kidney function.

Several caveats are in order. The only GFR equations that have been validated for use with the new standardized creatinine values are the IDMS-traceable version of the Modification of Diet in Renal Disease Study (MDRD) four-parameter equation⁴ and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.⁵ These equations were designed to be used only for adults 18 years and older. Furthermore, the MDRD equation was developed to detect renal insufficiency; numeric values higher than 60 mL/min/1.73 m² are less accurate and should not really be used.

It is probably worth noting that as a result of this creatinine standardization, there is much less method-to-method variation and that, in all likelihood, the new GFR estimates more closely match the original ⁵¹Cr-EDTA clearance values.

In any case, the most important point is to ensure that the maximum GFR value clinicians use in the Calvert equation is 125 mL/min.

References

Gregory Miller, PhD
Professor of Pathology
Virginia Commonwealth University
Richmond

Consultant, CAP Chemistry
Resource Committee

Q. What is the standard of reporting basal cell carcinoma excision margins when the clearance is less than 0.5 mm? Does one mention the specific distance, for example, margins negative with 0.3 or 0.2 mm clearance from superficial lateral margin?

A. While there are excellent guidelines for the clinical approach to treating basal cell carcinoma, including planning of surgical margins, there is no “industry standard” for the reporting of basal cell carcinoma margins in pathology reports. The approach outlined here is a largely empiric one based on personal experience signing out more than 150,000 skin specimens.

The assessment of a “negative” margin is based on not only distance of tumor from margin, but also on tumor growth pattern (infiltrative versus superficial multicentric versus nodular), the nature of the specimen (shave biopsy versus excision), and stromal alteration. In the many routine cases of excision specimens containing basal cell carcinomas with nodular growth patterns, margins separated by any degree of unaltered dermal collagen from tumor with a pushing border may be reasonably reported as uninvolved.

In other instances in which tumor nests are close to the specimen edge, there are clues that cast doubt on the margin clearance, even after deeper sectioning. In such cases, reporting the distance of the tumor from the margin may help to convey to the clinician the uncertainty of the margin clearance.

These cases include:

1. Any tumor in diagnostic shave biopsies.
2. Superficial basal cell carcinoma with altered stroma at the margin.
3. Scar present between the tumor nests and margin.
4. The distance between the most peripheral or deepest nest to the margin is less than the distance between nests. (When tumors are infiltrative, it is our laboratory’s practice to report these margins as involved without further qualification.)

Lastly, it is our practice not to imply clearance of the margin by a short distance, but merely to state that distance, for example, “tumor is present within 0.2 mm of peripheral margin.”

Bibliography

David P. Frishberg, MD
Department of Pathology
and Laboratory Medicine
Cedars-Sinai Medical Center
Los Angeles

Member, CAP Cancer Committee