Results Confounded by a Disregard for Basic Dose–Response Radiobiology

TO THE EDITOR: Every now and then, one comes across a publication on radionuclide therapy prognosis using qualitative descriptors, without due regard for basic dose–response radiobiology (1–3). Like the parable of the blind men and an elephant, these authors draw erroneous conclusions based on insufficient information unbeknownst to themselves. The scientific language of dose–response radiobiology is the radiation absorbed dose expressed in grays, not the injected activity expressed in becquerels. Any prognostic study whose design does not account for absorbed radiation doses to tissue will have no reliable method of data stratification for accurate response analysis, casting doubt on the scientific validity of its results.

The recent publication by Ulrich et al. (3) used the semiempiric body-surface-area (BSA) method for ⁹⁰Y resin microsphere activity prescription in a study to determine whether the visual degree of tumoral ^99mTc-macroaggregated albumin (MAA) implantation carried any predictive value for response. Use of the BSA method was not explicitly mentioned in the article but was subsequently confirmed by its corresponding author. Unless Ulrich et al. invest additional effort in accurately translating their visual descriptors of “low” versus “high” ^99mTc-MAA implantation into absorbed radiation doses to tumor, their results cannot be verified. This is because inherent to the BSA method is the assumption of a fixed and favorable mean tumor–to–normal liver ratio for all patients (4,5)—an assumption that confounds their results.

To illustrate this point, say we have patients A and B with advanced colorectal liver metastases, identical height (170 cm), identical body mass (65 kg), a negligible lung shunt (<1%), a 1-kg lung mass, a 300-g tumor mass, and a 1,400-g nontumorous liver mass. Both A and B have good but slightly different mean tumor–to–normal liver ratios of 2.5 and 2.0, respectively. By visual scintigraphic appearance, both patients would be classified as “high” ^99mTc-MAA implantation by the study of Ulrich et al. The BSA method will prescribe an identical ⁹⁰Y activity of 1.73 GBq for both. However, tricompartmental MIRD macrodosimetry will show that A received a satisfactory mean tumor dose of 100 Gy whereas B received a suboptimal mean tumor dose of only 86 Gy. It follows—to no surprise—that A will have some treatment response whereas B will not, even though both been classified in the “high” group.

It is common sense that ^99mTc-MAA is an imperfect surrogate for ⁹⁰Y microspheres. It is a tool, and the usefulness of any tool is only as good as its user and the complexity of the task at hand. To conduct a scientifically robust study on the predictive value of ^99mTc-MAA yielding reproducible and radiobiologically meaningful results, one must have accurate means of, first, delineating artery-specific planning target volumes (e.g., catheter-directed CT angiography or, at minimum, cone-beam CT); second, determining technical success in accordance with the intended radiation therapy plan (e.g., ⁹⁰Y time-of-flight PET/CT or, at minimum, ⁹⁰Y bremsstrahlung SPECT/CT); and third, quantifying the predictive radiation absorbed dose of technically successful cases by ^99mTc-MAA SPECT/CT (5). Clinical validation of predicted radiation absorbed doses by ^99mTc-MAA may be achieved either indirectly by follow-up diagnostic imaging (5) or directly by ⁹⁰Y PET/CT quantification (subject of current research).

In the discussion by Ulrich et al., they showed some awareness of the importance of the radiation absorbed dose and the tumor–to–normal liver ratio but did not explain why these were not factored into their analyses. Readers of their publication are advised to be cautious of their results and conclusions.

• © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.