Hemoglobin level significantly impacts the tumor cell survival fraction in humans after internal radiotherapy

Abstract

Background: Anemia is usually not taken into account in internal radiotherapy. We investigated whether the hemoglobin (Hb) level could have an impact on the tumor response, as observed in external beam radiotherapy (EBRT).

Methods: Absorbed doses of 25 hepatic metastatic sites in eight patients who underwent a liver selective internal radiotherapy (SIRT) were computed by a 3D convolution of a dose deposition kernel with the 90Y time-of-flight positron emission tomography (TOF-PET) images acquired following therapy. Early tumor response was assessed by comparing a follow-up FDG TOF-PET scan with a baseline scan. Hb level was measured on the day of the SIRT procedure.

Results: All patients displayed early tumor response increasing with the tumor-absorbed dose. Significant differences between patients were noted, the response slope correlating with the Hb level. After applying a global fit on all metastases using a tumor radiosensitivity modulated by a Hb enhancement factor (HEF) linearly dependent on the Hb level, a strong correlation (R = 0.96) was observed between the early response and the absorbed dose. Hb level had a major impact on tumor response by modulating HEF by a factor 6.

Conclusions: These results prove the significant impact of Hb level on the tumor response and support the study of methods for correcting tumor hypoxia, such as intensively performed in EBRT. The quantitative analysis of the relationship between tumor doses and early response has the power to allow fast screening of such correction methods in limited patient series. Internal radiotherapy could be more efficient if performed earlier in the therapy line, when the disease- and treatment-related anemia remains limited.

Figure 1

PET scans. One transverse slice of the patient No. 6 showing the metabolic sites of its large necrotic tumour that received different absorbed dose. The FDG uptake of the metabolic sites 1,2,3,5, that were well targeted by the microspheres, decreased between the FDG-BL and FDG-FU scans, while the metabolic site 4 not targeted by the microspheres rapidly increased in FDG uptake and in size as well, to become a new large necrotic metastatic site. The VOI on the FDG-FU scan was increased to encompass all the FDG activity originating from the increased site 4.

Figure 2

Relationship between absorbed doses Dand tumor metabolic ratio (MR). MR for the responding tumors are lower than 1. Each color refers to each patient (black - 1, blue - 2, brown - 3, red - 4, pink - 5, green - 6, cyan - 7, and grey - 8). Open circles and hexagons correspond to metastases from CRC, and open squares refer to metastases from melanoma. The patient gender and the Hb level (in gram per deciliter) on the day of the SIRT procedure are indicated at the extremity of each fitted line. Individual patient tumors were fitted by $gf{e}^{-\overline{\alpha }D}$, where gf is the growing fraction in the absence of an absorbed dose and $\overline{\alpha }$ is the overall cell radiosensitivity, i.e., containing the HEF factor. The box in the upper left corner identifies outliers (see ‘Results and discussion’). The lines are the patient data individually fitted with this single exponential.

Figure 3

Tumors survival fraction. Relationship between absorbed dose D corrected by the HEF and the tumor cell survival fraction (left axis) and metabolic ratio (right axis) calculated at week 7 post-therapy using the doubling time obtained by the global fit. For colors and symbols refer to Figure 2. The line corresponds to Equation 4 with the parameters α, k and DT minimizing Equation 2, excluding the four metastases with SF > 1, which proved their shorter DT (using the actual metastasis DT in Equation 3 should necessarily give SF ≤ 1). These four metastases were already considered as outliers from Figure 2. See animation of the fit in Additional file 1.

Figure 4

Optimal values of HEF for each patient in relation with their Hb level. Relationship between the Hb level and the optimal values of the HEF_p parameter obtained by individually fitting HEF for each patient dose-response using α and DT values determined from the global fit. The line corresponds to Equation 5, with k obtained by the global fit. R is the correlation coefficient obtained by making a linear regression of these optimal HEF_p.