Radiation Induced Lymphopenia Is Associated With the Effective Dose to the Circulating Immune Cells in Breast Cancer

Abstract

Background: Lymphopenia is a known significant factor for treatment outcome in cancer patients, with underlying risk factor poorly understood in breast cancer. We hypothesize that the effective dose to the circulating immune cells (EDIC) which was related with lymphopenia in lung cancer will also have significant effect for radiation induced lymphopenia (RIL) in patients with breast cancer.

Material and methods: Patients treated with adjuvant radiotherapy (RT) and with complete blood tests within one week from RT end/start (post/preRT) were eligible in this study. Radiation dosimetric factors were collected retrospectively, and EDIC for each patient was calculated based on the doses to lung, heart and total body according to the model description, as previously reported. RIL was defined by the CTCAE5.0 based on postRT peripheral lymphocyte count (PLC). Linear regression was first used to test the correlation between EDIC with post/preRT PLC ratio and postRT PLC, using all these as continuous variables. Normal tissue complication probability (NTCP) was used to develop models that predict the CTCAE graded RIL from EDIC.

Results: A total of 735 patients were eligible. The mean post/preRT PLC ratio was 0.66 (95% CI: 0.64-0.68) and mean EDIC of breast cancer was 1.70Gy (95% CI: 1.64-1.75). Both post/preRT PLC ratio and postRT PLC were significantly correlated with EDIC (P<0.001), with R² of 0.246. For patients with normal preRT PLC, the post/preRT PLC ratio was better associated with EDIC, and postRT PLC was expressed as PLC _preRT × (0.89 - 0.16 × EDIC). For patients with preRT lymphopenia, postRT PLC was better associated with EDIC and it was 1.1 - 0.17 × EDIC. Using binned EDIC as the dose variable, the bootstrap validated NTCPs fit the data nicely with R² of 0.93, 0.96, and 0.94 for grade-1, grade-2, and grade-3 RIL, respectively. The corresponding EDIC to induce 50% of grade-1, grade-2 and grade-3 RIL was 1.2, 2.1 and 3.7 Gy, respectively.

Conclusion: EDIC is a significant factor for RIL in patients with breast cancer, and may be used to compute the risk of lymphopenia in each individual patient with the use of the conventional NTCP modeling. External validation is needed before the EDIC can be used to guide RT plan.

Keywords: breast cancer; effective dose to the circulating immune cells (EDIC); lymphopenia; prediction model; radiation.

Figure 1

Inverse linear relation between post/preRT PLC Ratio and EDIC for (A) all 735 patients; (B) 732 patients excluding 3 patients with grade 3 preRT lymphopenia; (C) 714 patients excluding additional 18 patients with grade 2 preRT lymphopenia; (D) 630 patients excluding additional 84 patients with grade 1 preRT lymphopenia.

Figure 2

Inverse linear relationship between EDIC and postRT peripheral lymphocyte counts (PLC) for (A) all 735 patients; (B) 732 patients excluding 3 patients with grade 3 preRT lymphopenia; (C) 714 patients excluding additional 18 patients with grade-2 preRT lymphopenia.

Figure 3

Post/preRT PLC ratio versus EDIC for (A) 21 patients with grade-2+ preRT lymphopenia; (B) 105 patients with grade-1+ preRT lymphopenia; PostRT PLC versus EDIC for (C) 21 patients with grade-2+ preRT lymphopenia; and (D) 105 patients with grade-1+ preRT lymphopenia.

Figure 4

EDIC NTCP model for (A) Grade 1+, (B) Grade 2+ and (C) Grade 3+ postRT lymphopenia. Patients were divided into 8 groups with a 0.5 Gy increment in each group (<1, 1-1.5, 1.5-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, >4.5). NTCP, Normal Tissue Complication Probability. EDIC, Effective Dose to the circulating Immune Cells.