Temporal dynamics of lymphocytes in prostate cancer patients treated with proton therapy

Abstract

Radiotherapy can be both immunosuppressive and immunostimulatory. Radiation-induced lymphopenia (RIL) is an ongoing challenge in cancer treatment. We investigated weekly changes in the absolute lymphocyte count (ALC) during proton radiotherapy, evaluating the effects of different dosage, fractionation schedules, and pelvic node irradiation (PNI). Prostate cancer patients were prospectively chosen for this study, due to their relatively homogenous treatment plans. Treatment protocols were categorized into three groups: Group A (n=52) received 36.25 Gy/5-fractions, Group B (n=60) underwent 63 Gy/21-fractions and group C (n=69) received 63 Gy/21-fractions plus PNI. To account for individual characteristic differences, a new categorization method was made, according to the change in ALC relative to the baseline. Lymphopenia (ALC < 1000 K/μL) developed in 8%, 17% and 84% of patients in groups A, B, and C, respectively. An initial increase in ALC occurred in 44%, 47% and 28% of groups A, B and C, respectively, and declined with proceeding fractions. Patients with PNI had the most pronounced reduction in their ALC relative to the baseline. Increased dosage and fractionation led to a higher incidence of lymphopenia. Understanding which factors influence ALC in particle therapy is vital for leveraging the immune-enhancing effects of radiotherapy, while minimising its immunosuppressive impacts.

Keywords: hypofractionation; immunostimulation; lymphopenia; prostate cancer; proton therapy; radiation oncology.

Figure 1

A flowchart illustrating the study’s patient selection process, the final cohort included in the analysis, and the three subcohorts. Numbers at each step represent the counts of patients included or excluded.

Figure 2

Box plots of the absolute lymphocyte count throughout treatment for groups A, B and C. Absolute lymphocyte count measurements are shown at baseline (prior to the start of radiotherapy) and at regular intervals during treatment. The boxes represent the interquartile range (IQR), the horizontal line within each box indicates the median, and the whiskers extend to the minimum and maximum values. Outliers are shown as individual points.

Figure 3

Heatmap of cross-categorisation between nadir absolute lymphocyte count grade (lowest count during treatment) and the relative decline in absolute lymphocyte count by the end of treatment compared to the baseline, for groups A, B and C. Darker colours indicate higher frequencies of patients within specific categories.

Figure 4

Bar charts showing the distribution of patients across lymphocyte count levels (L+ to L4) at the first week of treatment and at the end of treatment, for groups A, B and C. ALC thresholds defined as: L+ – ALC increase of more than 5% relative to the baseline, L0 – ALC increase of less than 5% and decrease of less than -5% relative to the baseline, L1 – ALC decrease between 5–25% relative to the baseline, L2 – ALC decrease between 25–50% relative to the baseline, L3 – ALC decrease between 50–75% relative to the baseline, L4 – ALC decrease of more than 75% relative to the baseline. ALC = absolute lymphocyte count.

Figure 5

Scatter plots illustrating the relationship between the cumulative radiation dose delivered at the absolute lymphocyte count nadir, for groups A, B and C. Each point represents an individual patient, with the nadir dose corresponding to the lowest recorded lymphocyte count.

Figure 6

Transversal (A) and coronal (B) CT slices overlaid with a colourwash representation of the dose distribution for the treatment of prostate cancer with pelvic lymph node irradiation. High dose of 63.0 Gy to PTV of the prostate (shaded red), lower dose of 48.3 Gy to PTV of the lymph nodes and seminal vesicles (shaded pink, seminal vesicles not seen in these sections). Treatment planning done using the Raystation^® treatment planning system (RaySearch Laboratories AB).