Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Abstract

Purpose: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC).

Methods and materials: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival.

Results: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002).

Conclusions: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Fig. 1

Percentage of blood exposed to >0.5 Gy as a function of fraction number and planning target volume (PTV). Dose to circulating blood increases with fraction number and PTV diameter. Abbreviations: diam = diameter; IMRT = intensity modulated radiation therapy; SBRT = stereotactic body radiation therapy.

Fig. 2

Graphic summary of the development of lymphopenia in the SBRT and CRT cohorts. All box-and-whisker plots show median (middle horizontal line), 75th percentile (top horizontal line), 25th percentile (bottom horizontal line), 91st percentile (top whisker), and 9th percentile (bottom whisker) for TLC obtained at baseline and at 1 and 2 months after starting radiation therapy. (A) TLC; (B) percentage of change in TLC per patient; (C) percentage of patients with severe lymphopenia. Abbreviations: CRT = chemoradiation therapy; SBRT = stereotactic body radiation therapy; TLC = total lymphocyte count.

Fig. 3

Kaplan-Meier curve showing survival for all patients (n=133), stratified by severe lymphopenia (TLC: <500 cells/mm³) 2 months after starting radiation therapy. HR and P values are derived from univariate Cox regression analysis. Censored patients are represented by +. Abbreviations: CI = confidence interval; HR = hazard ratio; TLC = total lymphocyte count.