Impact of neoadjuvant radiation therapy modalities on post-surgical lymphopenia in operable pancreatic cancer.
Authors: Low Soon Khai , Thalji Samih Z , Aldakkak Mohammed , Ying Grace , Yohay Stephanie , Auckley Elizabeth , Vakili Parnian , Shahjehan Faisal , Evans Douglas B. , Christians Kathleen K. , Seo Yongwoo David , Erickson Beth , Small Christina Julia , Heyer Vaughn , Neupane Bhabishya , George Ben , Kothari Anai , Hall William Adrian , Kamgar Mandana 
Published: January 2025

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Background:
Recent advances in therapeutic vaccines show promise for
KRAS
-mutated pancreatic cancer (PC), with ongoing clinical trials exploring their potential further. Lymphocytes are essential in generating vaccine-induced immune response. Patients who develop lymphopenia following neoadjuvant radiation therapy (RT) are frequently excluded from these vaccine trials. We aimed to assess how different modalities of neoadjuvant RT impact the severity and incidence of lymphopenia.
Methods:
We identified patients with PC who received neoadjuvant therapy including RT followed by surgery at our institution between March 2009 and June 2024. Patients were stratified by the type of RT they received: conventional long-course chemo-RT (LCRT) with 50.4 Gy over 28 fractions (Fr), short-course chemo-RT (SCRT) with 36 Gy over 15 Fr, and stereotactic body RT (SBRT) with 30 Gy over 5 Fr. The absolute lymphocyte count (ALC, 10
3
cells/µL) was compared at various timepoints: baseline, during RT, 6-weeks after surgery (post-op), and every 3-month interval up to 1 year post-op. Moderate lymphopenia was defined as ALC <1.0 and severe lymphopenia as ALC <0.5.
Results:
Among the 627 patients included in the study, 522 had baseline pre-RT ALC data available for analysis. There was no difference in baseline ALC among the different RT groups (Table). During RT, patients receiving LCRT experienced a higher incidence of severe lymphopenia (86.1%; median ALC (mALC) nadir 0.28) compared to SCRT (41.9%; mALC nadir 0.50) or SBRT (20.0%; mALC nadir 0.72, p<0001). No difference in the mALC or rates of lymphopenia was observed beyond 6 weeks post-op. Notably, 53% of the patients experienced lymphopenia for as long as 1 year after surgery.
Conclusions:
LCRT resulted in more severe lymphopenia compared to SCRT or SBRT during RT, but this difference in severity diminished 6 weeks after surgery. Alternatives in treatment sequencing for operable pancreatic cancer can have profound effects on patterns of disease recurrence. When applying multiple treatments in series, toxicities such as lymphopenia may impact receipt of therapy. Techniques to mitigate such toxicities, while maximizing response, will be important to consider.

Absolute lymphocyte count (ALC, 10
3
cells/µL) at different time point.

Patients with baseline ALC
LCRT (n=454)
SCRT (n=34)
SBRT (n=34)
P-value

Baseline ALC, median (IQR)
1.48 (0.74)
1.27 (0.94)
1.51 (0.74)
0.74

6-week lymphopenia, n (%) No Moderate Severe
173 (37)219 (46)79 (17)
13/27 (48)11/27 (41)3/27 (11)
18/35 (51)16/35 (46)1/35 (3)
0.10

1-year lymphopenia, n (%) No Moderate Severe
101/217 (47)90/217 (41)26/217 (12)
3/8 (37)5/8 (63)0/8 (0)
9/13 (69)1/13 (8)3/13 (23)
0.054