A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma

Abstract

BackgroundPreclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50–54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.MethodsTo address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.ResultsWe found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.ConclusionHypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.Trial registrationClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0149-6) contains supplementary material, which is available to authorized users.

Lymphocyte-Sparing Effect of Proton Therapy in Patients with Esophageal Cancer Treated with Definitive Chemoradiation

“…These findings have important implication for treatment planning because beam arrangements could be made to minimize specific organ doses so as to mitigate lymphopenia risk in patients. Additionally, other potential lymphocyte-sparing radiation treatment strategies could be considered, such as hypofractionation [12, 26]. …”

Exploring the rationale for combining ionizing radiation and immune checkpoint blockade in head and neck cancer

“…Daily, low dose, fractionated IR for HNSCC results in peripheral lymphopenia and the degree of drop in peripheral lymphocyte levels correlates to disease-free survival after treatment with either IR alone or IR plus chemotherapy (14–16) . Does this mean that how we give IR to patients with advanced HNSCC is immunosuppressive?…”

“…Lymphocytes are highly sensitive to IR-induced death and lymphopenia is a side effect of fractionated radiotherapy, and this effect appears to be fractionation dependent (16, 28) . Yet, cumulative effects of therapeutic IR on lymphocyte activation within the TME are diverse.…”

“…Daily, low-dose, fractionated ionizing radiation for HNSCC results in peripheral lymphopenia and the degree of drop in peripheral lymphocyte levels correlates to disease-free survival after treatment with either ionizing radiation alone or ionizing radiation plus chemotherapy. [14][15][16] Does this mean that how we give ionizing radiation to patients with advanced HNSCC is immunosuppressive? How ionizing radiation alters antitumor immunity at the level of the tumor microenvironment can be very complex and peripheral lymphopenia may not be a good surrogate measure of local antitumor immunity.…”

Hematological Toxicity of Hypofractionated Radiotherapy: A Review of the Available Evidence

“…Interesting data was provided by Crocenzi et al [24], who examined 20 patients from 2 prospective clinical studies with preoperative radio(chemo)therapy for locally advanced and borderline resectable pancreatic cancer. In the first of these studies, 10 patients were treated with conventionally fractionated radiotherapy (1.8 Gy/fr., total dose 50.4 Gy).…”