Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer

Erta Kalanxhi, Sebastian Meltzer, Jakob Vasehus Schou, Finn Ole Larsen, Svein Dueland, Kjersti Flatmark, Benny Vittrup Jensen, Knut Håkon Hole, Therese Seierstad, Kathrine Røe Redalen, Dorte Lisbet Nielsen, Anne Hansen Ree, Erta Kalanxhi, Sebastian Meltzer, Jakob Vasehus Schou, Finn Ole Larsen, Svein Dueland, Kjersti Flatmark, Benny Vittrup Jensen, Knut Håkon Hole, Therese Seierstad, Kathrine Røe Redalen, Dorte Lisbet Nielsen, Anne Hansen Ree

Abstract

Background: Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy.

Methods: In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS).

Results: In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046).

Conclusion: In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Serum Flt3L levels during the neoadjuvant treatment course in the Oslo and Copenhagen patient cohorts. The horizontal line in each data cluster represents the median value. CRT chemoradiotherapy, Flt3L fms-like tyrosine kinase 3 ligand, NACT neoadjuvant chemotherapy

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