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

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

doi:10.1038/s41416-018-0085-y

Abstract

BackgroundSystemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy.MethodsIn 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).ResultsIn 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).ConclusionIn high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression.

Highlights

In locally advanced rectal cancer (LARC), locoregional neoadjuvant chemoradiotherapy (CRT) with a fluoropyrimidine in a noncytotoxic radiosensitising dose and resection of the residual tumour results in low local recurrence rates.[1]
Circulating levels of the haematopoietic factor fms-like tyrosine kinase 3 ligand (Flt3L) increased in two independent cohorts of LARC patients during induction neoadjuvant chemotherapy (NACT) and further over sequential CRT, both modalities containing oxaliplatin
In the Oslo cohort, the higher Flt3L level following the induction NACT, the more favourable 5-year progression-free survival (PFS) without metastatic progression. This cohort had available dose scheduling and toxicity data, which revealed that oxaliplatin dose reduction during CRT, undertaken to avert breach of radiation delivery, was associated with the advantageous PFS

Summary

Introduction

In locally advanced rectal cancer (LARC), locoregional neoadjuvant chemoradiotherapy (CRT) with a fluoropyrimidine in a noncytotoxic radiosensitising dose and resection of the residual tumour results in low local recurrence rates.[1]. In a phase II single-arm LARC study, patients were given oxaliplatin-/fluorouracil-containing induction NACT and sequential CRT with concomitant oxaliplatin and capecitabine.[14] Acknowledging the concerns arising from protraction of the total treatment time, theoretically permitting tumour cell repopulation and selective pressure towards the survival of therapy-resistant cell clones, only 4 weeks of the induction NACT (two cycles of the Nordic FLOX regimen15) were given This induction phase was found to be highly tolerable[14] and alone led to substantial tumour volume reduction.[16] in a study population with a high proportion of T4 disease and lymph node involvement, 5-year progression-free survival (PFS; almost all of PFS events were metastatic progression) and overall survival (OS) were remarkably good.[14]. CONCLUSION: In high-risk rectal cancer, oxaliplatin-containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression

Methods

Results

Conclusion