Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative
CTRT approach results in significant tumor downstaging and local control with a complete
pathological response rate of about 15% even if additional therapeutic strategies should be
explored to improve outcomes, expecially for T4 cancers.
Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in
cancer treatment among different tumor types, including CRC. An ICB strategy could lead up to
a 40% of response in metastatic CRC with deficient mismatch repair (MMR) status.
Unfortunately, the activity of ICBs in MMR proficient mCRC is extremely low but it might be
improved using immunomodulatory strategies as demonstrated by Bendell et al.
In this context, the role of RT in revert the tolerance to a low neoantigen-burden (such as
in MMR proficient CRCs) by the induction of antigen release from the tumour and activation of
dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been
widely elucidated. Moreover, antineoplastic agents can be exploited to target other crucial
cellular effectors of immunosuppressive tumor microenvironment (i.e. regulatory T cells and
myeloid-derived suppressor cells).
In line with these evidences, Hecht et al. have recently reported that in rectal cancer
patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a
neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. The integration of
immunotherapy in the neoadjuvant setting (instead of adjuvant one) for the management of LARC
is also supported by preclinical findings showing that in metastatic breast cancer mice
models, neoadjuvant immunotherapy is superior in inducing long-term survivors, compared with
adjuvant strategy with a greater magnitude of tumor-specific T cell expansion in neoadjuvant
treated mice and a better anti-tumor T cell-mediated immune response.
On the basis of such considerations, there is a strong biological and clinical rationale for
testing the addition of avelumab, an anti-PD-L1 moab, to capecitabine-based CTRT in patients
with technically resectable, LARC. The aim of this strategy is to lead to significant
improvements of pCR and, ultimately, patients' survival.