Page 183 - EJMO-9-2

Eurasian Journal of
Medicine and Oncology PD-1/L1 inhibitors in advanced CC: Multicenter retro

the ORR of patients with microsatellite stable/mismatch immunological heterogeneity. Smaller tumors may harbor a
repair proficiency was only 11% (95% CI: 0.25 – 0.48). less immunosuppressive microenvironment, characterized
This difference may stem from the unique immune by higher CD8 T-cell infiltration and reduced stromal
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microenvironment characteristics of high MSI/mismatch barriers, which could enhance the efficacy of ICIs. These
repair deficiency tumors, which are usually accompanied findings advocate for integrating PD-1/PD-L1 inhibitors
by massive tumor-infiltrating lymphocyte infiltration into the first-line treatment for stage IIIC cervical cancer
and highly immunogenic microenvironment formation patients with limited tumor burden, potentially delaying
– a biological characteristic that enables patients with recurrence and improving survival trajectories.
this subtype to achieve significant survival benefits from The rationale for prioritizing tumor size in therapeutic
anti-PD-1/PD-L1 monotherapy. decision-making is further supported by its correlation
Tumor size emerges as an underappreciated yet clinically with surgical resectability and metastatic potential.
actionable prognostic factor. Our analysis identified that Tumors ≤4 cm are more likely to remain localized, with
tumors ≤4 cm serve as a favorable prognostic factor, which limited lymphatic or vascular invasion, thereby presenting
aligns with the cohort study by Kornprat et al. involving a window for neoadjuvant or adjuvant immunotherapy to
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159 CRC patients. Their findings demonstrated that tumors eradicate micrometastasis. In contrast, larger tumors often
>4.5 cm (observed in 44% of cases) were significantly exhibit aggressive biological behavior, including hypoxia-
associated with advanced T/N stage, higher tumor grade, driven immunosuppression and upregulated alternative
and reduced cancer-specific survival. The biological immune checkpoints (e.g., lymphocyte activation gene 3
rationale may involve smaller tumors maintaining a less and T cell immunoglobulin and mucin domain 3), which
immunosuppressive microenvironment with lower stromal may necessitate combinatorial therapeutic approaches.
desmoplasia, facilitating immune cell infiltration and drug The KEYNOTE-A18 trial, which included patients with
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delivery. Moreover, tumor diameter inversely correlates stage IB2-IIB cervical cancer, established pembrolizumab’s
with surgical resectability and metastatic potential, efficacy in this setting, particularly when combined with
creating a therapeutic window for neoadjuvant or adjuvant chemoradiotherapy.
immunotherapy in locally advanced diseases. These The predictive value of PD-L1 expression as a biomarker
dimensional thresholds warrant further validation across in cervical cancer has garnered increasing research
histotypes, as optimal size cut-offs may vary by organ site attention. In a prospective investigation of 27 stage IIA
and tumor biology. The convergence of these findings has cervical SCC patients conducted by Kim et al., PD-L1
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profound clinical implications. First, they advocated for positivity was detected in 44.4% (12/27) of cases, with high
pretreatment molecular profiling encompassing PD-L1, PD-L1 expression correlating significantly with favorable
MSI status, and tumor mutational burden alongside clinicopathological characteristics, including lower
conventional staging to guide first-line therapy selection. preoperative serum SCC antigen levels and absence of
Second, they supported the integration of tumor size into parametrial invasion. These findings support the emerging
risk stratification models, particularly for surgical decision- hypothesis that PD-L1 upregulation in cervical malignancies
making and adjuvant therapy duration. For example, stage may not merely represent an immune evasion mechanism
IIIC CRC patients with <4 cm PD-L1-positive tumors but rather reflect an adaptive immune response – indicative
might benefit from extended adjuvant immunotherapy of a pre-existing “hot” tumor microenvironment primed
rather than conventional chemotherapy alone. Finally, for engagement with ICIs. Importantly, the therapeutic
these insights underscore the need for dynamic biomarker benefits of anti-PD-1/PD-L1 agents appear amplified in
monitoring during treatment, as PD-L1 expression and subgroups defined by both molecular and clinical criteria.
tumor immune landscapes can evolve under therapeutic Patients with smaller, PD-L1-positive tumors may represent
pressure. an “ideal” cohort for immunotherapy due to synergistic
Subgroup analyses in advanced cervical cancer have factors: (i) reduced tumor bulk lowers the threshold for
unveiled critical insights into the interplay between tumor immune-mediated cytotoxicity, (ii) preserved antitumor
size, molecular biomarkers, and therapeutic outcomes. T-cell function in less advanced disease, and (iii) higher
Specifically, patients with stage IIIC disease and tumors antigenicity from HPV-related neoantigens. Conversely,
<4 cm demonstrated significantly prolonged PFS, larger or PD-L1-negative tumors may require multimodal
reinforcing tumor diameter as a pivotal prognostic factor. strategies, such as ICIs combined with vascular endothelial
The 4 cm threshold adopted from the FIGO 2014 staging growth factor (VEGF) inhibitors (e.g., bevacizumab) to
system and validated in the KEYNOTE-A18 trial, serves normalize aberrant vasculature and enhance drug delivery
dual purposes: (i) it reflects anatomical tumor burden or radiotherapy to induce immunogenic cell death and
and (ii) acts as a surrogate for underlying biological and broaden the antigen repertoire.

Volume 9 Issue 2 (2025) 175 doi:10.36922/ejmo.8074