Cervical cancer (CC) remains one of the five most common malignancies among women in Thailand, with an annual incidence rate of 13.5 per 10,000 women and a mortality rate of 7.9% [1]. Approximately 95% of patients achieve complete clinical remission (CCR) after initial treatment; however, recurrence occurs in 3.8% of patients within the first year and in 8% within 5 years [2]. The management of recurrent CC depends on the site of recurrence: local, regional, or distant. The treatment options include external beam radiation therapy with concurrent chemotherapy (CCRT), brachytherapy, surgery, and systemic chemotherapy (CMT) [3]. Host immune function, particularly white blood cell (WBC) response, plays a significant role in treatment tolerance and prognosis.

Several studies have reported the prognostic implications of hematologic biomarkers in patients with solid tumors. Commonly evaluated pretreatment biomarkers include the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, hemoglobin level, and baseline WBC count, which reflect the host’s systemic inflammatory and immune status at diagnosis. Post-treatment markers, including CMT-induced leukopenia (CIL) or neutropenia, represent dynamic changes in the bone marrow response and drug exposure during therapy. Elevated NLR and WBC counts before or during treatment have been correlated with poorer survival, whereas CIL may indicate adequate drug exposure and chemosensitivity, leading to better treatment outcomes [4-7]. However, limited evidence exists regarding the prognostic role of CIL, specifically in recurrent CC, particularly in Asian populations.

This study focused on the first three CMT cycles because early hematologic toxicity most accurately reflects intrinsic chemosensitivity and pharmacodynamic responses before cumulative toxicity or dose modification occurs [8]. Previous pharmacodynamic studies have demonstrated that hematologic toxicity, particularly leukopenia or neutropenia, correlates with systemic drug exposure and cytotoxic effects on rapidly proliferating cells. They reported that leukopenia during early CMT cycles was associated with improved overall survival (OS) in small-cell lung cancer, supporting its role as a surrogate marker for optimal dose intensity [9]. In CC, these studies showed that leukopenia or neutropenia during CCRT or systemic CMT were associated with improved survival [5,8].

This study aimed to investigate whether grade ≥2 leukopenia within the first three cycles of systemic CMT is associated with improved 3-year post-recurrence survival (PRS) outcomes in patients with recurrent CC.

The study protocol was reviewed and approved by our institutional review board (REC.67-632-12-3). The requirement for informed consent was waived due to the retrospective nature of the study. All patient data were anonymized prior to analysis to ensure the confidentiality and protection of personal information.

This study demonstrated that the development of grade ≥2 CIL during early CMT cycles was associated with improved 3-year PRS in patients with recurrent CC. Patients in the leukopenia G2+ group showed a significantly higher 3-year PRS than those in the non-leukopenia G2+ group (38.8% vs. 16.9%). On multivariate analysis, leukopenia remained an independent favorable prognostic factor, conferring a 47% reduction in mortality risk (HR, 0.53; 95% CI, 0.31-0.91; P= 0.021).

In addition, platinum-based chemotherapy and the interval between complete remission and recurrence were independently associated with PRS. Patients receiving platinum-based regimens had significantly better survival outcomes than did those treated with non-platinum-based CMT.

These findings suggest that moderate leukopenia during early CMT cycles may serve as a pragmatic surrogate marker of chemotherapeutic efficacy and intrinsic tumor chemosensitivity. Leukopenia may reflect adequate pharmacodynamic drug exposure, preserved dose intensity, and enhanced tumoricidal activity. In the absence of infectious complications, early hematologic suppression could indicate optimal systemic exposure rather than excessive toxicity. Clinically, routine hematologic monitoring, which is already a part of standard care, may provide indirect insight into treatment effectiveness and help clinicians contextualize the dose intensity and treatment response during early cycles of systemic CMT.

Our findings are consistent with those of previous reports demonstrating a favorable prognostic association between hematologic toxicity and survival outcomes in patients with gynecologic malignancies. Mabuchi et al. [5] and Bogani et al. [8] reported that leukopenia or neutropenia during CMT or chemoradiation is associated with improved survival in cervical and ovarian cancers. In addition, Thiangphak et al. [13] demonstrated that a lower pretreatment total lymphocyte count was independently associated with survival in patients with recurrent CC after definitive radiation-based therapy, emphasizing the prognostic relevance of host immune status. Similar associations have been observed in other solid tumors, supporting the hypothesis that WBC suppression is correlated with enhanced therapeutic efficacy [9,14-17]. Mechanistically, this relationship has been attributed to more effective drug exposure, resulting in both bone marrow suppression and improved antitumor activity as well as potential immune modulation that may augment antitumor immune responses [8,15,17].

Regarding CMT regimens, our findings are consistent with existing evidence showing superior outcomes with platinum-based CMT. Non-platinum agents, such as ifosfamide and gemcitabine, have demonstrated limited response rates (15-20% and 13-17%, respectively), whereas platinum-taxane combinations have achieved response rates of approximately 36% with improved survival outcomes in recurrent CC [18-21]. In our cohort, platinum-based CMT remained an independent prognostic factor even after adjusting for confounding factors.

However, the prognostic significance of the timing of recurrence remains controversial. Although Kozaki et al. [22] reported that a longer therapy-free interval after definitive chemoradiotherapy was associated with improved OS, our study demonstrated the opposite trend, with longer intervals associated with worse 3-year PRS. Notably, Chen et al. [23] reported findings similar to ours, showing better early PRS among patients with earlier recurrence. Differences in surveillance practices and the timing of recurrence detection may partially explain these discrepancies.

It is important to interpret the findings of this study in the context of the evolution of systemic therapy paradigms for recurrent CC. During the study period (2000-2022), treatment decisions were largely guided by clinical factors and cytotoxic CMT regimens, as routine molecular or immune biomarker testing, such as programmed death-ligand 1 (PD-L1) expression, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), or human epidermal growth factor receptor 2 (HER2) status, was not widely available or incorporated into standard practice. Otherwise, known simple clinical parameters, such as hematologic responses during treatment, are among the few feasible indicators of treatment efficacy and the interaction between the host and tumor.

In contrast, the most recent National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for CC [3] emphasize biomarker-directed systemic therapy with immune checkpoint inhibitors and antibody-drug conjugates, which are now central to first-line and subsequent treatment strategies. Universal testing for PD-L1, MSI/MMR, and HER2 is strongly recommended to guide the use of pembrolizumab-based combinations, tisotumab, vedotin, and other targeted agents. These advances represent a substantial shift toward precision oncology and have significantly improved outcomes in selected patient populations. Nevertheless, cytotoxic CMT, particularly platinum-based regimens, remains a fundamental component of treatment either alone or in combination with immunotherapy or targeted agents. In this context, CIL may continue to reflect meaningful pharmacodynamic drug exposure and preserved dose intensity even in the modern era. Moreover, emerging evidence suggests that CMT-related immune modulators may interact synergistically with immunotherapeutic agents and potentially enhance antitumor immune responses [24].

As with many retrospective studies, this study had certain limitations. First, the retrospective design may introduce selection bias and limit causal inference despite the use of predefined eligibility criteria and multivariate adjustment. Although detailed RDI data were unavailable, early cycle leukopenia can serve as a clinically meaningful surrogate for effective systemic CMT exposure. This approach minimizes the influence of subsequent cumulative dose modifications. Residual confounding from unmeasured variables cannot be excluded, including baseline bone marrow reserve influenced by prior radiotherapy versus surgery and human papillomavirus-related tumor biology, which were not available in this cohort. Second, leukopenia was assessed using routine pre-cycle complete blood counts. Although transient nadir leukopenia between cycles may not have been captured, any misclassification is likely non-differential and tends to bias the results toward the null. In addition, treatment delays and variability in supportive care cannot be fully controlled. Third, cause-specific mortality data were not consistently available, raising the possibility of a competing risk bias due to non-cancer-related deaths contributing to the survival estimates. Finally, in the context of recent population-based cancer registry data demonstrating an increasing incidence of CC in East Asia, our historical cohort may not fully reflect contemporary epidemiological patterns or survival trends in the current treatment era [25].

This single-center study was conducted at a tertiary referral hospital. Differences in patient characteristics, healthcare infrastructures, follow-up strategies, and treatment availability may limit the external validity of these findings. Therefore, caution is required when extrapolating these results to other populations or healthcare settings. Importantly, these findings do not support the intentional induction of leukopenia. CIL is a post-hoc indicator of treatment exposure and host response, rather than a therapeutic objective. Our findings do not conflict with contemporary guideline-directed care but rather provide complementary insights into the host response during systemic treatment. CIL is a pragmatic, low-cost, and universally available marker that may be particularly informative in settings where advanced molecular testing is unavailable, delayed, or inconclusive.

Future prospective studies are warranted to validate CIL as a prognostic biomarker and explore its integration into treatment stratification or dose-optimization strategies. The incorporation of standardized surveillance protocols, immune-related biomarkers, and molecular tumor characteristics may further clarify the biological mechanisms underlying this association, improving individualized care for patients with recurrent CC.

In our study, we discovered that leukopenia during early cycles of systemic CMT is independently associated with improved 3-year PRS in patients with recurrent CC. These findings suggest that early CIL may serve as a post-treatment prognostic indicator reflecting adequate pharmacodynamic drug exposure and treatment efficacy. Importantly, leukopenia should not be interpreted as a therapeutic target but rather as an observational marker that may assist in prognostic stratification during systemic CMT.