Simple Blood Count Predicts Immunotherapy Outcomes in Elderly Esophageal Cancer Patients

A routine blood test that is inexpensive and quickly repeatable may help doctors predict which elderly patients with inoperable esophageal cancer will benefit from a combination of radiotherapy and immunotherapy, according to a new retrospective study from China. The research, published in Frontiers in Oncology, found that the absolute lymphocyte count (ALC) measured before treatment was independently associated with tumor response, progression-free survival, and overall survival among patients aged 60 and older who received definitive radiotherapy together with a PD-1 inhibitor. In a cohort of 102 patients, those with higher baseline lymphocyte counts responded to treatment at dramatically higher rates and lived substantially longer without disease progression than patients whose counts fell below a statistically derived threshold. Because ALC is already part of the standard complete blood count that nearly every cancer patient undergoes, the findings point to a readily accessible marker of immune fitness that could eventually inform patient selection in this difficult-to-treat population.

Esophageal cancer remains one of the most lethal malignancies worldwide. According to GLOBOCAN 2020 estimates, more than 600,000 new cases are diagnosed and over 540,000 deaths occur each year, with a disproportionately heavy burden in East Asia. In China, esophageal squamous cell carcinoma (ESCC) accounts for more than 90 percent of esophageal cancer cases, making it a major public health concern. For patients whose tumors cannot be removed surgically, definitive chemoradiotherapy has long been the standard approach, but historical results have been sobering. In the landmark RTOG 85-01 trial, the two-year and five-year overall survival rates were only 36 percent and 26 percent, respectively, and RTOG 94-05 demonstrated that escalating the radiation dose did not improve survival. Elderly patients face additional obstacles, including comorbidities, poor nutritional status, and limited physiological reserve, which frequently preclude surgery or intensive chemotherapy and have historically left this group with unsatisfactory long-term outcomes.

The arrival of immune checkpoint inhibitors has reshaped the treatment landscape. Phase III trials such as CheckMate 648 and ESCORT-1st showed that adding immunotherapy to chemotherapy dramatically increased survival compared with traditional regimens in advanced ESCC, establishing immunotherapy-based combinations as a standard option. Definitive radiotherapy remains a key modality for patients with inoperable disease, and mounting evidence suggests it may work in concert with immune checkpoint inhibitors. Radiation can enhance T-cell infiltration into tumors, increase PD-L1 expression, and promote antigen presentation, potentially priming the immune system for a stronger attack on the tumor. Several studies have reported that radiotherapy combined with immune checkpoint inhibitors is an effective and tolerable strategy for advanced ESCC. What has been missing, however, is a reliable way to identify which elderly patients are most likely to benefit from this combination.

The new study retrospectively enrolled consecutive elderly patients with inoperable ESCC treated at Yancheng Third People’s Hospital between June 2020 and June 2024. Eligible patients were at least 60 years old, had a performance status score of 0 or 1, and had histologically verified ESCC with no prior antitumor therapy. All received intensity-modulated radiation therapy at a total dose of 50.4 to 61.2 Gy in 1.8 to 2.0 Gy fractions once daily, five days per week, delivered with 6 MV photon beams. Immunotherapy consisted of camrelizumab at 200 mg every three weeks, given either concurrently with or sequentially after radiotherapy. Chemotherapy was prescribed according to each patient’s condition and tolerance, ranging from no chemotherapy to oral S-1 or intravenous paclitaxel plus cisplatin given concurrently. The researchers recorded a complete blood count within one week before treatment, along with demographic and clinical variables including age, sex, body mass index, serum albumin, smoking and drinking history, tumor location and length, clinical stage, and immunotherapy timing.

The combined treatment performed encouragingly across the cohort. The objective response rate, defined as the percentage of patients achieving a complete or partial response by RECIST version 1.1 criteria three months after therapy, reached 70.59 percent. Median progression-free survival was 21 months and median overall survival was 28 months. To determine whether pretreatment ALC could discriminate responders from non-responders, the team performed receiver operating characteristic (ROC) curve analysis using the Youden index as the selection criterion. This identified 1.24 × 10^9/L as the optimal cutoff, with an area under the curve of 0.708 (P = 0.001; 95 percent CI: 0.595–0.821), sensitivity of 68.06 percent, and specificity of 73.33 percent. Bootstrap resampling with 1,000 iterations confirmed the stability of the result, yielding a median AUC of 0.709 and a median optimal cutoff of 1.185 × 10^9/L, with the original estimate falling comfortably within the bootstrap interval.

The contrast between patients above and below the cutoff was striking. Among the patients in the high-ALC group, 86.0 percent achieved a complete or partial response, compared with only 51.1 percent of the low-ALC group, a difference that was highly significant (P < 0.001). Notably, the two groups were well balanced in nearly every other respect: age, sex, smoking and drinking history, performance status, body mass index, serum albumin, tumor location and length, disease stage, chemotherapy regimen, immunotherapy timing, and number of immunotherapy cycles all failed to differ significantly. In univariate logistic regression, serum albumin, tumor stage, ALC, and the platelet-to-lymphocyte ratio were related to short-term response, but in the multivariate model only ALC (OR = 4.716, 95 percent CI: 1.167–19.062, P = 0.030) and advanced tumor stage (OR = 0.337, 95 percent CI: 0.120–0.951, P = 0.040) retained independent associations. Bootstrap analysis confirmed that both factors remained significantly associated with response.

Survival analysis told a consistent story. Patients with ALC above 1.24 × 10^9/L had a median progression-free survival of 27 months, compared with just 12 months in the low-ALC group, with Kaplan-Meier curves differing significantly (P = 0.001; HR = 2.078, 95 percent CI: 1.250–3.457). Median overall survival was 36 months in the high-ALC group versus 24 months in the low-ALC group (P = 0.005; HR = 2.040, 95 percent CI: 1.166–3.568). In multivariate Cox regression, higher ALC remained independently related to improved progression-free survival (HR = 0.450, 95 percent CI: 0.213–0.951, P = 0.036) and improved overall survival (HR = 0.425, 95 percent CI: 0.184–0.982, P = 0.045), while stage III–IV disease independently worsened both outcomes. Exploratory subgroup analyses found similar directions of association across chemotherapy regimens and immunotherapy timing, with no significant interaction between ALC and chemotherapy regimen for either endpoint. For overall survival, the interaction between ALC and immunotherapy timing was not significant before adjustment (P = 0.125) but became significant after adjustment (P = 0.031), a finding the authors note requires confirmation in larger studies, particularly because the sequential treatment group was small.

Why would a simple lymphocyte count carry such prognostic weight? The authors propose that ALC reflects baseline immune competence, which is essential for effective immunotherapy. Lymphocytes, particularly CD8+ T cells, are the primary effectors of cancer cell killing and immune memory formation. When circulating lymphocyte levels are reduced, the immune activation induced by radiotherapy and immunotherapy may be blunted, leading to poorer outcomes. Radiotherapy can enhance antigen presentation, upregulate MHC-I expression, promote T-cell infiltration, and induce immunogenic cell death, all of which potentially amplify the efficacy of PD-1 inhibitors, but it can also deplete lymphocytes and damage the local immune environment. A higher baseline lymphocyte reserve may therefore help patients maintain antitumor immune responses despite treatment-related lymphocyte loss. This interpretation is supported by previous work in ESCC: a prospective cohort analysis of neoadjuvant chemoradiotherapy plus immunotherapy demonstrated improved pathological complete response and prolonged progression-free survival in patients with higher baseline ALC, while low ALC has been linked to shorter overall survival in recurrent or metastatic ESCC treated with immune checkpoint inhibitors. The authors also suggest that ALC outperformed composite inflammatory ratios such as the neutrophil-to-lymphocyte ratio because it directly measures circulating lymphocyte abundance rather than reflecting a balance between different blood cell types. They caution, however, that this remains a possible explanation only, since the study did not assess lymphocyte subsets, immune markers, tertiary lymphoid structure status, or changes in ALC during treatment.

The findings carry two main clinical implications. First, ALC is routinely available, inexpensive, and easily repeatable, making it a practical indicator in clinical settings. Second, baseline ALC may help identify elderly patients with different expected outcomes after combined radiotherapy and immunotherapy; patients with markedly reduced lymphocyte counts may warrant closer monitoring and more careful clinical assessment before treatment, and serial ALC measurement during therapy may eventually prove more informative than a single baseline value, although its role in guiding treatment adjustment requires further validation. The study also has important limitations that temper enthusiasm. It was retrospective and drawn from a single institution, creating potential selection and information bias, and including patients who refused surgery may have further skewed the sample. Treatment regimens varied, and factors such as PD-L1 expression, tumor mutational burden, nutritional status, and comorbidities were not fully available for analysis, so residual confounding cannot be excluded. The small non-response group may have made the multivariable logistic model prone to overfitting, and the ALC cutoff was derived and assessed in the same cohort, with some variation remaining after bootstrap analysis. Adverse event data were incomplete and some follow-up was relatively short. The authors conclude that baseline ALC holds potential for guiding patient selection and individualized treatment planning in this population, but its clinical value must be examined in larger prospective multicenter studies before it can be incorporated into routine decision-making.

Subject of Research: Pretreatment absolute lymphocyte count and outcomes of radiotherapy plus immunotherapy in elderly patients with inoperable esophageal squamous cell carcinoma

Article Title: Association between absolute lymphocyte count and outcomes of radiotherapy combined with immunotherapy in elderly patients with inoperable esophageal squamous cell carcinoma

Article References: Jiang, Y., Chen, W., Ni, D., & Liang, X. (2026). Association between absolute lymphocyte count and outcomes of radiotherapy combined with immunotherapy in elderly patients with inoperable esophageal squamous cell carcinoma. Frontiers in Oncology, 16, 1953153. https://doi.org/10.3389/fonc.2026.1953153

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1953153

Keywords: absolute lymphocyte count, esophageal squamous cell carcinoma, immunotherapy, radiotherapy, PD-1 inhibitor, biomarker, prognosis, elderly patients, retrospective study, cancer outcomes, Association, between