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Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer
© Kitayama et al; licensee BioMed Central Ltd. 2010
Received: 30 March 2010
Accepted: 3 June 2010
Published: 3 June 2010
Although neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer (RC), markers to predict the treatment response have not been fully established. In 73 patients with advanced RC who underwent CRT in a neoadjuvant setting, we retrospectively examined the associations between the clinical effects of CRT and blood cell counts before and after CRT. Clinical or pathological complete response (CR) was observed in 10 (14%) cases. The CR rate correlated significantly with the size and the circumferential extent of the tumor. Hemoglobin level, white blood cell (WBC) count and platelet count before CRT did not show a significant difference between CR and non-CR cases. Interestingly, however, lymphocyte ratio in WBC was significantly higher (p = 0.020), while neutrophil ratio tended to be lower (p = 0.099), in CR cases, which was shown to be an independent association by multivariate analysis. When all the blood data obtained in the entire treatment period were evaluated, circulating lymphocyte count was most markedly decreased in the CRT period and gradually recovered by the time of surgery, while the numbers of neutrophils and monocytes were comparatively stable. Moreover, the lymphocyte percentage in samples obtained from CR patients was maintained at a relatively higher level than that from non-CR patients. Since tumor shrinkage is known to be dependent not only on the characteristics of tumor cells but also on various host conditions, our data raise the possibility that a lymphocyte-mediated immune reaction may have a positive role in achieving complete eradication of tumor cells. Maintenance of circulating lymphocyte number may improve the response to CRT in rectal cancer.
Preoperative chemoradiotherapy (CRT) is currently used worldwide as the initial treatment for advanced RC, since it can produce down-staging in approximately half of patients with locally advanced rectal cancer RC, resulting in a lower rate of postoperative local recurrence and a higher rate of sphincter-preserving surgery as well as longer survival [1–3]. However, in unresponsive cases, it may have disadvantages such as delaying surgery or immune suppression. Although many clinical factors [4, 5], radiologic findings [6, 7] and molecular markers [7–10] have been suggested to be related to the therapeutic response, the clinical usefulness of these markers remains controversial, and thus, identifying factors that can predict the efficacy of neoadjuvant CRT is essential for decision-making in the management of patients with RC.
Correlation between clinical and pathological factors before CRT and pathologica Response in rectal cancer patientsl
63.4 ± 9.9
65.4 ± 11.2
Distance from anal verge
Multivariate analysis of Complete response (CR) rate
Odds (95% CI)
Circumferential extent (>60% vs. ≤60%)
% Lymphocytes in WBC
% Neutrophils in WBC
Peripheral lymphopenia, especially reduced T lymphocytes, after RT was first described in the 1970's [11, 12], but the clinical significance of this drop in the circulating lymphocyte count has not been well evaluated. A literature search yielded no previous report of a significant correlation between circulating lymphocyte count and RT response. However, the degree of recovery of lymphocyte count after RT has been shown to correlate with tumor recurrence [13, 14]. These facts allow us to speculate that the radiation-induced depression of circulating lymphocyte may provide an opportunity for re-growth via proliferation of tumor cells that survived the irradiation damage, thereby reducing the likelihood of CR after RT.
In fact, radiosensitivity has been shown to be dependent not only on the biological characteristics of tumor cells but also on the tumor microenvironment [15, 16]. Although circulating leukocyte count reflects the host immune status, neutrophils usually act as the first responders to microbial infection in acute inflammation, while lymphocytes recognize specific "non-self" antigens and eliminate a specific pathogen or pathogen-infected cells. Since tumor cells usually have a tumor-associated antigen, lymphocytes, especially T cells, are thought to play a central role in anti-tumor immunity, and the absolute number of host lymphocytes could be biologically relevant for tumor response to CRT. Since the first report in 1979, , it has been proposed that tumor shrinkage is not simply dependent on direct damage to irradiated tumor cells, but also to be greatly affected by the host immune response . In fact, in vivo studies have suggested that cancer cells, dead or dying due to radiotherapy or chemotherapy, can present tumor-associated antigens to host immune cells and thereby evoke anti-tumor immune responses [19, 20]. Moreover, accumulating clinical data suggest the presence of radiation-induced anti-tumor immunity in humans [21, 22]. Therefore, the marked reduction in the circulating lymphocyte count during CRT may be a significant disadvantage for patients. Together with these facts, our observations suggest the possibility that the lymphocyte-mediated immune response against damaged tumor cells is important for achieving CR during CRT in RC cases.
In our data, the association between lymphocyte ratio and clinical efficacy was observed in primary tumor, but not in metastatic lymph nodes (data not shown). Since tumor shrinkage is more dependent on local immune response, this may be reasonable that the clinical effects during CRT are largely different between in lymph nodes and in primary tumors. Further analysis on tumor infiltrating lymphocytes (TIL) in malignant tissues is essential to see the accurate contribution of host immune reaction on CRT response.
In contrast to lymphocytes, the neutrophil count showed an inverse correlation with tumor response. An increase in neutrophil count usually reflects an acute inflammatory response against bacterial infection. In our series, other inflammatory markers, such as platelet count and serum levels of C reactive protein (CRP) and fibrinogen also showed a similar association, although not statistically significant (data not shown). Previous studies have shown that neutrophils can suppress the T cell response through the production of reactive oxygen species (ROS), nitric oxide (NO) and arginase [23, 24]. This suggests that the presence of an acute inflammatory response during CRT may cause suppression of lymphocyte-mediated immunity through increased circulating neutrophils and thus elicit unfavorable effects on tumor response.
Although the results obtained from this retrospective analysis have limitations, the significant association between the circulating lymphocyte number and CR rate supports the hypothesis that total eradication of tumor cells after CRT is dependent, at least in part, on host immune reaction. Enhancing lymphocyte-mediated immunity during CRT may be a lead to the improvement of the clinical efficacy of CRT in RC patients. Further analysis of the phenotypic and functional characteristics of circulating as well as tumor infiltrating lymphocytes may clarify the novel mechanisms underlying the responsiveness of tumors to CRT.
JK participated in the study design and data retrieval and analysis. KY, KK, ES participated in data retrieval and analysis. HN participated in the management of this study. All authors read and approved the final manuscript.
This study was funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labor and Welfare of Japan.
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