Higher circulating lymphocyte ratio before and during treatment had been shown to be associated with good response to preoperative CCRT in patients with locally advanced rectal cancer 7. However, no previous study has verified the relationship between lymphopenia and survival outcomes in patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy. This retrospective study found that severe lymphopenia during CCRT was significantly associated with shorter DFS in patients with locally advanced rectal cancer receiving surgery and adjuvant chemoradiotherapy. Severe lymphopenia can be used as a useful prognostic factor for locally advanced rectal cancer. Furthermore, pre-S TLCs were associated with severe lymphopenia in the present study. We suggest that severe lymphopenia was the result of combined effects of surgery, radiotherapy, chemotherapy, and clinical characteristics.
Treatment-related lymphopenia has been recognized as an important independent predictor of survival outcomes in patients with cancers treated with radiotherapy in recent years. Tang et al. 9reported that lower TLCs were associated with shorter event-free survival and OS in patients with non-small-cell lung cancer receiving definitive radiotherapy. Cho and coauthors 13 demonstrated that TLC nadir during treatment and TLCs posttreatment were considered the predictors of progression-free survival and OS in limited-stage small-cell lung cancer treated with radiotherapy and chemotherapy. The above studies are in line with our findings. To our knowledge, this is the first study that identified the association between treatment-related lymphopenia and DFS in patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy.
Pretreatment lymphopenia was also found to be significantly associated with shorter PFS and poorer OS in patients with advanced colorectal cancer receiving chemotherapy 6. Higher pretreatment lymphocyte ratio was significantly associated with better DFS and OS in locally advanced rectal cancer 7. Furthermore, Choi and coauthors 11 demonstrated that initial TLCs were associated with progression-free survival in cervical cancer treated with CCRT. However, treatment-related lymphopenia was not investigated in the above studies. In contrast, we found that initial TLCs were not associated with DFS and that severe lymphopenia was the only independent prognostic factor in the present study. Several studies had evaluated the association between TLCs and survival outcomes in patients treated with CCRT regarding both initial TLCs and posttreatment TLCs. Tang and coauthors 9 reported that TLCs before treatment were marginally significantly associated with OS on univariate analysis in patients with non-small-cell lung cancer (p = 0.09). However, lymphocyte nadir was the only significant prognostic factor for event-free survival and OS on multivariate regression analysis. Similarly, Cho and coauthors 13 found that initial TLCs were significantly associated with OS on univariate analysis but not on multivariate analysis in limited-stage small-cell lung cancer patients. Additionally, treatment-related lymphopenia but not initial lymphopenia was found to be associated with survival in patients with resected pancreatic cancer 14. These studies have consistent conclusions as ours, and the present study supports the existing evidence that treatment-related lymphopenia is a more robust prognostic factor of survival outcomes compared with initial TLCs in patients with cancer treated with radiotherapy.
TLCs declined significantly from the beginning to the end of CCRT in this study. Moreover, there was no significant difference between pre-S TLCs and pre-RT TLCs, which suggests that surgery and chemotherapy may have less profound effect on TLCs. Campian et al. 15 found that neither neoadjuvant chemotherapy nor different regimens had influence on TLCs in patients with non-small-cell lung cancer receiving CCRT. Wild and coauthors 16 found that neoadjuvant chemotherapy had no effect on the TLCs in patients with pancreatic cancer receiving definitive CCRT. Balmanoukian et al. 14found that most patients had normal TLCs following surgery, while TLCs dropped significantly during adjuvant CCRT in patients with pancreatic cancer. These studies, in line with ours, demonstrate that radiotherapy has a more profound effect than surgery and chemotherapy on TLCs since lymphocytes has high sensitivity to radiotherapy.
However, we found that pre-S TLCs were significantly associated with severe lymphopenia, and pre-RT TLCs were marginally significantly associated with severe lymphopenia during CCRT in the present study. Similarly, Campian et al. 17 reported that initial lymphopenia was associated with severe treatment-related lymphopenia after CCRT in patients with head and neck cancers. Taken altogether, initial TLCs may have an impact on severe lymphopenia, while radiotherapy is not the single cause of severe lymphopenia. Severe lymphopenia is the result of combined effects of surgery, radiotherapy, chemotherapy, and patient characteristics, although radiotherapy is a profound factor for the reduction of TLCs. Hence, it is reasonable that initial TLC was considered a predictor of survival outcomes in some of the abovementioned studies.
Six patients had died, and the shortest survival time is 18 months. All of them died of disease progression, and no patient died of infection. Patients with lymphopenia are prone to be infected; however, lymphopenia-induced infection is not the cause of poorer DFS in the present study. We suggest that patients with lymphopenia may have a less robust immune system against cancer, which may result in a poorer DFS. Lymphopenia may be not only a prognostic factor but also a causal factor of poorer survival. Davuluri and coauthors 10found that proton therapy could reduce total body irradiation dose and decrease the incidence of grade 4 lymphopenia compared with photon radiotherapy. Proton therapy was associated with better OS on univariate analysis but not on multivariate analysis. It is possible that reducing the rate of severe lymphopenia could improve survival outcomes, and further study is warranted. Similarly, stereotactic body radiation therapy decreased the severity of lymphopenia in patients with locally advanced pancreatic cancer compared with conventional CCRT 18. Lymphocyte-sparing technique should be further investigated, while radiotherapy is one of the most profound factors that have an impact on severe lymphopenia.
Only one local failure was identified in these patient cohorts. Distant metastases were the main failure, which was in accordance with the literature in the TME era 3, 4. Positive lymph node was defined as a prognostic factor and was included in tumor-node-metastasis staging system 19. However, positive lymph nodes (stage III) were associated with inferior DFS with marginal significance on log-rank analysis but were not on multivariate analysis. It may be due to the small sample size, hence its insufficiency to detect the association between positive lymph node and DFS.
Although the patients received quite uniform treatments and had complete clinical data, the present study has many limitations. Firstly, it was a small-sized retrospective study from a single institution; hence, selection bias and imbalance are highly possible. Secondly, the follow-up period was short, and death events were too few to evaluate the association between TLCs and OS. Thirdly, some patients had only 3 or 4 times of weekly TLCs during CCRT, and TLC nadir may only be an approximate. Although the association between severe lymphopenia and poorer DFS was identified, causality cannot be established. Furthermore, TLCs may not adequately reflect immune function in patients with cancer.