Original StudyPrimary Tumor Resection in Patients With Metastatic Colorectal Cancer Is Associated With Reversal of Systemic Inflammation and Improved Survival
Introduction
Colorectal cancer (CRC) is one of the most common malignancies worldwide, accounting for around 1,350,000 new cases and nearly 700,000 deaths annually.1 Advances in the medical and surgical management of metastatic CRC (mCRC) cancer have led to significant improvements in survival. However, with the exception of a proportion of patients with surgically resectable isolated metastases, the treatment intent has remained palliative.2, 3, 4, 5 For patients with incurable de novo metastatic disease, the optimal management of the primary tumor remains an unanswered clinical question, in particular, in patients with a minimally symptomatic or asymptomatic primary lesion.
Several retrospective studies and meta-analyses have demonstrated an association between primary tumor resection and improved survival outcomes in patients with metastatic disease at presentation, with a ∼30% relative reduction in risk of death and a 3- to 6-month improvement in overall survival (OS).6, 7, 8, 9, 10, 11 However, the data have not been entirely consistent across the published studies.12, 13 In the absence of a persuasive biologic mechanism, a confounding effect of selecting patients for primary resection who already have superior survival has yet to be excluded as the explanation for the observed survival benefits. Countering the argument for routine primary tumor resection is the associated risk of surgical morbidity and mortality, the potential detrimental effects on survival of the consequent delay in the delivery of systemic therapy, and the results from multiple series suggesting that the large majority of intact primary tumors will ultimately never require intervention.11, 14, 15, 16, 17
Inflammation within the primary tumor, reflecting a robust local anticancer immune response, has been shown to positively affect the outcomes, such as recurrence and survival, in multiple tumor types.18 In contrast, the presence of tumor-associated systemic inflammation in patients with both localized and metastatic cancer negatively affects survival.18, 19, 20 The reversal of this systemic inflammatory response after effective systemic chemotherapy has been shown to be associated with improved OS in patients with mCRC.21, 22, 23, 24 One well-established biomarker of systemic inflammation is the peripheral blood neutrophil/lymphocyte ratio (NLR), which is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The NLR has demonstrated prognostic utility in early stage25, 26 and advanced colorectal cancer.27, 28, 29, 30 Moreover, it is easily calculated from the blood tests performed routinely in the pre- and postoperative setting.
In a previous study from our group, we demonstrated a significant survival advantage from primary tumor resection in a cohort of patients with mCRC compared with no resection.27 Moreover, exploratory analyses have suggested that a small subgroup of patients with reversal of an elevated NLR after primary tumor resection had outcomes similar to those with a low NLR at baseline.27
The present study aimed to further evaluate the prognostic effect of reversal of systemic inflammation, as measured by the NLR, after primary tumor resection in a larger patient cohort. In addition, we planned to evaluate the primary tumor and patient characteristics that might predict for increased likelihood of a reversed NLR.
Section snippets
Patient Cohort
Patients presenting with de novo mCRC from January 1, 2000 to July 1, 2010, who had undergone primary tumor resection, were identified from the multisite CRC Australian Comprehensive Cancer Outcomes and Research Database (ACCORD), which prospectively records the point-of-care comprehensive clinicopathologic and follow-up data for consecutive patients with CRC treated at the participating centers. The patients were excluded from the present analyses if a delay had occurred of ≥7 weeks between
Results
From the ACCORD, 145 patients with de novo metastatic CRC who met the eligibility criteria were identified. The patient and tumor characteristics are listed in Table 1. No significant associations were found between the baseline NLR and gender, Eastern Cooperative Oncology Group (ECOG) performance status, chemotherapy use after surgery, or primary tumor site. However, significantly more patients with a high baseline NLR required emergency surgery (surgery within 24 hours of presentation) than
Discussion
We have demonstrated that primary tumor resection in patients presenting with de novo mCRC can be associated with significant changes in systemic inflammation, including reversal of an elevated NLR in some patients. In patients with a high NLR at baseline, the likelihood of NLR reversal correlated with the size of the primary lesion. Most importantly, an association between NLR reversal after primary resection and improved survival was found. This suggests that resection of the primary tumor
Conclusion
We have shown, for the first time to our knowledge, that resection of the primary tumor in patients with mCRC can be associated with reversal of systemic inflammation. We have also shown that this is more likely to occur in patients with larger primary tumors, increasing the biologic plausibility of this association. Most importantly, reversal of systemic inflammation with primary tumor resection appears to have prognostic significance in those with mCRC. With additional validation of our
Disclosure
The authors have stated that they have no conflicts of interest.
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Cited by (47)
Survival outcome of palliative primary tumor resection for colorectal cancer patients with synchronous liver and/or lung metastases: A retrospective cohort study in the SEER database by propensity score matching analysis
2020, International Journal of SurgeryCitation Excerpt :Compared to local tumor inflammation, systemic inflammation is associated with enhanced tumor growth and survival, possibly caused by T cell anergy and loss of cytotoxicity [37,38]. It is supposed that pPTR could probably reverse systemic inflammation and restore the immune function [33,39]. Furthermore, some studies equally found that the addition of chemotherapy to pPTR was associated with better survival, which may be attributed to a better response to chemotherapy after reduction of systemic tumor burden [40].
Does postoperative inflammation or sepsis generate neutrophil extracellular traps that influence colorectal cancer progression? A systematic review
2020, Surgery Open ScienceCitation Excerpt :In this study, it was found that CRP, higher mGPS, NLR, and PLR were all predictors of poorer CSS [36]. Other included studies included in this review demonstrated results largely consistent with the results of the studies from Glasgow and the Scottish Cancer Registry, with only 2 studies demonstrating conflicting findings in respect to CSS [39,40]. Mallappa et al found that higher preoperative NLR was associated with poorer CSS in patients undergoing elective resection of CRC [41], and Neal et al mirrored this association in resection of potentially curative resection of colorectal liver metastases [42].
N.T. and B.T. contributed equally and are considered co-first authors.