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The Relationship Between the Local and Systemic Inflammatory Responses and Survival in Patients Undergoing Curative Surgery for Colon and Rectal Cancers

  • 2009 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

Both local (Klintrup criteria) and systemic (Glasgow Prognostic Score, mGPS) inflammatory responses have been reported to be independent predictors of cancer-specific survival in colorectal cancer. However, high-grade local inflammatory response appears more common in rectal and high mGPS more common in colonic tumors. Whether relationships with survival are similar in colon and rectal tumors is unclear. The present study assesses the prognostic value of local and systemic inflammation in colon and rectal cancers and defines 3-year survival according to inflammation-based criteria for stage II/III disease.

Methods

Two hundred forty colon and 140 rectal cancer patients underwent potentially curative surgery between 1997 and 2007. C-reactive protein and albumin (mGPS) were measured preoperatively. Routine pathology specimens were scored according to Klintrup criteria for peritumoral infiltrate.

Results

Patients with colon cancers were older (P < 0.05) and had higher T stage (P < 0.001) and mGPS (P ≤ 0.001) compared with rectal cancers. The proportions of patients with a high-grade tumor inflammatory cell infiltrate were similar in colon and rectal cancers. mGPS and Klintrup criteria were independent predictors of cancer survival. The mGPS hazard ratios were 1.56 and 1.76 for the mGPS, and the Klintrup hazard ratios were 2.12 and 5.74 for colon and rectum, respectively. For stages II and III colorectal cancer, 3-year survival was 91% and 73%, respectively. Three-year survival varied between 100% and 68% depending on Klintrup score/ mGPS in stage II disease and between 97% and 60% in stage III disease.

Conclusion

Local and systemic inflammatory responses are important independent predictors of survival in colon and rectal cancers. These scores combined with tumor–node–metastases stage improve the prediction of survival in these patients.

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Author information

Authors and Affiliations

  1. University Department of Surgery, Faculty of Medicine, University of Glasgow, Royal Infirmary, Glasgow, G31 2ER, UK

    Campbell S. D. Roxburgh, Paul G. Horgan & Donald C. McMillan

  2. University Department of Pathology, Faculty of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK

    Jonathan M. Salmond

  3. Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Glasgow, UK

    Karin A. Oien

Authors
  1. Campbell S. D. Roxburgh
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  2. Jonathan M. Salmond
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  3. Paul G. Horgan
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  4. Karin A. Oien
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  5. Donald C. McMillan
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Corresponding author

Correspondence to Campbell S. D. Roxburgh.

Additional information

Dr. Kirk A. Ludwig (Milwaukee, WI): Congratulations to you and your colleagues on a very nice study. The data suggest that for patients with colorectal cancer, inflammatory changes at the level of the tumor are associated with increased survival, while systemic inflammatory responses are associated with a decrease in survival. Furthermore, both local and systemic inflammatory responses can be determined by routine pathologic examination and limited laboratory measurements.

Let me start by thanking the authors for providing me with a copy of the manuscript. In reviewing the manuscript, a number of questions come to mind but I have four that I wonder if you can answer for me.

First, it is known that colorectal tumors that arise via the mismatch repair gene mutation pathway or microsatellite unstable tumors often elicit a local inflammatory response known as a Chron’s-like reaction. There is some evidence that these tumors have a better overall prognosis than those tumors that arise via the classic pathway. Given this, did you assess these tumors for microsatellite instability, and if so, is there a relationship between the microsatellite unstable tumors and the good prognosis tumors that you identify?

Second, it appears that 110 patients in your series received adjuvant chemotherapy, and I assume that most of these were stage 3 patients. Were the stage 3 patients receiving chemotherapy evenly distributed across your subgroups as defined by the Klintrup criteria and the modified Glasgow Prognosis Score? And could the use of chemotherapy, in some, but not all of these patients, have confounded your results?

Third, did you look to see if there was a relationship between the variable you measured and other commonly evaluated tumor characteristics, such as tumor grade or differentiation, number of involved lymph nodes in the stage three patients, or more detailed staging systems that break stage 2 and 3 patients into those with stage 2 or 3A or stage 3 or 3B?

Finally, given your data, are you ready to suggest that the power of these variables in predicting prognosis is strong enough to use them in making decisions about who is and who is not offered chemotherapy for their stage 2 or 3 disease?

Closing discussant

Dr. Campbell Roxburgh: The first question relates to microsatellite instability. Unfortunately, we do not perform microsatellite instability analysis on our colorectal cancer patients, and therefore, the data are not available in terms of whether those are related to local inflammatory responses. This is, however, a very interesting point and, potentially, something we will look at in the future.

However, the Crohn’s-like reaction described previously with MSI-H tumors was also discussed in the original manuscript by Klintrup and colleagues in the development of their own score. So there is, potentially, a link there, and that is something I think we will take away and look at.

You asked about chemotherapy, and whether TNM stage and provision of chemotherapy was evenly distributed across the subgroups as defined by the Klintrup criteria and a modified Glasgow Prognosis Score.

I can tell you that they were. There were no significant differences between patients who had adjuvant chemotherapy within these different subgroups. In terms of whether chemotherapy was a confounder, we did not identify chemotherapy was a prognostic factor on univariate or multivariate analysis. Such analysis should control for potential confounding variables.

I do know, however, that for patients who did not receive chemotherapy, the prognostic value of the local and systemic inflammatory response still holds true within that group.

And you also asked if the individual criteria were related to any of the actual tumor characteristics. I can tell you that the GPS is not related to any of the actual tumor characteristics. However, in the Klintrup criteria there is a relationship between our low-grade local inflammatory response and increasing T stage. In addition, we have also looked at tumor budding or de-differentiation along the invasive margin. It appears that low-grade local inflammatory responses are related to an increased percentage of tumor budding at that invasive margin.

Finally, am I ready to recommend that the results of these data are ready for use in clinical practice for gauging adjuvant chemotherapy? I can tell you that, at our institution, we routinely measure the systemic inflammatory response in all of our patients.

It has been known for some time that these patients are at higher risk, and our oncologists take this into consideration when prescribing adjuvant chemotherapy. However, whether adjuvant chemotherapy is the most appropriate treatment for patients at high risk, as stratified by these means, remains to be seen. Maybe some other form of immunomodulation may be a more appropriate target.

However, regarding attempts at stratification, I would absolutely recommend that these scores can stratify high risk and have been validated at a number of centers now.

Presentations Data from the following manuscript were presented as a plenary presentation at (1) the SSAT Annual Meeting at Digestive Diseases Week, 2009, Chicago and (2) the SSAT Annual Residents and Fellows Research Conference 2009, Chicago.

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Roxburgh, C.S.D., Salmond, J.M., Horgan, P.G. et al. The Relationship Between the Local and Systemic Inflammatory Responses and Survival in Patients Undergoing Curative Surgery for Colon and Rectal Cancers. J Gastrointest Surg 13, 2011–2019 (2009). https://doi.org/10.1007/s11605-009-1034-0

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