Real-World Data Show More Research is Needed for Risk Stratification in Advanced Colon Cancer

For patients with stage III colon cancer, prognostics based on risk category have been outlined in the IDEA trial (EudraCT 2009-010384-16). However, the stratification standards are based on select risk factors that do not cover all high-risk features that patients can present with.

By analyzing the Surveillance, Epidemiology and End Results (SEER) database, a group of investigators sought to assess how risk factors like pathologic T4 disease, perineural invasion, lymphovascular invasion, having an inadequate lymphadenectomy consisting of less than 12 lymph nodes harvested, and poorly differentiated tumors may impact overall survival (OS) as well as cancer-specific survival (CS) in stage III colon cancer.

The study demonstrated that those with high-risk features have lower OS and CS compared with those who did not harbor high-risk features. Results also signaled that patients with high-risk features should be considered to be at a high risk for mortality.

In an interview with Targeted Oncology ™, Luv Hajirawala, MD, a resident in the Section of Colon and Rectal Surgery at LSU Health New Orleans School of Medicine, discussed the relevance of high-risk features in patients with stage III colon cancer, and how a recent real-world analysis may change risk stratification in the future.

TARGETED ONCOLOGY: Can you describe the high-risk features of stage II colon cancer and have these features impact outcomes?

Hajirawala: There are many high-risk features, which include the perineural invasion, which is invasion into the neurons in the nervous system structures next to the colon; lymphovascular invasions; poor differentiation at presentation; advanced T stage, which is how much the tumor has grown through the wall; having less than 12 lymph nodes; and inadequate margins.

In stage II colon cancer, these have been associated with an adverse prognosis for patients. So, some of the patients who have stage II disease without these, we tend to not give them adjuvant therapy, because surgery's curative, but when the patients have these high-risk features, they are at higher risk of recurrence or adverse survival. So, the [depending on the] stage [for] patients with these risk factors, we'll elect to give them chemotherapy. Understanding how these factors affected patients with stage III disease is very important.

How have previous studies explored this topic?

First, oncologists have to understand that our incidence rates are decreasing. We're doing something with advanced screening practices, and new cancers are found and we're treating them. Our incidence of colon cancer has also gone down and our survival has been better. But what we find is an equal number of patients have localized disease, which is stage I and II, and locally advanced disease, which is stage III at presentation. So, when you look at all patients who are diagnosed with colon cancer in a population, when we diagnose them, an equal portion, about 35%, are localized. So surgery is curative, and an equal amount have locally advanced disease, stage III, and chemotherapy is the mainstay of therapy after surgery for these patients.

So, our understanding of risk in this population is evolving. Most recently, if you look at the NCCN [National Comprehensive Cancer Network], our current stratification of risk in these patients depends on the TNM staging. The IDEA trial established this high-risk group of patients with stage III colon cancer. What they found was patients who had T4 disease or N2 disease had an adverse prognosis and they benefited from a longer course of adjuvant therapy with FOLFOX. And that is kind of where we stand within the NCCN guidelines about the risk stratification. We don't have any data on stage III disease, and how these features affect outcomes, in addition to our normal stratification of high risk, which is either T4 or N2.

How did you conduct the SEER database analysis around mortality risk in patients with stage III colon cancer?

We looked at our SEER database between 2010 and 2017 and identified patients with stage III colon cancer. We first compared patients by stratification based on high-risk features. So, we broke the group down into 3 categories, which included stage III colon cancer with zero risk factors, stage III colon cancer with 1 risk factor, and stage III colon cancer with 2 or more risk factors. And these risk factors included inadequate lymphadenectomy, meaning less than 12 nodes harvested during surgery; high-grade disease; poor differentiation; perineural invasion; and T for disease.

What we wanted to look at was, how does the presence of high-risk features affect the patient's overall survival and cancer-specific survival?

What were the key findings of the analysis?

Patients who had 1 high-risk feature had a worse overall and cancer-specific survival compared to patients who did not have any. And when we looked at more than 2 high-risk features, that overall and cancer-specific survival was even lower. What we wanted to know then was, is this because of a single-risk factor, or do all of them have a combined effect on it?

We then looked at how individual risk factors impact overall and cancer-specific survival in patients with stage III disease. We found that less than 12 lymph nodes, inadequate lymphadenectomy, high-grade disease, and perineural disease all have similar impact on the overall and cancer-specific survival. These factors bring bring survival down to 65% in that range, and T4 disease had more pronounced effect on this. T4 disease brings your survival down to 57%.

We also found that patients who had more than 2 risk factors, their survival was almost 44% for overall survival, and 51% for cancer-specific survival, which is lower than the lowest survival conferred by any individual high-risk feature. So, what we can summarize is that if a patient has more than 2 risk factors, the effect on survival is cumulative.

Were there any notable subgroup findings?

Within the stage III group, we also stratified the patient within a low-risk and high-risk groups. This was done based on the IDEA trial, which currently is the benchmark for risk stratification in stage III disease. So, we looked at the impact of high-risk features in low-risk stage III cancer and found that presence of 1 or more high-risk feature had both impact on overall and cancer-specific survival.

Then, we repeated that analysis for a patient who had high-risk disease, and we found the same. We found that the presence of 1 or more high-risk features that had an adverse effect on overall and cancer-specific survival, which is cumulative. This signifies the highest features have an impact on survival.

How do you interpret these results?

These findings imply that our current risk stratification based on the TNM status is likely not enough to provide adequate prognostic information. Our current risk stratification is based on T4N2 disease, but what we find is that despite of your overall tumor nodes, and metastatic disease status, the high-risk features have an adverse survival. So, high-risk features or the presence of more than 2 high-risk features should be considered a high-risk population in stage III disease.

How should future research evaluate risk stratification for stage III colon cancer?

Further studies need to focus on these patients to see which chemotherapeutic agents or adjuvant therapy would be beneficial. We wanted to look, [in] particular at the SEER database, so we were only able to look at some high-risk feature. There are more high-risk features that are not captured in this database. So, we'd like to look at the impact of those. I think going forward, we want to characterize all of the high-risk features and the risks that may portend for the survival of these patients because, ultimately, the cancer treatment is going to be personalized. And I think each patient, based on their high-risk features, should get appropriate therapy that may not be applicable to somebody else. So, we want to find the best therapy and the best individual therapy that we can provide for stage III colon cancer. I think that's a little far away, but we're making strides towards it.

_REFERENCE

_{Hajirawala, LN, Yi Y, Bergeron MA, et al. 6315 - Are a subset of patients at higher risk for mortality in stage III colon cancer: An analysis of the SEER database. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 6315.}