Episode 101: Colorectal Cancer Series, Pt. 3 - Adjuvant Therapy in Stage II Colon Cancer and ctDNA
In this week’s episode, we discuss the management of stage II colon adenocarcinoma, which is defined by a lack of nodal involvement and invasion through the muscularis layer of the colon. If you have not done so already, be sure to check out episode 099 (overview of colorectal cancer) and episode 100 for stage III colon cancer, as we will building on concepts discussed already.
Adjuvant chemotherapy is not offered to all stage II colon cancer patients. What factors go into determining the need for adjuvant chemo?
With some exceptions, MSI high or MMR deficient cancers do not benefit from adjuvant chemo, with the thought being that the chemotherapy blunts the normal immune surveillance response to kill off the cancer
Recall that a study by Gunderson and colleagues suggested that some stage II patients (T4bN0) did worse than Stage III (T3N1 patients).
IMPACT B2 (JCO 2009) was the first large study showing that stage II patients did not have a benefit from adjuvant chemotherapy
Over 1000 patients were included and there was no benefit seen from those who got adjuvant 5-FU compared to surgery alone
5 year EFS was around 75% for both groups
5 year OS was around 80% for both groups
This was supported by a meta-analysis (2008) of older studies that also showed no difference in DFS or OS in stage II patients
T4a (invasion to the visceral peritoneum) & T4b (invasion to surrounding structures) are higher risk than T3 (invasion through the muscularis propria) and therefore, more likely to benefit.
High risk clinicopathologic features that suggest possible benefit: bowel obstruction, perforation, less than 12 nodes examined surgically, poorly differentiated histology, and perineural or vascular invasion
Why does risk stratification matter in stage II colon cancer?
No meta-analysis shows overall survival benefit from chemotherapy for stage II disease
The QUASAR study showed some benefit for rectal cancer but no statistically significant benefit for colon cancer patients.
There were nearly 3000 patients enrolled who had stage II colorectal (note BOTH colon and rectal!) disease randomized to some sort 5-FU monotherapy (with or without levamisole and differing doses of leucovorin) vs. observation
About a third of patients had T4 disease or vascular invasion
There was a reduced risk of recurrence with an OS benefit of an absolute 3.5%
The big issue was that most of the benefit in recurrence was seen in rectal cancer and there was no statistically significant benefit in colon cancer patients
Study limitations:
Pathologic data to determine other high risk features were only available for 20% of the population
Heterogeneous treatment among patients
This did show that the benefit in survival is very marginal with adjuvant chemotherapy in this patient population
A study published in 2000 suggested routine testing for perineural and vascular invasion. It is unclear if patients were correctly staged due to a lack of preoperative imaging and inadequate lymph node dissections so these risk factors may not be as relevant in the current era
Patients without clinical pathologic high-risk features and T3 disease should not be offered chemotherapy based on this data.
What about patients with T4 disease or high-risk factors who are not MSI-high?
For patients with T4 disease or high-risk features, numerous observational retrospective studies have shown decreased cancer recurrence and occasionally survival benefit when comparing adjuvant chemotherapy to observation.
These studies overall have a low level of evidence but there are a few pooled analyses with larger patient populations
The first study was a systematic review and meta analysis looking including 15000 patients with stage II colon cancer. There was no difference in DFS or OS with adjuvant chemotherapy vs. observation.
The second study was a population based analysis of 1700 patients who were grouped as “high risk” if they had T4 disease and/or one of the high risk features we discussed vs. “low risk” if T3.
There was improved recurrence free survival and OS benefiting chemotherapy but this was limited to the T4 patients.
Patients with other high risk features but who were not T4 did not derive benefit!
Both studies show unclear benefit for adjuvant chemotherapy.
T4 might be much more important than the other risk factors which were first described in an outdated era.
We are at risk of over treating for high-risk clinical and pathologic features other than T4. What about adding oxaliplatin to 5-FU?
Looking on the stage II patients included in the MOSAIC trial, the 5-year DFS and OS were not different between FOLFOX and 5-FU monotherapy. Based on this, patients should not routinely be offered oxaliplatin based chemotherapy.
What is the role of circulating tumor DNA for patients with stage II colon cancer?
At this time, circulating tumor DNA is still being evaluated in clinical trials, and we don’t know exactly know what to do with it in the current treatment algorithm.
Why is 5-FU monotherapy detrimental for MSI high disease?
A pivotal 2010 pooled analysis showed that MSI-high or deficient MMR tumors had a worse DFS and OS with 5-FU monotherapy as adjuvant treatment particularly in patients with stage II disease. The thought was that chemotherapy blunts the immune system and does not allow for immune surveillance to get rid of residual disease after surgery.
The MOSAIC trial was investigating if FOLFOX had a benefit by MMR status. Compared to 5-FU monotherapy, there was a trend towards DFS and OS in patients with deficient MMR though not statistically significant.
Is there any role for immunotherapy in the adjuvant setting?
There are ongoing trials evaluating this question.
The 2022 NICHE-2 study looked at ipilimumab + nivolumab for high-risk stage II and stage III patients in the neoadjuvant setting with promising complete response rates at the time of surgery.
References:
https://ascopubs.org/doi/10.1200/JCO.2009.24.0952?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed#F1: Article discussing high risk pathologic features for colon cancer
https://pubmed.ncbi.nlm.nih.gov/10334519/: IMPACT B2 showing that stage II patients did not benefit from adjuvant chemotherapy
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61866-2/fulltext: QUASAR Study showing benefit for stage II rectal cancer patients, but no statistically significant difference in stage II colon cancer patients
https://pubmed.ncbi.nlm.nih.gov/10888773/: An article from 2000 that attempts to determine high risk pathologic features for colorectal cancer
https://www.tandfonline.com/doi/full/10.3109/0284186X.2014.975839: A systematic review and meta analysis looking at Stage II colon cancer patients and finding no difference in DFS or OS with adjuvant therapy vs. observation
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.29072: A population based study showing that T4 may be more important than other “high risk” features
https://ascopubs.org/doi/10.1200/JCO.2015.63.4238?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed: MOSAIC trial comparing FOLFOX vs. 5-FU monotherapy
https://ascopubs.org/doi/10.1200/JCO.2009.27.1825?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed: A 2010 pooled analysis showing MSI-high/dMMR tumors had worse DFS and OS with 5-FU monotherapy, especially in stage II colon
https://www.annalsofoncology.org/article/S0923-7534(22)03894-7/pdf: NICHE-2 study looking at ipilumumab + nivolumab, study in progress.
The crew behind the magic:
Show outline: Vivek Patel
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Madeline Fitzpatrick, Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
Quick reminders:
Mismatch repair proteins: MSH2, MSH6, MLH1, and PMS2
MSI-low = pMMR; MSI-high = dMMR [more mutations]
Staging Reminders!
Image source: Figure 1. Chang et. al. 2023. Radiologic T staging of colon cancer: renewed interest for clinical practice. Abdominal Radiology. https://link.springer.com/article/10.1007/s00261-023-03904-2
