This article offers detailed guidance on adjuvant chemotherapy for stage II and III colon cancer, focusing on treatment effectiveness, toxicity control, and personalised strategies using risk factors and molecular markers to improve patient outcomes.

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For stage 3 colon cancer

1. 2- and 3-year disease-free survival (DFS) are accepted endpoints for clinical trials looking at the benefit of adjuvant therapy based on the ACCENT collaborative group analysis which showed that 2- and 3-year DFS correlated with 5- and 6-year OS in colon cancer patients who received 5-fluorouracil (5-FU) based adjuvant chemotherapy.
2. An update of this analysis showed that most relapses occur early (i.e., within 2 years after surgery) and that recurrence rates were less than 1.5% per year after five years.

Fluoropyrimidine-based adjuvant chemotherapy

1. These provide an approximately 30 per cent reduction in the risk of disease recurrence and a 22 to 32 per cent reduction in mortality. Regimens include the Mayo Clinic regimen (daily 5-FU bolus for five days in a 28-day cycle, for 6 months) or the Roswell Park regimen (weekly 5-FU bolus for 6 weeks in an 8-week cycle, for 6 months.

2. The toxicity profile did, however, differ, with the former showing greater stomatitis and neutropenia and the latter showing diarrhoea.  Infusional 5-FU regimens have also been found to be as efficacious as bolus regimens with fewer toxicities. In the X-ACT trial, oral capecitabine was established to be a convenient, safe and equally effective alternative.

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Oxaliplatin-based therapies

The benefit of adding oxaliplatin to 5-FU or capecitabine carries a 20% relative risk reduction for DFS, which translates into similar improvements in overall survival.

In the landmark MOSAIC trial, the addition of oxaliplatin to 5-FU-based chemotherapy contributed to an absolute improvement of 5-year DFS rates and 6-year OS rates by 5.9% and 2.5% respectively.

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Duration and timing of adjuvant chemotherapy

1. Adjuvant therapy should be initiated as soon as possible after surgery, and ideally no later than eight weeks.
2. Six months of oxaliplatin-based chemotherapy had been accepted as the standard for the last 15 years. However, cumulative doses of oxaliplatin increase the risk of long-term sensory neuropathy which can be debilitating.
3. This led to the investigation of whether a shorter duration of adjuvant chemotherapy for colon cancer would lessen toxicities but provide similar survival benefits.
4. The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration randomly assigned either three or six months of adjuvant chemotherapy with either FOLFOX or CAPOX.
5. The primary endpoint of 3-year DFS did not meet the prespecified cut-off for noninferiority in the overall population. In the pre-specified subgroup analysis according to treatment (CAPOX vs. FOLFOX), six months of adjuvant FOLFOX was superior to three months, with a difference in DFS rate of 2.4% (73.6% vs. 76.0%). Among patients who received CAPOX, three months of CAPOX was non-inferior to six months for all stages combined.
6. Specifically, in the low-risk (T1-3, N1) subgroup, the DFS for three months of CAPOX was non-inferior to six months of CAPOX (HR, 0.85; 95% CI, 0.71–1.01).
7. However, in the high-risk (T4 and/or N2) subgroup, DFS for three months of FOLFOX was inferior to six months of FOLFOX (HR, 1.20; 95% CI, 1.07–1.35). The study also demonstrated that shorter length of chemotherapy was related to lower rates of adverse events and peripheral neuropathy than longer duration of chemotherapy.
8. This has led to a change in practice whereby in low-risk stage III disease (T1-3, N1), the duration of adjuvant oxaliplatin-based chemotherapy may be reduced to three months. In high-risk stage III disease (T4 and/or N2), six months of adjuvant chemotherapy with an oxaliplatin-based doublet treatment is still standard. A shared-making approach with the patient is encouraged.

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For stage 2 colon cancer

Surgery alone produces great results, and the little benefit of adjuvant chemotherapy in unselected individuals, when balanced against toxicities, inconvenience, and cost, makes it difficult to suggest this treatment for all patients.

The analysis of survival outcomes by the American Joint Committee on Cancer (AJCC) shows that patients with stage IIB or IIC (T4 disease) are inferior in outcomes compared to stage IIIA (T3 disease). Thus, the recommendation for consideration of adjuvant chemotherapy despite the lack of direct evidence from randomised controlled trials is based on extrapolating the relative benefits of adjuvant therapy in stage III disease.

Certain high-risk clinicopathological features help in selecting patients with stage II colon cancer for adjuvant treatment. These include:

1. Fewer than 12 sampled lymph nodes in the surgical specimen
2. Perineural or lymphovascular invasion
3. Poorly differentiated or undifferentiated histology
4. Clinical intestinal obstruction
5. Tumour perforation
6. Grade BD3 tumour

For patients with a pT4 primary tumour or two or more other high-risk features adjuvant chemotherapy is preferred. For patients with one high-risk clinicopathologic feature other than a T4 primary, individualised decision-making is advised.

MSI-H or dMMR status are used as prognostic and predictive molecular biomarkers in stage II disease. Approximately 20% of stage II colon cancers have dMMR phenotype, and this is a prognostic marker of a more favourable outcome.

These patients receive no benefit from fluoropyrimidine-based adjuvant therapy. Routine MSI status testing should be performed on all patients with stage II colon cancer to identify those with an excellent prognosis and save them from adjuvant 5-FU chemotherapy.

Most studies support the view that adjuvant, single-agent, fluoropyrimidine-based chemotherapy is less beneficial, or even potentially harmful, for patients with MSI-H or dMMR stage II or III colon cancer compared with pMMR tumours.

For patients who have dMMR stage II tumours and high-risk features who choose adjuvant chemotherapy, it is recommended to use an oxaliplatin-based regimen rather than fluoropyrimidines alone.

According to a preliminary report of data from the IDEA collaboration, the absolute benefit of three additional months of an oxaliplatin-based regimen is greater than that seen in stage III disease (3.3 per cent in DFS), but it is also small and must be balanced by the increased risk of toxicity with six months of treatment.

Newer approaches

Gene expression signatures like Oncotype DX colon have been studied which can identify a subset of stage II patients with increased risk of disease recurrence but they have a limited role in predicting the true benefit of adjuvant therapy.

Other promising biomarkers include tumour DNA (ctDNA) and Immunoscore. Immunoscore is the calculation of the mean of the four percentiles obtained for CD3+ and CD8+ T cell counts at either the tumour centre or invasive margin.

Adjuvant therapy in older adults

1. Multiple population studies have shown benefits in older populations.
2. In the National Cancer Database with more than 100,000 patients with stage III colon cancer, Margalit and colleagues found that low-risk patients older than 72 years (defined by IDEA collaborators as T3 and N1) and high-risk patients (T4 or N2 disease) older than 85 years did not benefit from doublet chemotherapy; suggesting that omission of oxaliplatin can be considered in IDEA low-risk patients older than 72 years old.
3. The QUASAR research found no benefit in adjuvant chemotherapy for people over the age of 70 with average-risk stage II illness.  Given the modest absolute benefit in the general population, it is appropriate to avoid adjuvant treatment in this group of elderly people.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bipinesh Sansar, DM Medical Oncology, Associate Professor Medical Oncology at MPMMCC and HBCH, Varanasi.