Chemotherapy and radiotherapy for colorectal cancer

Acute and long-term toxicity

Fluoropyrimidine chemotherapy is commonly associated with lethargy, mucositis, diarrhoea and hand-foot syndrome. Although the risk of neutropenic sepsis is generally low, a very small proportion of patients (<1%) are deficient in the enzyme dihydropyrimidine dehydrogenase (DPD) and consequently may develop severe and life-threatening toxicity, usually within the first 3 weeks of treatment. This deficiency can be detected by either identifying DPYD gene variants (genotype) that encode DPD activity or by phenotyping (e.g., measuring DPD activity in peripheral blood mononuclear cells or endogenous uracil levels). Fluoropyrimidines are contraindicated in patients with complete DPD deficiency, and should be used with caution in patients with partial deficiency. Routine testing before commencing fluoropyrimidines is currently recommended in guidelines.

The addition of oxaliplatin increases risk of diarrhoea and neutropenia. Oxaliplatin also causes neurotoxicity, particularly cumulative peripheral sensory neuropathy (PSN), developing in the latter cycles of adjuvant chemotherapy but with some recovery over time. In the MOSAIC trial, grade 3 PSN (functional impairment) reduced from 12.5% during treatment to 0.7% by 18 months, however, a further 15% reported permanent grade 1-2 symptoms.

Therefore the potential risks should be weighed against the potential survival benefits of adding oxaliplatin. In general, higher-risk patients with good performance status should be considered for an oxaliplatin-based combination, as their risk of death from cancer significantly outweighs their risk of death from unrelated causes.

Older patients

Whilst it is accepted that selected older patients with colon cancer benefit from adjuvant fluoropyrimidine chemotherapy, a meta-analysis suggested no further benefit with the addition of oxaliplatin to 5FU. However, data from the most recent XELOXA trial suggest that patients over 70 years gained as much as younger patients. Due to the higher risk of grade 3-4 toxicity in older patients, careful individual assessment must be made of the competing risks of toxicity, death from cancer and death from unrelated causes to make the most appropriate recommendation.

Stage II colon cancer

The main evidence to support the use of adjuvant chemotherapy in stage II (lymph node negative) disease comes from the UK QUASAR 1 trial, which randomised 3239 patients (91% with stage II) to 5FU or observation. Use of chemotherapy reduced risk of recurrence by 22% (HR 0.78, P = 0.008) and improved OS by 3.6%.

A number of clinical and pathological features indicate increased risk of systemic recurrence in stage II cancer, including TNM pT4, extra-mural vascular invasion, obstructed or perforated cancers, poor or mucinous differentiation, and fewer than 12 lymph nodes assessed in the specimen. A stage II cancer with multiple high-risk features will be associated with a similar or higher recurrence risk than a stage III cancer with none of these features. Although oxaliplatin is not licensed or usually recommended for routine use in stage II cancers, it can be considered in selected high-risk patients.

Approximately 15% of stage II colon cancers have defects in the deoxyribonucleic acid (DNA) mismatch repair system (MMR) leading to microsatellite instability (MSI), which is associated with a better prognosis than microsatellite-stable tumours. A meta-analysis suggested that patients with MSI tumours do not derive benefit from adjuvant chemotherapy using 5FU alone. The UK Royal College of Pathologists recommends routine assessment of MSI either genetically or by immunohistochemistry for the four MMR proteins in stage II patients who are being considered for adjuvant therapy.

Timing and duration of adjuvant chemotherapy

Most clinical trials recommend a 6–8-week time point for the commencement of adjuvant chemotherapy. A meta-analysis of 15 410 patients in 10 trials concluded that delay of 4 weeks beyond this time point was associated with a significant decrease in OS. Chemotherapy should therefore start soon after surgery, although the authors acknowledge that a benefit for chemotherapy may still exist if a significant delay is needed.

Previous trials demonstrated that 6 months of chemotherapy was as effective as 12 months. Six concurrent international trials including a total of 12 834 patients compared 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy using either CAPOX (capecitabine and oxaliplatin) or FOLFOX (fluorouracil, leucovorin [LV] and oxaliplatin). Through the International Duration Evaluation of Adjuvant Therapy (IDEA) Collaboration, a combined analysis of the stage III patients in these trials was performed to see if 3 months could be considered to be non-inferior to 6 months, thus reducing the duration, toxicity and cost of treatment. ^, Non-inferiority of 3 versus 6 months was not confirmed for DFS nor OS in the overall cohort by a very small margin (absolute 0.4% difference in 5-year OS, 82.4% vs. 82.8%). Although the selection of CAPOX or FOLFOX was not randomised, a pre-planned subgroup analysis showed an unexpected but strong interaction between choice of regimen and duration of treatment. Three months of CAPOX was non-inferior to 6 months (HR 0.98; 95% confidence interval [CI], 0.88–1.08). Although this finding was only confined to lower-risk (T1-3 and N1) tumours, the absolute difference in high-risk (T4 or N2) tumours remained small. Three months of FOLFOX was inferior to 6 months (HR 1.16; 95% CI, 1.07–1.26) in both groups. As expected, significantly more patients receiving 6 months experienced grade 3 neurotoxicity than 3 months of treatment (15.9% vs. 2.5% for FOLFOX and 8.9% vs. 2.6% for CAPOX, P <0.0001).

Fewer patients (3273) with high-risk stage II disease were included in the IDEA Collaboration. The results were similar to the data on stage III disease, although non-inferiority could not be established because of the lack of statistical power.

These data provide a framework for discussion of risks and benefits of individualised adjuvant therapy approaches, taking into consideration the risk factors present and the regimen used.