eUpdate - Early Colon Cancer Treatment Recommendations
Published: 23 September 2019. Authors: ESMO Guidelines Committee
Clinical Practice Guidelines
This eUpdate refers to the Early Colon Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. R. Labianca, B. Nordlinger, G. D. Beretta, S. Mosconi, M. Mandalà, A. Cervantes, D. Arnold. Ann Oncol 2013; 24 (Suppl 6): vi64–vi72.
New section: Acknowledgements
The ESMO Guidelines Committee would like to thank the following expert group, who drafted and reviewed the eUpdate before it was approved by the ESMO Guidelines Committee: Guillem Argilés, Julien Taieb, Timothy Iveson, Daniel Hochhauser, Ramon Salazar, Roberto Labianca, Phillip Quirke, Pierre Laurent Puig, Takayuki Yoshino, Josep Tabernero, Erika Martinelli.
Management of local/locoregional disease
Treatment by stage
Stage III tumours
The current standard of care for the adjuvant therapy in a stage III colon cancer is a combination of fluoropyrimidine and oxaliplatin. The benefit of these combinations has been demonstrated in three landmark trials: MOSAIC, NSABP C-07 and XELOXA, all of which showed significant improvement in disease-free survival (DFS) when compared with fluoropyrimidine single agent (reduction in risk of recurrence by 20%–23%). With longer follow-up, all three trials showed improved overall survival (OS) from the addition of oxaliplatin, with a risk reduction of death of 12%–16%, only significant for stage III colon cancer [1-3].
The major cumulative toxicity from a fluoropyrimidine/oxaliplatin doublet is sensory peripheral neuropathy. In the IDEA pooled analysis of 6 studies, 12 834 patients with stage III colon cancer were randomised to receive either 3 months or 6 months of a fluoropyrimidine/oxaliplatin doublet [either 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX), the choice of regimen was mainly the clinician’s choice and not randomised] . The 3-year DFS was very similar, 74.6% [95% confidence interval (CI) 73.5–75.7] and 75.5% (95% CI 74.4–76.7), for 3 months and 6 months, respectively) but despite the large numbers non-inferiority was not proven statistically [hazard ratio (HR) 1.07, 95% CI 1.00–1.15, P=0.11]. However, sensory peripheral neuropathy grade 2 or worse was remarkably reduced from 34% with 6 months of treatment to 11% compared with 3 months of treatment. For patients receiving CAPOX, 3 months of treatment was noninferior to 6 months (HR 0.95, 95% CI 0.85–1.06), with 3-year DFS of 75.9% (95% CI 74.2–77.6) and 74.8% (95% CI 73.1–76.6), respectively, with a P=0.02 after adjustment for multiple comparisons, whereas for FOLFOX, 3 months was inferior to 6 months (HR 1.16, 95% CI 1.06–1.26, P=0.001 for superiority of 6 months), with 3-year DFS of 73.6% (95% CI 72.2–75.1) and 76.0% (95% CI 74.6–77.5), respectively. Thus, both CAPOX 3 months and FOLFOX 6 months can be recommended as adjuvant chemotherapy (ChT) regimens for stage III colon cancer [I, A] . It is important to mention that CAPOX and FOLFOX selection in the IDEA trials were not randomised precluding any formal comparison between the two regimens.
IDEA also conducted an exploratory analysis based on risk subgroups. In the lower-risk subgroup (defined as patients with T1, T2 or T3 and N1 disease), 3 months of adjuvant therapy appeared to be sufficient when CAPOX was chosen [II, B]. In the higher-risk group (patients with T4, N2 or both), 6 months of treatment may be necessary, especially when FOLFOX is the chosen regimen, but also with CAPOX, which missed the noninferiority margin in this subgroup [V]. The recommendations based on the establishment of stage III risk subgroups, though capturing to the currently adopted clinical practice, needs to be taken with caution since this was a post hoc analysis. T4 versus T1-2-3 and N2 versus N1 subgroups analyses were pre-specified in the protocol but their combination in high versus low-risk subgroups was not, and its interaction test was not significant (P=0.11). If patients cannot tolerate oxaliplatin, either capecitabine or LV5FU2 (de Gramont) infusion are acceptable adjuvant regimens for a 6-month duration, as there is no evidence of a shorter duration being noninferior [I, A] (See Figure 1).
- Adjuvant strategies may take into consideration high (T4 and/or N2) and low-risk (T1-3 N1) stratification in patients with stage III colon cancer, although this was based on a post hoc, not significant for interaction combination in the IDEA pooled analysis [V].
- The length of oxaliplatin-based adjuvant treatment for stage III colon cancer based on the IDEA data may be tailored to 3 months for CAPOX (T1-3 N1 disease) [II, B], 6 months for CAPOX (T4 or N2 disease) [I, A] or 6 months for FOLFOX (T4 or N2 disease) [I, A], also taking into consideration pathological risk characteristics, patient comorbidity and risk perception. (See Figure 1).
- For patients not fit for oxaliplatin, either capecitabine or LV5FU2 (de Gramont) infusion are acceptable adjuvant regimens for a 6-month duration [I, A].
Stage II tumours
While follow-up is the option for low-risk stage II patients, ChT is recommended for high-risk patients [I, B]. Among the various clinical, pathological and molecular markers that have correlated with progression-free survival (PFS) and OS, only microsatellite instability (MSI) versus microsatellite stable (MSS), T3 versus T4 and number of examined lymph nodes >12 versus <12, primary tumour perforation or occlusion and tumour grade have been repeatedly validated in prospective randomised clinical trials . Only de Gramont regimen has demonstrated efficacy [I, B], although capecitabine can be an option in case of difficulties or contraindication of the insertion of a central line [V]. Patients with very high risk (MSS and T4 or more than one validated risk factor) may be considered for the addition of oxaliplatin based on a trend to an increased benefit, which did not achieve statistical significance, in the stage II high-risk subgroup analysis of MOSAIC trial [I, C] . For this high-risk population, the IDEA pooled analysis explored the optimal length of the oxaliplatin-based adjuvant treatment, finding identical results to those reported for stage III patients, a non-proven, noninferiority for 3 months of treatment . When looking at treatment regimens, a proven noninferiority of CAPOX and inferiority of FOLFOX 3 months when compared with 6 months of FOLFOX was shown , with all the limitations of these post-hoc analyses as stated before.
- For patients with low-risk stage II colon cancer, follow-up is recommended, while fluoropyrimidine ChT should be considered for high-risk patients [I, B] (T4, number of examined lymph nodes <12, primary tumour perforation or occlusion, tumour grade 3, in the absence of MSI).
- Patients with very high risk (MSS and T4 or more than one validated risk factor) may be considered for the addition of oxaliplatin [I, C].
- Patients with high risk stage II colon cancer may be considered for 3 months of CAPOX, as the IDEA pooled analysis showed noninferiority of 3 months of CAPOX and inferiority of 3 months of FOLFOX when compared with 6 months of FOLFOX, with all the limitations of post-hoc analyses [II, B].
- Andre T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27: 3109–3116.
- Kuebler JP, Wieand HS, O'Connell MJ et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007; 25: 2198–2204.
- Haller DG, Tabernero J, Maroun J et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011; 29: 1465–1471.
- Grothey A, Sobrero AF, Shields AF et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 2018; 378: 1177–1188.
- Iveson T, Sobrero AF, Yoshino T et al. Prospective pooled analysis of four randomized trials investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with high-risk stage II colorectal cancer. J Clin Oncol 2019; 37 (18_Suppl): abstr 3501.