Treatment of stage IV colorectal cancer: A retrospective cohort study assessing whether failure of first‑line treatment indicates failure of second‑line treatment

Colorectal cancer (CRC) is one of the most frequent malignancies and, despite screening programs, it is often diagnosed at late stages. Although current first- and second-line therapies stratify for KRAS/NRAS/BRAF mutations, microsatellite instability, tumour location and co-morbidities, the therapeutic mainstay for the first- and second-line treatment of the majority of patients consists of 5-fluorouracil (5-FU)-based chemo-immunotherapy. The present study evaluated the responses of patients with stage IV CRC, treated at the University Hospital Krems between January 1, 2015 and December 31, 2021, who received at least two therapy lines (n=49), with the aim of investigating whether the response to first-line therapy could predict the response to second-line therapy. All patients with first-line complete response (CR) had at least stable disease in response to second-line treatment [overall response rate (ORR)=66.6%]. On the other hand, all patients with progressive disease (PD) in response to first-line treatment (n=7) did not respond to second-line therapy (ORR=0%). These findings also translated to overall survival (OS): Patients with first-line CR had a median OS time of 80 months, whereas patients with PD had a median OS time of 12 months (P<0.001). Furthermore, different parameters were analysed for their impact on OS; the results revealed that BRAF alterations were associated with poor prognosis. Other factors (sex, tumor sidedness, KRAS and MSS/MSI status) had in this cohort no significant effect on OS. In conclusion, the present study demonstrated that, with current treatment strategies applying 5-FU-based chemo-immunotherapy as first- and second-line treatment for patients with metastatic CRC, response to first-line therapy may be a strong predictor for the response to second-line therapy and OS. By exchanging the chemotherapeutic combination partner from oxaliplatin to irinotecan or vice versa, plus the additive anti-epidermal growth factor receptor/anti-vascular endothelial growth factor antibody, the negative factor of non-response to first-line therapy could not be overcome by second-line treatment in this study population. These findings must be confirmed in larger studies, but indicate the need for novel treatment options, especially for patients not responding to first-line 5-FU-based chemo-immunotherapy.