Quality of Life and Prognostic Factors That Aid Treatment Decision Making in Curatively Treated Colorectal Cancer Patients

Colorectal cancer (CRC) is the third most common cancer and ranks second in mortality. Early detection, improved treatments, and increases in the age of the population have led to a rising prevalence of patients living with a diagnosis of CRC in the Western world. The only curative treatment for CRC is surgery. According to recurrence risk based on tumour, node, metastasis (TNM) classification, CRC patients resected with curative intent are referred for follow-up or adjuvant chemotherapy. Follow-up is accomplished via colonoscopy, computed tomography (CT), and measuring of carcinoembryonic antigen (CEA) in the patient´s blood. About 25% of patients with local disease will have a recurrence within 5 years, indicating misdetection of residual disease. Some patients with high-risk disease will have a recurrence despite adjuvant therapy and there is still no method in clinical use for detection of residual disease associated with primary resistance to therapy or in those patients with a low risk for recurrence. Patients with recurrent disease are treated with curative intent, whenever possible, with metastasectomy with or without neoadjuvant treatment. Patients with unresectable disease are treated with non- curative systemic treatment. The cancer and its treatments affect the patient’s health- related quality of life (HRQoL) during the treatment trajectory and in the remission phase if the patient is cured.

Study I included 444 patients with metastatic CRC (mCRC) participating in the RAXO substudy. The study evaluated HRQoL cross-sectionally using four validated measures: 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29. HRQoL declined transiently in conjunction with metastasectomy but was high after curative treatment, similar to that seen in the general population. HRQoL was also high during non-curative treatment phases from first- to later-line treatments but clearly declined in the best supportive care (BSC) phase. The most frequent symptoms during treatment trajectory included sexual aspects, urinary frequency, fatigue, distress, and insomnia.

Studies II and III included patients from the LIPSYT study with 147 CRC patients treated with curative intent. We measured CEA, carbohydrate antigen 19-9 (CA19-9), and C-reactive protein (CRP) as part of clinical routine, and interleukin 6 (IL-6), and YKL-40 post hoc. All patients were included in lead-time analysis between the elevated biomarker and radiological relapse. CEA had a lead time of 7.8 months, other markers investigated had lead times from 10 to 53 months and the lead time for all five markers combined was 27 months. In further analysis, 12 patients relapsing during adjuvant treatment were excluded. A total of 135 patients were included in an analysis that showed that elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired disease-free survival (DFS), and IL-6 and CRP were also associated with impaired overall survival (OS). Elevated post-adjuvant IL-6 associated significantly with outcome in a multivariate analysis investigating patients with normal CEA values. The same LIPSYT study population was used to investigate the kinetics of the abovementioned five biomarkers during adjuvant treatment. An association between a transient increase in CEA level during adjuvant treatment and improved outcome was noted compared to those patients with constantly increasing CEA levels. Patients with a transient increase in CEA had roughly similar DFS and OS when compared to patients with stable CEA levels. Similar trends were observed with CA19-9 and YKL-40.

Study IV described a patient history from the FINCRC study that recruited 82 CRC patients to investigate molecular residual disease after primary tumour resection or metastasectomy. Repeated circulating tumour DNA (ctDNA) measurements demonstrated clonal heterogeneity in tumour samples and revealed residual disease resistant to administered therapy. Drug sensitivity and resistance testing (DSRT) was used in a patient-derived organoid model to evaluate possible treatments. Patient samples exhibited MEK/MAPK signal cascade activation but differing driver mutations in the primary tumour and in metastases. A rise in a rare BRAFL597Q ctDNA in blood samples heralded a rise in a clinically aggressive recurrence during adjuvant treatment. In the organoid model, BRAFL597Q-mutated cells were sensitive to MEK/MAPK-targeted therapies.

In conclusion, HRQoL remains high during and after aggressive treatment strategy in mCRC patients treated with metastasectomy. By combining several biomarkers, the lead time before recurrence revealed by a biomarker increase can be clearly prolonged before radiological relapse. Elevated IL-6 after adjuvant treatment helps in identification of the elevated risk of relapse and, in turn, a transient increase in CEA level is a sign of improved prognosis. We also found that BRAFL597Q-mutated CRC may be related to aggressive disease.