Age-related disparity of survival outcomes and treatment-related adverse events in patients with metastatic colorectal cancer

Abstract

Background: While the incidence of newly diagnosed early-onset colorectal cancer has been increasing, age-related disparity of survival outcome and treatment-related adverse events in patients with metastatic CRC (mCRC) has been inadequately studied with inconclusive findings. In this study, we aimed to evaluate such age-related disparity in this patient population. Methods: We used individual patient data from three clinical trials (Study 1: NCT00272051, NCT 00305188 and Study 2: NCT00364013) in Project Data Sphere. All patients were diagnosed with mCRC and received first-line 5-fluorouracil and oxaliplatin. Clinical and genomic data of 763 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external and real-world validation cohort to evaluate overall survival (OS) disparity. Survival outcomes and treatment-related adverse events were estimated and compared in patients among three age groups: <50, 50-65, and >65 years. Results: Among 1223 patients from previous clinical trials, 179 (14.6%) were younger than 50 years. These patients had significantly shorter progression-free survival (PFS) (HR=1.46; 95%CI=1.22-1.76; p<0.001) and OS (HR=1.48; 95%CI=1.19-1.84; p<0.001) compared to patients in the 50-65 group of both Study 1 and Study 2 after adjustment for gender, race, and performance status. Significantly shorter OS was also observed in patients from the <50 group in the Moffitt cohort. When compared to other age groups, the <50 group had significantly higher incidence of nausea/vomiting (69.3% vs 57.6% vs 60.4%, p=0.019), severe abdominal pain (8.4% vs 3.4% vs 3.5%, p=0.018), severe anemia (6.1% vs 1.0% vs 1.5%, p<0.001), and severe rash (2.8% vs 1.2% vs 0.4%, p=0.047), but significantly lower incidence of fatigue, severe diarrhea, severe fatigue, and severe neutropenia. The <50 group had earlier onset of nausea/vomiting (1.0 vs 2.1 vs 2.6 weeks, p=0.012), mucositis (3.6 vs 5.1 vs 5.7 weeks, p=0.051), and neutropenia (8.0 vs 9.4 vs 8.4 weeks, p=0.043), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks, p=0.006). In the <50 group, severe abdominal pain and severe liver toxicity were associated with both shorter OS and PFS. In contrast, moderate peripheral neuropathy was associated with longer PFS. Our genomic data showed that the <50 group had higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%, p=0.047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%, p=0.005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%, p=0.050), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%, p=0.002). Conclusions: Patients with early-onset mCRC had worse survival outcome and unique adverse-event patterns, which could be partially attributed to distinct genomic profiles. Our findings might improve an individualized approach to chemotherapy, counseling, and management of treatment-related adverse events in this patient population.

Young-onset colorectal cancer: treatment-related nausea, vomiting and diarrhoea

“…10 Similarly, Meng et al, dividing in three age subgroups patients treated with first line FOLFOX (<50 yars vs 50-65 years vs >65 years), identified differences in incidence of nausea/vomiting (69.3% vs 57.6% vs 60.4%, p=0.019), and the EO-CRC group had also earlier onset of nausea/vomiting (1.0 vs 2.1 vs 2.6 weeks, p=0.012). 11 In a population of both non-metastatic and metastatic CRC patients, similar findings were obtained with patients with EO-CRC being more likely to report nausea and vomiting. 6 Finally, in one study female gender and age lower than 50 were significantly associated with the onset of gastrointestinal toxicities.…”

“… 10 Similarly, Meng et al , dividing in three age subgroups patients treated with first line FOLFOX (<50 yars vs 50–65 years vs >65 years), identified differences in incidence of nausea/vomiting (69.3% vs 57.6% vs 60.4%, p=0.019), and the EO-CRC group had also earlier onset of nausea/vomiting (1.0 vs 2.1 vs 2.6 weeks, p=0.012). 11 …”

“…Out of 2318 screened, 38 records were identified through database searching (PUBMED, EMBASE and SCOPUS) plus 3 additional records by manual searching through bibliographies of selected manuscript (online supplemental figure 1). Nine records were eligible for inclusion, all being full-text articles [3][4][5][6][7][8][9][10][11] accounting for a total of 59 783 patients of whom 8681 patients with EO-CRC) (table 1). Most of the studies included CRC only patients.…”

“…3 Moreover, even in the advanced setting when receiving a triplet combination, patients with EO-CRC had a lower risk of diarrhoea. 9 Similarly, Meng and et al 11 found lower incidence of severe diarrhoea (6.1% vs 9.1% vs 13.0%, p=0.02) in patients with EO-CRC treated with first line FOLFOX. Also from the Valentino trial, no significant differences in any grade diarrhoea (54% vs 52%, p=0.855) were reported.…”