Age-related disparity of survival outcomes and treatment-related adverse events in patients with metastatic colorectal cancer
Authors: Meng Lingbin , Thapa Ram , Delgado Maria G. , Gomez Maria F. , Ji Rui , Knepper Todd C. , Hubbard Joleen M. , Wang Xuefeng , Permuth Jennifer B. , Kim Richard D. , Laber Damian A. , Xie Hao 
Published: October 2022

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 ofCTNNB1mutation (6.6% vs 3.1% vs 2.3%,p=0.047),ERBB2amplification (5.1% vs 0.6% vs 2.3%,p=0.005), andCREBBPmutation (3.1% vs 0.9% vs 0.5%,p=0.050), but lower prevalence ofBRAFmutation (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.