2 reasons that i could think of:
1. The airplane of that route is getting old - check the airplane condition when you edit the route. Hover mouse over the airplane icons will show u the condition. If there's an "exclamation mark" next to the plane icon
it's for sure too old. To see a summary - simply go to airplane screen, select the model you own and click on the airplane icon in the inventory to inspect all the airplanes. They are sorted in condition so whatever is first in the inventory list is the one with lowest condition. You can simply replace the old ones by clicking the "replace" button
2. If a route has high frequency, then it's more likely to have some cancellation compared with route with low frequency.