WRT your #2 - the distant mets....
That has actually been the subject of almost all debate in the last 2 weeks on Ymb, SA, and IVmb.
Biotech Sage is basically a plant, just a large short trying to get out, on SA. But lots of awesome comments on the two bear articles. The issue is what other studies to use to try to compare results from - NOTHING is apples to apples.
If you look for roseny on the Ymb, a lot of his posts address the local v distant mets issue.
My own opinion is that distant will occur later on average than local, and so using local as a proxy is fairly conservative. As you say, death and ex-hep are even more rare.