I believe he means that with the type of game being talked about performance shouldn't be a problem. He's saying that even if there were an L2 cache miss per every memory read/write, he thinks it wouldn't affect the game play experience for a 2D puzzle game.
From experience I can say that I really don't think it is true that the handmade way is orthogonal to the reality of shipping an indie game. Unless you are working under a tight deadline, I think building up from scratch can have serious benefits. Yes, it is a hard initial investment to build the infrastructure your game will need from scratch - but I think in the long run it pays off.
For example, I've done Linux porting work in this community for both Motionbox and Milton. Both are great pieces of software, but one is built in a more traditional style with C++ and dependencies like boost and Qt. The other is essentially built from scratch with a platform layer like handmade hero. Working on Linux support for Milton was a blast, and you can see how easy (and FAST!) it was on riscy.tv
(shameless plug). Whereas with Motionbox it has been more like "idk what is going on, it doesn't work, better ask bunjee".
I don't mean that in any offensive way, as I say, both are great projects. However, I've definitely observed that the handmade style code-base makes it easier and faster to get real work done. If you started a project like a video browser or a painting software, would you consider going "hardcore" and doing it from scratch? It might sound crazy, but even for projects like these - it definitely pays off in the long-term.