I highly recommend to not use that setup because:
- You get less macro space for the actual casting. To overcome this you you can install an addon that makes macro space unlimited but which might not work anymore once the macros become server-side in WOTLK.
- In the basic setup, true.
But there are some tricks to you need much less macro spaces, f.e. :
- use of a standard button the long "/target [mod:alt,nomod:shift....." line lies on, and simply using a /click Actionbutton... instead
- use the little bit tweaked version, which isn't targetless, but also leaderless and focusless (and in my opinion better suited for a pve-setup)
Focusless, targetless, 'leaderless' setup.

You can't use modifiers for combining spells underneath one button because these modifiers are used already (thus you get less buttons available that you can use for other class types in your group).
- not entirely true, you can use modifiers even with the normal ftl-setup by simply defininf another keybinding/keymap for the version with the modifier.
If you again used the only leaderless/targetless setup i mentioned you can een use keybindings like you would do now

Your group is not flexible anymore, you can't just put any character in your team and have a go with that same team, because the names of your party members are hardcoded in your macros.
True, but this the only thing you have to change is the assist-macro, and if you use this with the /click.. like i mentioned before its only one macro you need to change. Additionaly also in a normal focus-based approach you need to change at least one macro, if you are not using party1 and so on...
..and if you are using party1, what do you do in groups, where you are not the groupleader, or even not all in one group?

For casting with anything but the standard toon you have to constantly press at least 1 or 2 modifiers, which is highly annoying and makes casting slower (because you can 't move your fingers around as flexible as you should be able to). This also limits the keypresses you can reach because you have to press the modifiers constantly, thus you have less buttons available to cast with. This is especially a problem as you need a macro for each spell, as you can't use the modifiers for putting multiple spells in 1 macro.
- here i honestly don't know what you are meaning, you are aware, that you never ever have to press the wired combinations you use in the macros, like alt+shift+2 for Lightning Bold ? -you simply press '2' and the keymaps translate it to the 'alt+shift+2' part...