Oh man, so many good points! I don't know that I have much to add. But let's see.
I think it's important to remember that Safu isn't just Shion's best friend, she's his
only friend.
Mother and I were very similar. We were both a little over-sensitive, and didn't like to socialize much. The people around us were nice, so nice there was nothing bad to say about them. My classmates, the citizens around us, were genial, intelligent, and minded their manners. No one raised their voice to insult anyone, or treated people with hostility. There were no strange or devious people. Everyone kept up such meticulously healthy lifestyles that even slightly plump figures like my mother's were rare. In this peaceful, stable and uniform world where everyone looked the same, my mother grew fatter, every other word "a pain in the neck" or "dull"; and I began to find the presence of other people oppressing.
(Volume 1, Chapter 1)
It's weird to think about, because Shion and his mother seem so friendly, but in reality both of them are pretty much alone. That's probably why Safu is so important to Shion. She is completely irreplaceable. I agree with Elanra that he's guilty of taking her for granted, though. But really, there was no reason for him to expect that she would be in danger, that he might lose her. While he was getting into his adventures with Nezumi, he expected her to be safe in a completely different town. She came back early due to the death of her grandmother. That was something he couldn't have forseen. Although he knew that bees were killing people in town, he didn't even know that she would be in the vicinity of them. It's quite natural that he should get caught up in his new life and forget about her to some extent. It's as Ahiku said. Safu had no chance.
Now that I think about it, it is really weird that Safu waited 4 years to ask Shion about why he had gotten kicked out of Chronos. It makes me wonder how her feelings for him developed. In the anime, it was clear that she had had a crush on him since they were both kids. But I wonder. I feel like I've sort of been like Safu before. She's a very logical person, who believes firmly in science, and I think that, like Shion, her emotions come into conflict with her rationality a lot. I think that her development of feelings for him was much more gradual than implied by the anime, and that at first she'd think she was just feeling really deep friendship for him. I forget who said it, but the essential question really is what their relationship was like before Shion complemented her sweater. In my imagination, they were strangers beforehand. Shion's compliment brought him to Safu's attention, and she made an effort to start up a friendship with him. Did she feel the spark of love from the very beginning? If she did, I don't think she recognized it. And when she finally realised it was love, she was afraid of losing that friendship. Maybe she even told herself that she was just feeling the effects of random chemical sparks in her brain, that it was silly and meant nothing, that nothing would ever happen, etc., etc. It's really hard to tell, because the story just doesn't explore her relationship with Shion properly. How frustrating is that!
"Also my first time seeing you stumble over yourself trying to explain things. That's alright if you have a girlfriend. I don't mind if you've already got someone on your mind. ―No, that was a lie. Look at me, I always try to put up a strong face in any situation. It's a bad habit of mine."
(Safu, Volume 1, Chapter 2)
From these lines, I'd say that Safu is not an optimist about this relationship. Why did she wait until the day before she was going away to tell her feelings to Shion? Probably because she expected him to say no. If she expected him to say yes, she would have asked him a while ago so that they could enjoy being together for a while before she left. I almost wonder if she considered leaving to be a mistake, knowing that she was leaving Shion behind. I also wonder at Safu's permanent return to No. 6 upon her grandmother's death. I think maybe she was glad to have an excuse to come back and be near Shion again. Of course, in the anime she enjoyed being in the other city. But again, the anime was different. And I'm not saying that she was glad her grandmother died, obviously. I'm just saying that her grandmother's death was an excuse for her to let herself act on her true feelings about leaving No. 6.