Nowhere in my post did I say that escalation beyond 60 Gy was "useless." If you look again at Raygun77's post, the "positive" dose escalation studies were not randomized phase III trials. A phase I/II study can give tantalizing results worthy of further study, but many therapies that look promising in the phase II setting wither under the rigor of a phase III study.
Notice that the two phase III (not phase II, not institutional reports) studies he mentions- RTOG 93-05 and RTOG 74-01/ECOG 1374- showed no benefit to dose escalation beyond the "standard." I am not suggesting that no patients will ever benefit from escalation beyond ~60 Gy (a dose that was itself established through a phase III trial)- just like not all patients may need 60 Gy- and the peculiar radiobiology of carbon irradiation may be beneficial for some patients, for issues of hypoxia, higher 'quality' of DNA damage, whatever.
Sorry for my late response. I really do apologize if my previous post implied that you mentioned dose escalation for GBM was useless. I did not mean to imply that at all and, if it came across like I did, it was really unintentional. So, I do fully apologize for that and for not being clear.
With that being said, I do agree with you that phase III trials don't show any benefit of dose escalation. And, unfortunately, I don't think it's likely that we'll see future dose escalation phase III studies. You're right that I didn't solely take phase III's into account when I made my previous statement.
Again, as I said in my original post, "Preclinical and clinical studies will spell out the real role for these types of treatments." Dose escalation is not dead for GBM, but we also have to respect the results of existing phase III studies and also remember that there are many tumors we treat for which indiscriminate dose escalation will only take you so far. There are many examples in oncology where a bigger hammer was not the answer. Things like PARP inhibitors and other rationally designed targeted therapies should be explored with at least as much fervor as particle therapy.
This, I definitely agree with you about. I'm actually working with PARP inhibitors and radiosensitization of GBMs. Like I mentioned previously, I'm extremely excited to see the results of the current phase II (IIRC) trial looking at TMZ + ABT-888 + radiotherapy against GBMs. With all the preclinical data I have looked at, as well as being immersed in this area of research, I'm predicting that the results of this trial will be positive (especially since ~40% of GBMs tend to be PTEN -/-, which really sensitizes them to the action of PARP inhibitors). I'm fully for the research into radiosensitizers and radioprotectors. With that being said, however, I do think that the differential DNA damage induced by particle therapy offers advantages that even radiosensitizers might not provide (this is purely speculative, based on the studies I've read, and I don't have any hard evidence to back this statement...so please don't rip me apart for this!
). Like I mentioned in my OP though, while I'm fairly well-versed in the basic science behind these things, I don't know what impact they would have in the clinic; I just do not have the clinical background to assess studies in that manner. So, I truly appreciate all the responses I've gotten from you guys (even when they point out that I've made some foolish statements
)!
As for the tumor stem cell issue, again this is a controversial area. There are preclincal studies that suggest cancer stem cells are relatively radioresistant (PMID: 17051156), and thus may benefit from the types of DNA damage induced by things like carbon ions. Although the Nature paper from Duke suggested that glioma stem cells are relatively radioresistant, other studies have not shown this, suggesting that carbon ions would not be necessary to overcome their resistance. Please look at PMID: 19671863. As with many other things regarding gliomas, we have much to learn about the role of this intriguing subset of cells.
It's very coincidental, but I'm actually reading through the McCord paper right now. I came across it about 2.5 weeks ago and started reading through it last week, so it's funny that you mention it as well! The reason I brought up the CSC stuff a couple of times is because, being involved in basic/translational research, I hear about CSC very, very often. So, it's near the front of my thoughts regarding research a lot of the time. My reasoning was based on the Nature paper by Bao, et al, which suggested that glioma stem cells have a more robust DNA damage response which contributes to their radioresistance (PMID: 17051156). However, I am reading through the McCord paper right now and will definitely comment on it in this thread after I finish analyzing it. If the Nature paper turns out to be further supported (ie. the idea of a more robust DDR), I would imagine that particle therapy would be more effective against CSCs. However, I'm fully open to changing my opinion based on the McCord paper and future studies that support the idea that glioma stem cells aren't radioresistant due to a better DDR.
Absolutely IMRT with photons can rival the conformality achieved with particles; however, it's at the expense of increased integral energy deposition compared to particle therapy. Thus the continued interest in particles even with highly sophisticated photon therapies available.
I truly did not know this, so forgive my previous ignorant comments. It's been hard finding good articles comparing technologies in a manner that I can understand them (of course, it's entirely possible that my keywords in PubMed just suck).
Finally, the "good understanding of the range, and dosimetry, of ion beams" is that we know enough to say that we do not know where the beams range out in tissue within several mm for many scenarios. Thus the SOBP must encompass this uncertainty. I am saying this from experience with protons- I am admittedly not experienced with the situation with heavier ions (and also acknowledge that this is underappreciated even for photon therapy). Please read PMID: 11286851 for more information on this.
This uncertainty in range has significant implications for beam design in proton therapy, with or without use of intensity modulation methods. If the range uncertainty is such that your beam may range out into a critical structure, you have to think twice about using that beam, especially since the RBE is highest at/near the end of a proton beam's range. If you look at proton beam arrangements for treatment of numerous tumor sites, you will notice that the beams often are designed to avoid this very problem. Use of things like proton CT and other methods can limit this uncertainty, but proton CT and things like PET imaging to map the pathway of heavy ions are not widely available at particle treatment facilities at the current time.
I really appreciate this part of your post and I thank you for mentioning it. My understanding is that, unlike with proton beams, the dose distribution of heavy ion beams can be "seen" due to positron emission (using PET). If this is the case, how hard is it to figure out where the ion beams range out? Even in preclinical models. I really don't mean this question to come off sarcastically and I hope you don't see it that way; I'm genuinely curious since, in my mind, it seems like it should be a relatively easy question to answer. But, since I'm not a physicist, I don't know what methods you can use to accurately answer the question. Maybe Werg can weigh in on this matter?
And please, do continue to post in this thread and point out things that I'm ignorant of. I will absolutely not take it as an insult and I absolutely
love learning more about this topic, so I truly do appreciate all your responses! Like I've said, I don't have a clinical background, so your perspective is pretty different than the way I view things. And it's nice to get a sense of the clinically relevant aspects of this type of work.
). In the case of heavy ions, their excellent dose distrubution coupled with their very high RBE probably render conventional fractionation irrelevant. Most probably, heavy ions can achieve in a week what covnetionaly fractionated photons/protons would take 1.5 months to accomplish. 
