I'm afraid for the BID disciples, nothing you say will change their minds. "Make BID great and glorious again"
Feel compelled to pull one from the fog of history. A Drew Turrisi editorial (ACR Journal Advisor; can't give you a link) on
this article from around 2003:
This is a nice article reflecting the experience at Duke over the course of 9 years when they used "local best therapy" rather than entering patients on studies. Despite the title, the consistency was to use daily, as opposed to twice daily, radiotherapy to a total dose in a range of 58 - 66 Gy. Half were treated concurrently, and half were treated sequentially. Only 17 of 65 (26%) received prophylactic cranial irradiation. Local failure was 40% at three years. Two year survival was about 30%.
At ASCO, the long awaited mature Mayo study was reported recently (Schild PASCO, abst 2356). Five year survival about 20%, either with the split-course BID (48Gy) or daily to 50.4 Gy, concurrent after three cycles of induction. Not sure how the 50 patients that progressed or were not randomized during the induction therapy were handled either. They said it was similar to the intergroup results, but they shaved 6% off the five year survival. Close, but this is not horseshoes, and this scores no points in my book.
RTOG has reported phase I facts with grade III esophagitis as the endpoint that allows them to fix total time to 5 weeks, and add a second fraction of 1.8 Gy (Komaki PASCO 2539)initially to the last three treatment days, then to the last 5 treatment days and ultimately to the last 11 of 25 treatment days. They report that the maximal tolerated dose was with 9 days of twice daily 1.8Gy, total dose 61.2 Gy. They do not report local control or survival of the group, but suggest a phase II study to do so is either planned or underway. Is grade 3 toxicity really dose limiting? Why 5 weeks?
Many comment that "the optimal dose and fractionation" is either "unknown" or "controversial." The intergroup study establish 1.5 Gy BID to 45 Gy as the standard. In 7 months, it will be 5 years since I published that paper in the New England Journal. Appallingly, no prospective research has been mounted in more than 7 years. Dabbling reports from single institutions or theoretic leaps that the fast growing clonogens emerge only toward the end of treatment have been tested tepidly. A serious study comparing high dose once daily treatment has twice been rejected by bureaucrats in Bethesda. One mor0n asserted that I wanted such a study to serve my personal interest. The fact is that the BID regimen reigns as champion despite puny efforts to knock it off its pedestal with retrospective research. Category I evidence cannot be beaten with institutional reports and retrospective data, particularly when not one has measured up to the multi-institutional study's survival benchmark of 26% at five years.
The local control that I published from that study is clearly WRONG. We scored all partial responders as local failures. However, partial responders survived at five years nearly as frequently as complete responders. This was not true with the patients treated with QD treatment.
Perhaps the magic is time rather than fractionation. Perhaps we need to get the treatment in in 3 or 4 weeks, and that taking longer allows for resistance. Similarly, if delays with "induction" chemotherapy consume patient tolerance and leave resistant cells, larger doses might be necessary for local control, but worse, resistant cells may travel outside the local target for radiotherapy.
The reality is there is not a controversy, there are just intransigent, stubborn, foolish people that do not believe data, and are unwilling to conduct research to prove their point, they want to argue the data away. "It's too toxic." "Patients don't like coming two times a day." "Our machines are too busy." Truth is that if a drug increased survival by 10% at five years and you did not do it, many would claim that your practice did not meet community standards. Not so with BID for small cell.
Cycle 1 concurrent BID treatment is the de facto "best treatment." It is standard. Doing anything else compromises patient survival. These are not new facts published in obscure journals that have not held up with time, these facts are solid as a rock. If you have a better treatment, prove it. Better yet, design a study and let's test it. In the mean time, dreaming up a theory or offering an excuse to risk patient survival seems perverse to me.
