Would you treat someone following FLAME protocol for prostate cancer without fiducials if using daily CBCT?

The underlying concept within this very practical question is how we rely on on-board imaging for target localization. In my practice, in which I have high confidence in my GTV contouring accuracy and daily setup, I would feel very comfortable using CBCT instead of fiducials.

My ideal process includes a planning MR in addition to a planning CT (not just the original diagnostic MR), and then also merging PET. I review and approve each merged image set (and I frequently make adjustments to match p...

Yes, I do it all the time. I treat with fiducials in patients who elect to have a spacer placed and without fiducials in the others. Both groups get focal RT tumor boost. We estimate the difference in daily setup accuracy at our center is 1 mm more confidence with fiducials (an additional benefit is RTTs are quicker when they have fiducials). The OARs are the same, and we are fairly conservative on constraints.

More than daily setup, I worry about the accuracy of (1) contouring of the lesion, (2...

If you think about it, there is no way to know how good an alignment is truly. IMO, the most objective way to get at this is to study the technology/technique via test-retest by a single observer and inter-observer variability among at least two observers. I did such a study several years ago Goff et al., PMID 29114611 comparing orthogonal kV images vs CBCT without fiducials and showed the variability was significantly less using fiducials. I can't imagine CBCT-fiducials could be worse than kV-f...

There can sometimes be a not-insignificant pitch variability, as noted by others here. Pitch misrotation can cause anterior or posterior misalignment at the bladder and urethra even if well aligned at midgland prostate and even with a spacing gel in place to spare the rectum. So great care must be taken in planning the case to use PRV margins on the urethra and exclude the GTV contour away from the urethra and bladder when treating without 6D couch correction even with fiducials in place. If you...

Fiducials improve the fidelity and interoperator reproducibility of an IGRT match, definitely preferable vs CBCT alone if you can have them placed.