The central issue.
Rad oncs afraid of the no-fly zone designed RTOG 0813, a dose-escalation trial for medically-inoperable, cT1-2N0 (per PET) NSCLC tumors within “or touching” a 2 cm perimeter around the central airway. They all received 5-fraction SBRT with sequential patients receiving 10 → 10.5 → 11 → 11.5 → 12 Gy per fraction delivered every 2-3 days. The goal was to determine the maximum tolerated dose (MTD) defined as the highest dose conferring <20% risk of grade ≥3 toxicity within one year. Patients blew through the first phases, and 71 were enrolled in the 11.5 - 12 Gy arms with an estimated rate of grade ≥3 toxicity at one year of 7%. Among the 71 receiving 11.5 - 12 Gy x 5 followed for a median of >3 years, there were eventually 15 grade ≥3 toxicities including four grade 5 esophageal or bronchopulmonary hemorrhages. It’s hard to say just how risky enrolled tumors were, though the authors note 13 of 71 patients had “ultra-central” tumors...without noting what exactly this means. As expected, local control was excellent. TBL: RTOG 0813 indicates even 12 Gy x 5 may be safe for centrally-located lung tumors. | Bezjak, J Clin Oncol 2019
Interestingly, only 60% of the 12 Gy cohort used IMRT. The rest were 3D. Curious what dose limiting toxicity would be for IMRT alone, and if the patients who experienced dose limiting toxicity at the highest dose cohort were 3D patients. There is an Israeli retrospective study from 2018 of 70 patients all < 2 cm from carina, most of whom received 60 Gy in 5 fractions (*all* IMRT or Rapid Arc), which reported only 1 grade 5 event (fatal bronchial bleeding) which was a patient who had prior surgery and RT. However, it does not go into the details of how they prioritized OAR over PTV. Interestingly, no constraints were applied for the PBT on this study.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918762/
Another paper worth mentioning in the context of 0813 is the Cleveland Clinic Maynam 2018 paper, which suggests Proximal Bronchial Tree D0.33 < 46.5 Gy (Roughly 95% Dmax, instead of 105% dmax for PBT on 0813) may be a better constraint to use than limiting the PBT to 105% for 5 fraction central/ultracentral SBRT.
https://www.redjournal.org/article/S0360-3016(18)31118-0/fulltext
Finally, MSKCC's retro from 2018 demonstrates fatal pulmonary hemorrhages only occurred with point doses to the PBT of >= 50 Gy, further driving the point home that Dmax of 105% is likely not an appropriate constraint for the PBT.
https://www.redjournal.org/article/S0360-3016(18)31118-0/fulltext
Great topic! Hopefully someone comments here if anything I've said is grossly incorrect, as I plan to treat my patients in this manner with 5 fraction SBRT, using updated constraints for the PBT as compared to per protocol on 0813, and certainly not 3D.
Oops, working link to MSKCC retro here: https://www.sciencedirect.com/science/article/pii/S0360301618311192
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