PRoT-BM.

Top Line: Does prophylactic cranial irradiation (PCI) improve survival in patients with non-small cell lung cancer (NSCLC)? 

The Study: The problem with PCI for NSCLC is that everyone knows it reduces the risk of developing brain mets but without improving survival and quality of life outcomes. In NVALT-11, PCI reduced the rate of symptomatic brain mets 27 → 7% at 2 years with no improvement in OS or PFS. RTOG 0214 also showed a reduction in brain mets from 28 → 17% with PCI, and an improvement in DFS emerged in long-term followup. The phase 2 PRoT-BM trial randomized 84 patients with “high risk” stage IIIB (12%) or IV (88%) NSCLC to PCI or observation after initial standard therapy. High risk was defined as adenocarcinoma, actionable EGFR or ALK mutation, or an elevated CEA (>20) at diagnosis. The study sought to determine if PCI reduced the incidence of brain mets at 24 months...a question to which we already kinda know the answer. PCI was 25 Gy in 10 fractions and was delivered 4-6 weeks after the end of chemo. Of note here, initial treatment regimens were heterogeneous with use of mostly 1st and 2nd generation TKIs and no regular immunotherapy. PCI indeed decreased the cumulative incidence of brain mets at 24 months from 38 → 7%. So, let’s skip to the provocative finding that PCI prolonged median OS a whopping 45 months (or 3.7 years) from 20 → 65 months. The sheer magnitude of this survival difference means we’ve either stumbled upon one of the most effective treatments in NSCLC history, or we’ve got some statistical ‘splaining to do. For one, 95% of patients in the PCI arm had actionable EGFR or ALK alterations compared to < 75% of the standard arm. Add to that the fact that the trial predated widespread immunotherapy use, and it becomes difficult to determine if the observed survival difference is a statistical false-positive or a result of other therapies and characteristics for which the trial did not stratify.

TBL: PRoT-BM confirms that PCI significantly reduces the incidence of brain metastases in patients with NSCLC while suggesting a rather dramatic improvement in overall survival not borne out by larger trials.  | Arrieta, Int J Radiat Oncol Biol Phys 2021

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