Aggressive concurrent hypofractionation increased fatal toxicity in unresectable stage II–III NSCLC

KEY POINTS

• This systematic technical review identified 26 studies including 1,155 patients with unresectable stage II–III NSCLC treated with hypofractionated RT; only one phase III trial was available. Thirteen contemporary photon studies using modern simulation techniques formed the core technical dataset of 644 patients.
• In patients unsuitable for concurrent chemotherapy, the only randomized comparison tested 60 Gy/15 fractions versus 60 Gy/30 fractions. One-year OS did not differ significantly, while 2-year local control numerically favored hypofractionation at 85.8% versus 66.1% (p=0.34).
• The same trial showed more grade 2 toxicity after 60 Gy/15 (52.0% vs 23.9%; p=0.006), but radiation-attributable grade 3–5 toxicity was broadly similar between arms and there was no survival improvement.
• The greatest concern emerged when hypofractionation was combined with concurrent platinum-based chemotherapy. Across contemporary concurrent studies, median study-level grade 5 toxicity was 5.5%, and 34 fatal events occurred among 431 evaluable patients (7.9%).
• Fatal toxicity clustered in regimens delivering BED10 ≥100 Gy to the entire tumor volume with concurrent platinum. In the most escalated settings, grade 5 toxicity reached 20.8% (11/53) and 22.2% (2/9) in individual high-dose cohorts.
• Importantly, high BED itself did not appear to be the only problem: one SIB strategy delivering BED10 112.5 Gy to a restricted iGTV without concurrent chemotherapy reported no grade ≥3 toxicity, suggesting that the high-dose volume and systemic therapy context may be critical determinants of safety.
• The review supports 4DCT-based iGTV definition, PTV margins ≤5 mm, intensity-modulated delivery and IGRT as minimum technical principles. Common historical OAR limits included lung V20 ≤30–35% and mean dose ≤16–20 Gy, although contemporary 60-Gy/15-fraction constraints are now tighter.

CLINICAL TAKEAWAY

SOURCE

Cancers