KEY POINTS
- HYPOCx-iRex randomized 40 patients with locally advanced cervical cancer to 44 Gy in 20 fractions versus 45 Gy in 25 fractions, using modern IMRT/VMAT, concurrent weekly cisplatin and MR-guided adaptive brachytherapy.
- A prespecified exploratory analysis added 28 nonrandomized EMBRACE-II patients, producing a pooled conventional-fractionation group of 47 and a total dataset of 68 patients. The pooled comparison should therefore not be interpreted as randomized evidence.
- Hypofractionation shortened median overall treatment time from approximately 46 to 39 days, a 7-day reduction, and brought brachytherapy forward by about three days.
- The key safety signal was late GI toxicity. In the pooled comparison, 2-year grade ≥2 GI toxicity was 23.8% versus 10.8%, while grade ≥3 toxicity was 19.1% versus 5.3%. Neither difference reached conventional statistical significance, but the absolute increase was clinically substantial.
- Oncologic outcomes numerically favored the shorter schedule but were severely underpowered: 2-year locoregional control was 95.2% versus 77.5%, and 2-year overall survival 100% versus 76.8% in the pooled comparison. These differences should not be interpreted as evidence of superiority.
- Brachytherapy conformity emerged as a potentially modifiable driver of toxicity. The iRex60 metric showed a dose-response relationship with GI toxicity, and the authors propose an exploratory target of iRex60 <1.7 together with rectum D2cc <65 Gy EQD2₃ for future trials.
- A second randomized brachytherapy optimization component demonstrated that iRex-guided planning reduced rectal D2cc from 66.3 to 59.8 Gy EQD2₃ and reduced the overall intermediate-dose bath.
- The 20-fraction regimen reduced 2-year societal cost by approximately $365 per patient, but the economic analysis used single-centre charge proxies and did not incorporate QALYs or the downstream cost of late toxicity.
CLINICAL TAKEAWAY
Reducing cervical EBRT from 25 to 20 fractions is attractive because it can materially shorten overall treatment time, but the late GI toxicity signal is too important to ignore. HYPOCx-iRex provides a strong rationale for phase III testing with tighter brachytherapy conformity and rectal constraints, not for routine adoption of 44 Gy/20 fractions today.