Severity and persistency of late gastrointestinal morbidity in locally advanced cervical cancer: lessons learned from EMBRACE-I and implications for the future.

Purpose To evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer (LACC). Material and methods Of 1416 patients from the XXX study, 1199 and 1002 were prospectively evaluated using physician-assessed (CTCAE) and patient-reported (EORTC) GI symptoms, respectively. CTCAE severe grade (G≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid and colon/small bowel). CTCAE G≥2 and EORTC "very much" and "quite a bit"+"very much" scores (≥"quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G≥1 and EORTC ≥"quite a bit" symptoms, defined if present in at least half of follow-ups. Results Incidence of G≥3 events was 2.8%, 1.8% and 2.3% for G≥3 anus/rectum, sigmoid and colon/small bowel events, respectively. Among G≥2 symptoms, diarrhea and flatulence were the most prevalent (8.4% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status and low body-mass-index were associated to GI symptoms with different impact. Among treatment-related factors, rectum D2cm3 and ICRU recto-vaginal reference point (RV-RP) correlated with G≥3 anus/rectum events, and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps and difficulty in bowel control. Bowel D2cm3 correlated with G≥3 sigmoid and colon/small bowel events, and moderate/persistent diarrhea and flatulence. For external beam radiotherapy (EBRT), prescription dose correlated with G≥3 anus/rectum, diarrhea and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G≥3 sigmoid events, moderate/persistent diarrhea, proctitis and cramps. Conclusion The analysis showed that both EBRT and IGABT contribute to GI symptoms after LACC treatment. Rectum D2cm3, ICRU RV-RP and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45Gy than 50Gy, and increased with larger V57Gy.