Intensity-modulated extended-field chemoradiation plus simultaneous integrated boost in the pre-operative treatment of locally advanced cervical cancer: a dose-escalation study

Objective: To investigate the feasibility and determine the recommended pre-operative intensity-modulated radiotherapy (IMRT) dose of extended-field chemoradiation along with simultaneous integrated boost (SIB) dose escalation. Methods: A radiation dose of 40 Gy over 4 weeks, 2 Gy/fraction, was delivered to the tumour and the lymphatic drainage (planning target volume, PTV3), which encompassed a volume larger than standard (common iliac lymphatic area up to its apex, in front of the L3 vertebra), concurrently with chemotherapy (cisplatin and 5-fluorouracil). Radiation dose was escalated to the pelvis (PTV2) and to the macroscopic disease (PTV1) with the SIB-IMRT strategy. Three dose levels were planned: Level 1 (PTV3: 40/2 Gy; PTV2: 40/2 Gy; PTV1: 45/2.25 Gy), Level 2 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 45/2.25 Gy) and Level 3 (PTV3: 40/2 Gy; PTV2: 45/2.25 Gy; PTV1: 50/2.5 Gy). All treatments were delivered in 20 fractions. Patients were treated in cohorts of between three and six per group using a Phase I study design. The recommended dose was exceeded if two of the six patients in a cohort experienced dose-limiting toxicity within 3 months fromtreatment. Results: 19 patients [median age: 46 years; The International Federation of Gynecology and Obstetrics (FIGO) stage IB2: 3, IIB: 10, IIIA-IIIB: 6] were enrolled. Median follow-up was 24 months (9-60 months). The most common grade 3/4 toxicity was gastrointestinal (GI) (diarrhoea, mucous discharge, rectal/abdominal pain). At Levels 1 and 2, only one grade 3 GI toxicity per level was recorded, whereas at Level 3, two grade 3 GI toxicities (diarrhoea, emesis and nausea) were recorded. Conclusion: The SIB-IMRT technique was found to be feasible and safe at the recommended doses of 45 Gy to PTV1 and PTV2 and 40 Gy to PTV3 in the pre-operative treatment of patients with locally advanced cervical cancer. Unfortunately, this complex technique was unable to safely escalate dose beyond levels already achieved with three-dimensional conformal radiotherapy technique given acute GI toxicity. Advances in knowledge: A Phase I radiotherapy dose-escalation trial with SIB-IMRT technique is proposed in cervical cancer. This complex technique is feasible and safe at the recommended doses.