IDEAL-GYN (Integrated Dose Escalation for Advanced Localized Gynecologic Cancers): A Dose Escalation Trial of Bowel Sparing Simultaneous Integrated Boosts for Node Positive Cervical and Vulvar Cancers

Abstract

Node positivity is a negative prognostic factor in gynecologic cancers. It is often technically and logistically challenging to give boosts to involved nodes due to the proximity of critical normal tissue. Sequential boosts often also result in an extended treatment time. Simultaneous integrated boosts (SIB), delivered at the same time as elective nodal treatment, may be a method to deliver sufficient dose to nodal targets in a compact time frame. However, the safety of total doses greater than 55 Gy with daily fractions greater than 2.2 Gy is unknown. Women with intact cervical or vulvar cancers and nodal involvement in the pelvis or para-aortic regions were accrued to a prospective, phase I 3+3 dose escalation trial utilizing SIB technique. All subjects were treated with definitive chemoradiation therapy with concurrent weekly cisplatin, followed by brachytherapy boost in the subjects with cervical cancer. The elective nodal volumes received 45 Gy in 25 X 1.8Gy fractions (fx), while the involved nodes received 25 X 2.4 – 2.8 Gy/fx, escalated in 0.2Gy increments to a final dose of 60-70 Gy. The SIB PTVs were specifically reduced to be 3 mm off the closest small bowel contour even if this brought the PTV within the nodal GTV. A strict dose limit was also applied to the small bowel, such that the D2cc was no greater than 55 Gy. The primary endpoint was to determine the maximum tolerated dose (MTD), defined by the occurrence of G3 or greater acute gastrointestinal (GI) or genitourinary (GU) toxicity. Toxicity defined by the CTCAE v4.0. Secondary endpoints include late GI and GU toxicity, acute hematologic toxicity, survival, and disease control. Twelve subjects were accrued from 2012-2016, 11 with cervical cancer, and one with vulvar cancer. Pelvic nodes were involved in all subjects; para-aortic nodes were also involved in four. The MTD criteria was not met and six subjects successfully completed the 2.8 Gy/fx (70 Gy) dose level. There were no ≥ G3 acute GI or GU toxicities. Eight subjects experienced G2 GI toxicity, four G1. One subject experienced G2 GU toxicity, 2 G1. At a median followup of 1 year, one subject in the 2.8 Gy cohort experienced late G3 GI toxicity at 7 months after completion, one late G2 GI toxicity at 11 months, one late G2 GU toxicity at 12 months, and one late G1 GU toxicity at 11 months. Simultaneous integrated boosts up to 70 Gy in 25 fx (2.8 Gy/fx) to nodal volumes within the pelvic and paraaortic regions did not result in excessive acute toxicity, provided small bowel is adequately spared. Further long-term followup is required in the high dose cohorts to determine if late toxicity is acceptable.