Phase III Randomized Trial of Postoperative Adjuvant Conventional Radiation (3DCRT) versus Image Guided Intensity Modulated Radiotherapy (IG-IMRT) in Cervical Cancer (PARCER): Final Analysis

Whether the use of image guided intensity modulated radiotherapy (IG-IMRT) reduces late bowel toxicity in patients undergoing adjuvant radiation for cervix cancer is presently not known. We conducted phase III study (Clinical trials.gov identifier NCT 01279135) to test if IG-IMRT was associated with reduced late bowel toxicity. Patients between 18-65 years planned for adjuvant pelvic (chemo) radiation (CRT) were randomized to receive either IG-IMRT or three-dimensional conformal radiation (3D-CRT) after stratification for type of hysterectomy (Wertheim’s or simple hysterectomy) and planned use of concurrent chemotherapy or not. CRT included 50 Gy/25 fractions/ 5 weeks with or without weekly cisplatin (40 mg/m2). This was followed by 2 fractions of high dose rate brachytherapy of 6 Gy. The primary endpoint was grade ≥ II late bowel toxicity and study had 80% power to demonstrate an absolute difference of 13% in the primary endpoint proportion between the two arms, estimated using time-to-event, intent-to-treat analysis, with a study-level type I error of 0.05 after accounting for one interim analysis. Secondary endpoints included difference in acute toxicity, patient reported quality of life and dosimetric predictors of late bowel toxicity. A total of 300 patients were randomly assigned to IGIMRT (n = 151) and 3DCRT (n = 149), of whom 279 patients received planned treatment after randomization (IGIMRT = 144, 3DCRT = 135). Patients receiving CTRT [n = 117 (76.5%) in IG-IMRT and 114 (77%) in 3D-CRT] and RT [n = 35 (23.5%) in IG-IMRT and 34 (23%) in 3D-CRT] were balanced between the arms. Similarly, the type of surgery was well balanced between two arms (p = 0.60). Use of IG-IMRT was associated with significantly lower V30 and V40 bowel bag doses (p<0.0001). At a median follow-up of 49 (2-108) months, 82 primary endpoint events were observed. The 4-year grade ≥ II late bowel toxicity in the IG-IMRT and 3D-CRT arms were 19.2% and 36.2% (HR = 0.53;95% CI: 0.33-0.83 p = 0.005), respectively, while the corresponding 4-year grade ≥ III late bowel toxicity in the IG-IMRT and 3D-CRT arms were 2.0% and 8.7%, respectively (HR = 0.23;95% CI: 0.06-0.81 p<0.01). The proportion of patients with acute Grade ≥ II diarrhea in the IG-IMRT and 3D-CRT arms were 17.2% and 27.2% (p = 0.004). In subgroup analysis for primary endpoint, there was a significant interaction (p = 0.01) between study intervention and type of treatment, with a greater impact in patients receiving CRT as compared to those receiving RT alone, while no significant interactions were observed with type of surgery. No difference was observed in disease free survival (73% vs 68%, p = 0.30) between IG-IMRT and 3DCRT arm. IG-IMRT results in significantly lower incidence of late grade ≥II bowel toxicity in patients receiving adjuvant post-operative RT or CTRT for cervical cancer with no difference in disease free survival. IG-IMRT should be considered as the new standard of care for postoperative pelvic radiation.