Image-Guided Intensity-Modulated Radiotherapy Shows Reduced Toxicity in Cervical Cancer

Image-guided intensity-modulated radiotherapy (IG-IMRT) caused less toxicity compared with three-dimensional conformal radiation therapy (3D-CRT) with no difference in disease outcomes in patients with cervical cancer undergoing postoperative radiation therapy, according to findings from the phase 3 PARCER trial (NCT01279135) that were published in the Journal of Clinical Oncology.

At a median follow-up of 46 months (interquartile range, 20-72), fewer primary end point events were observed in the IG-IMRT arm vs the 3D-CRT arm, at 29 vs 54, respectively. The 3-year cumulative incidence of grade 2 or greater late gastrointestinal (GI) toxicities in the IG-IMRT and 3D-CRT arms was 21.1% (95% CI, 14.7%-29.7%) vs 42.4% (95% CI, 33.7%-52.3%), respectively (HR, 0.46; 95% CI, 0.29-0.73; P < .001).

“The results of the PARCER trial in patients with cervical cancer suggest that postoperative IG-IMRT results in a lower rate of late toxicity compared with conventional 3D-CRT, with no differences in efficacy outcomes, and should be the preferred radiotherapy technique in this patient population,” lead study author Supriya Chopra, MD, of Tata Memorial Centre, and coauthors wrote in the study publication.

Adjuvant postoperative radiation therapy (PORT) reduces the risk of recurrence in patients with early cervical cancer and intermediate-risk features and improves survival in patients with high-risk features but is also associated with long-term GI toxicity.

Newer approaches like IG-IMRT can reduce the radiation dose to the bowel. Moreover, phase 2 studies have shown reduced acute GI toxicity with IMRT, and a randomized phase 3 study showed improved short-term patient-reported outcomes with IMRT compared with conventional radiation therapy.

However, it is not clear whether IMRT leads to reduced late GI toxicity compared with 3D-CRT.

To better understand the late symptom burden of IG-IMRT relative to 3D-CRT, patients were randomized to receive IG-IMRT or 3D-CRT and stratified by the type of hysterectomy and use of concurrent chemotherapy.

Eligible patients included women with cervical cancer who had an indication for PORT.

The primary end point was 3-year grade 2 or greater late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for 1 interim analysis.

Secondary end points included acute toxicity, health-related quality of life (QOL), pelvic relapse-free survival (PRFS), disease-free survival (DFS), and overall survival (OS).

Follow-up occurred every 3 months in the first 2 years, once every 6 months in the subsequent 3 years, and annually thereafter.

Between January 2011 and November 2019, 300 patients were randomized to IG-IMRT (n = 151) or 3D-CRT (n = 149).

Additional results showed less grade 2 or greater late GI toxicity with IG-IMRT vs 3D-CRT across stratification factors in subgroup analyses.

The cumulative incidence of grade 2 or greater any late toxicity was 28.1% (95% CI, 20.7%-37.4%) vs 48.9% (95% CI, 40%-58.7%), respectively (HR, 0.50; 95% CI, 0.33-0.76; P < .001).

The use of IG-IMRT was associated with a trend toward reducing grade 2 or greater acute diarrhea (17.2% vs 26.1%, respectively; P = .06) with no difference in overall grade 2 or greater acute GI toxicity (29.8% vs 28.8%, respectively; P = .38).

Univariate analysis revealed that the absence of grade 2 or greater acute diarrhea, absence of grade 2 or greater acute GI toxicity, large bowel volume receiving 40 Gy to less than 90 cc, and the use of IG-IMRT were significantly associated with a lower incidence of grade 2 or greater late GI toxicity. Multivariate analysis indicated that only IG-IMRT was associated with lower grade 2 or greater late GI toxicity (HR, 0.53; 95% CI, 0.32-0.86; P = .01).

Additionally, in the IG-IMRT and 3D-CRT arms, respectively, there were 30 and 25 PRFS events, 31 and 29 DFS events, and 29 and 23 OS events.

The 3-year PRFS rate was 81.8% (95% CI, 73.5%-87.7%) vs 84% (95% CI, 76.0%-89.5%), respectively (HR, 1.17; 95% CI, 0.68-1.99; P = .55). The 3-year DFS rate was 76.9% (95% CI, 68.4%-83.4%) vs 81.2% (95% CI, 72.9%-87.2%), respectively (HR, 1.03; 95% CI, 0.62-1.71; P = .89). The 3-year OS rate was 82.9% (95% CI, 74.6%-88.6%) vs 89.2% (95% CI, 82.1%-93.6%), respectively (HR, 1.23; 95% CI, 0.71-2.14; P = .44). No difference was observed in PRFS, DFS, and OS at 3 and 5 years.

Regarding QOL, after treatment completion, as well as at months 12, 36, and 60, 289, 250, 147, and 83 patients were eligible for QOL assessment. Most questionnaires were returned at all time points: 89.2% (n = 258/289), 86.8% (n = 217/250), 83.6% (n = 123/147), and 73.5% (n = 60/83), respectively.

Long-term follow-up indicated that patients in the IG-IMRT arm had improved functional scores and lower symptom scores. A significant increase was observed in the global health score (β = 3.17; P = .01) in the IG-IMRT arm. Patients who received IG-IMRT had improved physical functioning (β = 3.52; P = .042), role functioning (β = 4.46; P = .024), and emotional functioning (β = 5.46; P = .02) vs patients who received 3D-CRT.

Moreover, lower symptom scores were reported in patients treated with IG-IMRT. Patients who received IG-IMRT had less fatigue (β = –6.89; P = .004), appetite loss (β = –7.08; P = .008), diarrhea (β = –3.90; P = .048), and bowel symptoms (β = –4.51; P = .002) during follow-up. However, the QOL scores did not differ significantly when time by treatment arm interaction was performed.

Numerically, less patients in the IG-IMRT arm reported moderate to severe diarrhea (1.6% vs 3.8%), abdominal cramps (1.7% vs 9.1%), and difficulty in controlling the bowel (5.1% vs 14.9%) at 36 months. More patients in the 3D-CRT arm continued to report symptoms.

“Although no significant difference was observed between the two arms for any QOL domain in time by treatment arm interaction analyses, it is noteworthy that a higher proportion of patients in the 3D-CRT arm continue to report symptoms at an extended follow-up of 60 months,” concluded the study authors.

Reference

1. Chopra S, Gupta S, Kannan S, et al. Late toxicity after adjuvant conventional radiation versus image-guided intensity-modulated radiotherapy for cervical cancer (PARCER): a randomized controlled trial. J Clin Oncol. 2021;39(33):3682-3692. doi:10.1200/JCO.20.02530