A reduction in patient-reported symptomatic adverse events was observed with intensity-modulated radiotherapy compared with standard radiotherapy in patients with cervical or endometrial cancer, whereas no difference was observed with regard to clinician-reported AEs.
A reduction in patient-reported symptomatic adverse events (AEs) was observed with intensity-modulated radiotherapy (IMRT) compared with standard radiotherapy in patients with cervical or endometrial cancer, whereas no difference was observed with regard to clinician-reported AEs, according to a report from the NRG Oncology RTOG 1203 study published in the Journal of Clinical Oncology.
Results showed that clinicians also underreported symptomatic gastrointestinal (GI) AEs compared with patients, suggesting that patient-reported symptomatic AEs are important to assess in this disease setting.
Of 278 eligible patients, 234 consented, and completed the patient-reported outcomes (PROs) version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Approximately 19.1% of patients reported high-grade abdominal pain (P <.0001), 38.5% reported high-grade diarrhea (P <.0001), and 6.8% reported fecal incontinence more frequently than clinicians. Similar results were seen between grade ≥1 CTCAE toxicity and any-grade patient-reported toxicity.
Additionally, a between-arm comparison of patient-reported high-grade AEs demonstrated that at 5 weeks of radiotherapy, patients who received IMRT experienced fewer GI AEs versus patients who received 4-field pelvic radiotherapy; an 18.2% difference was observed with regard to the frequency of diarrhea (P = .01), an 8.2% difference with regard to fecal incontinence (P = .01), and an 8.5% difference with interference of fecal incontinence (P = .04).
“To our knowledge, this is the first reporting of a large-scale multi-institutional phase 3 trial using both PRO-CTCAE and clinician-reported CTCAE scores to assess symptomatic AEs,” lead author Anamaria R. Yeung, MD, of University of Florida Health, and co-authors, wrote in the study. “In this trial, physician-reported AEs revealed no difference between arms, whereas patient-reported AEs showed a reduction in symptoms with IMRT compared with standard [radiotherapy]. These findings suggest that patient-reported symptomatic AEs may be more sensitive than physician-reported AEs, which is important when comparing toxicity between 2 treatments.”
Patients with cervical or endometrial cancer requiring postoperative radiotherapy after hysterectomy based on pathologic risk factors were enrolled in the randomized controlled trial and were assigned 1:1 to receive either standard 4-field radiotherapy or IMRT. Patients received 45 or 50.4 Gy based on physician preference. Five cycles of cisplatin 40 mg/m2 per week were administered at physician discretion per predefined pathologic criteria. Additionally, patients were stratified by dose, use of chemotherapy, and disease site. The primary end point of the trial was a change in acute GI toxicity from baseline to 5 weeks measured with the bowel domain of the Expanded Prostate Cancer Index Composite PRO instrument.
Investigators assessed patient-reported toxicity before treatment, after 23 to 25 fractions at 5 weeks, at 4 to 6 weeks, as well as at 1 and 3 years following radiotherapy. Patients completed the 5-item PRO-CTCAE for GI toxicity, which evaluated severity and interference of abdominal pain, frequency of diarrhea, and frequency and interference of fecal incontinence over a period of 7 days.
Patients reported symptoms on a 5-point Likert scale regarding severity (ranging from none to very severe), interference (ranging from not at all to very much), or frequency (ranging from never to almost constantly), with 0 meaning none, not at all, or never. Patients also reported how many antidiarrheal medications were taken on average over the past 7 days.
Toxicities that occurred following the start of treatment were reported by treating physicians using CTCAE at various time points, including: weeks 3 and 5 of radiotherapy, 4 to 6 weeks following radiotherapy, followed by every 6 months from the start of radiotherapy for the first 2 years, on an annual basis for the next 5 years, and then at progression/relapse and death.
Of 279 eligible patients, 236 consented to participate in the QOL component of the trial, which included the PRO-CTCAE questionnaire. Of the 236 patients, 234 had PRO-CTCAE data at ≥1 time points, and thus, were observed for CTCAE reporting.
PRO-CTCAE patient-reporting compliance was noted to be high at all time points (95.8% at baseline, 85.2% at week 5 of radiotherapy, 83.1% at 4-6 weeks after radiotherapy, 76.3% at 1 year after radiotherapy, and 52.5% at 3 years after radiotherapy). The median follow-up time for all patients was 37.8 months (range, 0.33-66.2).
Results showed that overall, patients reported more AEs than clinicians. The clinician-reported any-grade CTCAE abdominal pain rate was 35.6% versus 80.1% of patients reporting at least mild abdominal pain and 69.5% reporting that the pain interfered with usual activities at least a little bit (P <.0001 for both). Additionally, the grade ≥3 CTCAE toxicity rate was 2.5%, whereas 21.6% of patients reported that they experienced severe or very severe abdominal pain, and 18.6% reported that their pain interfered with their usual activities either quite a bit or very much (P <.0001 for both).
The rate of any-grade CTCAE diarrhea was 75%, versus 86.9% of patients reporting diarrhea occurring at least rarely (P =.0002). Grade ≥3 CTCAE diarrhea toxicity rate was 4.7%, whereas the rate of patients reporting diarrhea that occurred frequently or almost constantly was 43.2% (P <.0001).
The rate of any-grade CTCAE fecal incontinence was reported by 3.0%, versus 52.5% of patients reporting fecal incontinence at least rarely and 51.7% reporting that their fecal incontinence interfered with their usual activities (P <.0001 for both). The rate of grade ≥3 CTCAE fecal incontinence reported was 0%, compared with 6.8% of patients reporting frequent or almost constant fecal incontinence, and 10.2% reporting that their fecal incontinence interfered with their usual activities either frequently or constantly.
Additionally, between-arm comparisons regarding whether a patient had a PRO-CTCAE score of ≥3 were performed at several time points. No between-arm differences were observed at baseline. At 5 weeks, patients who received IMRT experienced less toxicity than patients who received 4-field pelvic radiotherapy. This held true in terms of frequency of diarrhea, at 33.7% versus 51.9%, respectively (P =.01); frequency of fecal incontinence at 1.1% versus 9.3%, respectively (P =.01), and interference of fecal incontinence, at 4.4% versus 12.9%, respectively (P =.04).
No differences for severity or interference with regard to abdominal pain was observed at 5 weeks. No significant differences between the arms were observed at 4 to 6 weeks or at 3 years following radiotherapy.
However, 1 year after radiotherapy, more patients in the 4-field pelvic radiotherapy arm reported a higher frequency of diarrhea versus those in the IMRT arm (15.1% vs 5.8%; P =.042). At this time point, a significant difference in the number of women requiring antidiarrheal medication ≥2 times per day (4.6% with IMRT vs 13.0% with 4-field pelvic radiotherapy; P =.036) was also observed; this suggests a small improvement in early toxicity with IMRT, which disappeared by 3 years.
Data from the analysis showed that clinician-reported GI AEs significantly underrepresented the symptomatic toxicities experienced by patients during treatment with pelvic radiotherapy. Clinicians may not ask about a specific symptom when evaluating toxicity, particularly if they do not expect patients to experience a specific event. Additionally, because clinicians manage severe symptoms fairly frequently, that may skew their perceptions of symptom presence and severity.
Patients must also be able to communicate their symptoms to their treating clinicians; this could add another barrier to accurate clinician assessment of symptomatic AEs, according to the investigators, as some patients might feel uncomfortable sharing symptoms that they feel to be embarrassing. The discrepancy in the total reported symptomatic AEs underscores the need to use PRO measures to obtain a more accurate toxicity assessment, according to the study authors.
“Patients are the most qualified to report on their symptoms, and it is clear from the data that clinicians underreport symptoms,” the authors of the study concluded. “In trials for which the primary end point is a symptomatic AE, strong consideration should be given to using PROs as the primary toxicity outcome measure.”
Yeung AR, Pugh SL, Klopp AH, et al. Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG oncology RTOG 1203 study. [published online January 16, 2020]. J Clin Oncol. doi:10.1200/JCO.19.02381