Kate O'Rourke

September 28, 2016

BOSTON — Intensity-modulated radiation therapy (IMRT) to the pelvis results in fewer side effects and better quality of life (QOL) than conventional radiation for patients with cervical and endometrial cancer. These results come from the multicenter, randomized TIME-C trial.

"IMRT reduces the risk of short-term bowel and bladder side effects for patients with endometrial and cervical cancer," said Ann Klopp, MD, PhD, lead study author and an associate professor in the Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, in Houston.

She presented the results of the study here at the prestigious plenary session of the American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting.

The positive results do not change practice, said Supriya Chopra, MD, assistant professor of radiation oncology at Tata Memorial Center, Mumbai, India, who served as the discussant of the study.

Dr Chopra said it is too soon to conclude that IMRT represents the new standard of care for gynecologic cancers. "Postoperative IMRT for gynecological cancers continues to be investigational," she said.

The study enrolled 278 women with endometrial or cervical cancer who required postoperative pelvic radiation or chemoradiation at cancer centers in the United States, Canada, Japan, and Korea.

Patients were stratified by radiation dose (45 Gy or 50.4 Gy), use of chemotherapy (no chemotherapy or five cycles of weekly cisplatin at 40 mg/m2), and disease site. They were then randomly allocated to receive pelvic IMRT or four-field pelvic radiation treatment. Acute gastrointestinal and genitourinary toxicities and QOL were measured with various questionnaires. There were 227 patients in the primary endpoint analysis.

The primary endpoint was the average change in acute gastrointestinal toxicity from baseline to 5 weeks from the start of radiation, as measured by the Expanded Prostate Cancer Index Composite (EPIC).

Compared with patients who received conventional radiation, patients who received IMRT had fewer bowel-related toxicities, indicated by smaller average declines in the EPIC bowel domain scores (18.6 vs -23.6; P = .048), but there was no difference with respect to being bothered by bowel symptoms.

Urinary side effects were more common in patients who received conventional radiation than in those who received IMRT, evidenced by smaller declines in average urinary domain scores for the IMRT arm (-5.6 vs -10.4; P = .03).

Patients who received IMRT were less likely to experience diarrhea (33.7% vs 51.9%; P = .01), fecal incontinence (frequency, 1.1 vs 9.3; P = .01), and to report taking four or more antidiarrheal medications (7.8% vs 20.4%; P = .04). However, there were no differences in abdominal pain.

Also, patients who received IMRT had a less substantial decline in health-related QOL (-8.8 vs -12.8; P = .06) and physical well-being (-4.2 vs -6.1; P = .03), as determined on the basis of a standard questionnaire

"Pelvic IMRT reduces acute patient-reported GI and GU toxicity compared to standard pelvic radiation," said Dr Klopp. "Pelvic IMRT reduces the need for antidiarrheal medications as compared to standard pelvic radiation therapy, and it appears to improve quality of life with regard to physical functioning and other treatment-related effects during treatment."

Pelvic IMRT reduces acute patient-reported GI and GU toxicity compared to standard pelvic radiation. Dr Ann Klopp

She said longer-term follow-up was needed to determine whether the effects persisted.

What Another Trial, Another Expert Say

Meeting discussant Dr Chopra said there is no level I evidence for the superiority of gynecologic postoperative IMRT, either with regard to physician-reported outcomes or patient-reported outcomes.

She pointed out that there are two phase III trials evaluating postoperative gynecologic IMRT: the TIME-C study, and the Postoperative 3DCRT Vs IG-IMRT for reducing Late Bowel Toxicity in Cervical Cancer (PARCER) study, which is ongoing at her center.

At last year's ASTRO meeting, Dr Chopra reported interim findings from PARCER that showed that postoperative image-guided IMRT was associated with a 14% reduction in moderate to severe bowel side effects in comparison with 3DCRT, but the difference was not statistically significant. "The benefit of IMRT was considered nonexistent until [Dr Klop's] presentation today," said Dr Chopra.

Dr Chopra believes PARCER and TIME-C are coming to different conclusions because the population in the PARCER trial had a higher proportion of patients who received concurrent chemotherapy, around 88%. "One can presume that cisplatin would drive acute toxicity, but this is not conclusive, because it comes from a subanalysis of the study," she said. Only 25% of patients in the TIME-C trial received chemotherapy.

Dr Chopra said TIME-C was important "as the first completed trial of postoperative gynecologic IMRT," but she said that the P values in TIME-C have a lower relevance because of the reduced power of the study. In addition, she said, "When one looks at the evolution of the FACT over 5 weeks [in TIME-C], there is a definite benefit that IMRT has until week 5, but as you approach weeks 4 to 6, there is complete disappearance of treatment effect."

Long-term data from TIME-C and a final analysis of PARCER are needed to assess the impact on late GI, said Dr Chopra, and "pooled data from the PARCER and TIME-C trials are needed to assess the impact of IMRT for acute GI toxicity."

But another expert endorsed the use of IMRT for women's pelvic tumors.

Geraldine Jacobson, MD, MPH, chair of the Department of Radiation Oncology, West Virginia University, Morgantown, said, the study is "really important" because it shows that there is a definite difference in toxicity in patients who are treated with pelvic tumors.

We already use IMRT for pelvic radiation. Dr Geraldine Jacobson

"We already use IMRT for pelvic radiation, but for many years, it had very slow adoption, and there are some situations where third-party insurers don't want to pay for IMRT to the pelvis," said Dr Jacobson, who moderated a meeting press conference in which the new study was discussed.

Dr Jacobson said toxicity is very important to patients and sometimes causes delays in treatment. "If overall treatment time is delayed, it does affect the outcome," she said.

Dr Klopp and Dr Jacobson have disclosed no relevant financial relationships. Dr Chopra has received research funding from Varian.

American Society for Radiation Oncology (ASTRO) 2016 Annual Meeting. Abstract 5. Presented September 26, 2016.

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