ATLANTA—The perplexing outcome of the Radiation Therapy Oncology Group 0617 trial, that higher radiation doses were associated with worse survival outcomes (OT 10/25/11 issue)—may be explained at least in part by patient-reported quality of life. That was the conclusion of a plenary paper reported here at this year's American Society for Radiation Oncology Annual Meeting (Abstract 2—accessible via online.myiwf.com/astro2013/Abstract.aspx).
In the new study, presented by Benjamin Movsas, MD, Chair of the Department of Radiation Oncology at Henry Ford Health System, examination of the prospective quality-of-life data collected during the trial showed that after three months of therapy, patients on the high-dose arm (74 Gy) had a 46 percent decline in their quality of life, vs. a 31 percent reduction for patients on the standard-dose arm (60 Gy).
“When we look at the toxicity scored by the physicians, there were few if any differences between the study arms, but the patient-reported outcomes tell us at least part of the rest of the story, by showing significantly worse quality of life on the high-dose arm at three months,” he said.
RTOG 0617 was a randomized, Phase III study in which patients with Stage III non-small-cell lung cancer (NSCLC) received radiotherapy plus concurrent and consolidation carboplatin/paclitaxel chemotherapy with or without cetuximab. The question asked was whether escalating the radiation dose for patients extended survival.
The answer was no, but that then raised the question of why. Median survival was actually lower for patients who received the 74 Gy dose—20.7 months vs. 21.7 months for 60 Gy—even though no significant differences in toxicity were reported by clinicians.
Patients had been given the Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI), which included the Physical Well Being (PWB), Functional Well Being (FWB), and Lung Cancer Subscale (LCS) tests.
In his presentation, Movsas said that besides the decline in quality of life on the high-dose arm, the lower survival in this arm over time could also be due to other factors such as the volume of the heart irradiated and local failure rates.
But the data do support the study's primary hypothesis, he said, that a clinically meaningful decline in health-related quality-of-life scores on the LCS test would be greater among patients treated with the higher dose of radiotherapy at three months after treatment.
He said that although the trial was not designed to study the effect of radiotherapy technique on health-related quality of life, patients receiving intensity-modulated radiation therapy (IMRT) were less likely to have a clinically meaningful decline than were those receiving three-dimensional conformal radiation therapy (3-D CRT).
Baseline QoL Predicts Survival
The investigators also found that baseline quality of life significantly predicted for survival on multivariate analysis. “Every 10 points higher in the FACT TOI in the baseline corresponded to a 14 percent decrease in the risk of death,” Movsas said.
“Quality-of-life reported outcomes tell us what is really happening from the patient's perspective, and without this we are missing the most important aspect regarding patient care and how to improve this over time,” Movsas said. “Quality of life provides ‘the rest of the story’ directly from the patient.”
The study was supported by RTOG Grant U10 CA21661 and CCOP Grant U10 CA37422 from NCI & Bristol-Myers Squibb.
Discussant: Possible Other Relevant Factors
The Discussant for the study, Andrea Bezjak, MD, Professor of Radiation Oncology and Chair of the Department of Thoracic Radiation Oncology at the University of Toronto, pointed to the very clear survival difference between the two arms in RTOG 0617 in favor of the lower-dose arm, which starts very early and persists. She also noted that the standard-dose arm exceeded expectations when the sample sizes were calculated.
“The expectation was 17 months median survival, when in actual fact the 60 Gy arm had more than 21 months median survival, which is really excellent. So when we talk about this study, rather than discussing why the higher-dose arm wasn't better than the lower-dose, we should ask how we in clinical practice can achieve the excellent results with the 60 Gy plus chemotherapy plus or minus cetuximab.”
Bezjak asked several questions about other factors that could have affected outcomes. For example, fewer patients in the 74 Gy arm were able to be included the analysis at 12 months, because many of them had died by that time. Also, patients in the 60 Gy arm were getting worse at 12 months, whereas those surviving in the 74 Gy arm were getting better. She said she would like to see the trial outcome index data integrating this with the quality-of-life data.
This was the secondary analysis, Bezjak said, and is really a hypothesis-generating analysis, suggesting that patients with IMRT have fewer symptoms or additional concerns, especially at the 12 months point. However, IMRT was not selected at random, it was more likely to be performed in Stage IIIb patients.
“When the results of the two arms are compared by radiation technique, the results at three months were almost identical, but the 12-month comparisons were quite different,” she said. “To me, that suggests there is an interplay within tumor volume, dose, and technique that may influence outcome, and I wonder whether these differences are actually due to pneumonitis. In the toxicity assessment there was no comment about pneumonitis being different.”
She also wondered whether cardiac sparing with IMRT may lead to some kind of a quality-of-life or symptom benefit.
Nevertheless, Bezjak said, she thought the study conclusions were “fair enough” and were supported by the analyses.
“The take-home message is that the optimal dose of radiation for patients with Stage III NSCLC is not known. This study is very important, but it does not mean that dose escalation beyond 60 Gy is not to be considered or pursued. Quality-of-life data are prognostic for overall survival, which has been shown in many studies, and I think this study is definitely a reminder for doing quality-of-life assessment and stratifying by baseline.”
Provides More Evidence
Asked for his opinion for this article, Christopher A. Barker, MD, Assistant Attending Radiation Oncologist at Memorial Sloan-Kettering Cancer Center, commented via email that the study gives more evidence that “patient-reported health-related quality-of-life assessments are tools that can provide important information about patients participating in research studies. The data clearly showed an association between health-related quality of life and survival,” he said.
“However, the reason that patients with inferior health-related quality of life have inferior survival is still unclear. Previous studies have suggested that patients with more advanced medical comorbidities often have inferior health-related quality of life, and my suspicion is that health-related quality of life is associated with factors that lead to poor outcomes.”