Nick Mulcahy

October 02, 2013

ATLANTA — A new analysis of quality-of-life (QOL) data from a major lung cancer clinical trial, which showed that high-dose is not better than standard-dose radiation in stage III patients, has raised questions about the results.

Baseline QOL scores predicted how long patients would survive, according to a presentation here at the American Society for Radiation Oncology (ASTRO) 55th Annual Meeting.

A multivariate analysis of data from the Radiation Therapy Oncology Group (RTOG) 0617 trial showed that QOL was significantly predictive of survival at 12 months (P ≤ .02). In fact, the higher the QOL score, the greater the reduction in risk for death, said lead investigator Benjamin Movsas, MD, from the Henry Ford Health System in Detroit.

Every 10-point increase on the QOL instrument used in the trial corresponded to a 14% decreased risk for death, he said at a meeting press briefing. Notably, he added, QOL scores were patient-reported.

In contrast, toxicity was investigator-assessed, but there were no differences between the 2 study groups in terms of toxic effects.

"This study...emphasizes the critical importance of patient-reported outcomes," Dr. Movsas said in a press statement.

QOL analysis was a secondary outcome measure in RTOG 0617, which had "perplexing" survival outcomes, according to the study authors.

Those survival results — initially reported at the ASTRO meeting in 2011 — showed that the high dose did not improve survival, as expected, but instead resulted in inferior survival, which was unexpected and disappointing.

At 1 year, median overall survival was better with standard-dose (60 Gy) radiation than with high-dose (74 Gy) radiation (81% vs 70.4%)

The final survival results were reported earlier this year at the American Society of Clinical Oncology (ASCO) annual meeting. At the time, ASCO president Sandra Swain, MD, said that "after a decade of research, we can finally close the chapter on the high-dose vs standard-dose debate in lung cancer."

QOL Analysis Raises New Issue

However, the QOL analysis raises a new issue — that the survival difference between the 2 groups might be explained by patients in the high-dose group having worse lung cancer symptoms at 3 months, said Dr. Movsas.

He explained that his team collected QOL data from patients at baseline and at 3 and 12 months after the start of treatment, using the FACT–TOI (Functional Assessment of Cancer Therapy–Trial Outcome Index). The index consists of a set of physical and functional measures, and includes a lung cancer subscale, which measures 9 disease-specific symptoms.

The investigators focused on the lung cancer subscale because it was hypothesized that the high-dose radiation group would have a "clinically meaningful decline" at 3 months. In other words, they expected that high-dose radiation would worsen the patient's cancer symptoms in the short run.

Sure enough, at 3 months, the "clinically meaningful" decrease from baseline in the lung cancer subscale score was 46% in the high-dose group and 31% in the standard-dose group (P = .024).

At 12 months, however, survivors in the high-dose group bounced back, and changes from baseline in that group were not significantly different from changes in the standard-dose group (39% vs 36%; P = .7).

But the damage might have already been done, suggested Dr. Movsas.

"This analysis raises an intriguing question about whether the decline in QOL in the high-dose arm helps account for the survival decrement in this arm over time," he said.

However, there are "other factors" that might explain why patients in the high-dose group died more quickly, and they are being investigated, Dr. Movsas said. Those factors include the heart volume irradiated.

After the disappointing RTOG 0617 survival results were reported, a prominent radiation oncologist published a study on the trial that reminded the treatment community that radiation to the lungs can be dangerous (Int J Radiat Oncol Biol Phys. 2012;82:1042-1044).

"Considerable evidence...supports the hypothesis that the pulmonary or cardiopulmonary effects of thoracic RT can contribute to death," wrote James Cox, MD, from the University of Texas M.D. Anderson Cancer Center in Houston.

IMRT Might Lessen QOL Decline

The new analysis hints that some QOL differences might be related to the 2 different radiation techniques used in the trial, said Dr. Movsas.

He noted that RTOG 0617 was not designed to compare intensity-modulated radiation therapy (IMRT) with 3D conformal radiation therapy. However, because IMRT was used in roughly 40% of patients in both the high- and standard-dose groups, the investigators performed some analyses by treatment type.

Dr. Movsas reported that the patient demographics and treatment factors were not much different between IMRT and 3D radiation — with 2 important exceptions. There were significantly more patients with stage IIIB disease and larger gross tumor volumes treated with IMRT.

Even with those inequities, there was a trend toward a smaller decline in QOL (measured with lung cancer symptoms) at 3 months with IMRT than with 3D radiation (31% vs 43%; P = .06), and a significant difference at 12 months (23% vs 47%; P = .005).

Dr. Movsas noted that IMRT appears to be associated with a "reduced clinically meaningful decline in quality of life," compared with 3D radiation.

The study was supported by grants from the RTOG and Bristol-Myers Squibb. The authors have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 55th Annual Meeting. Abstract 3. Presented September 23, 2013

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