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SINGAPORE -- Intensity-modulated radiation therapy (IMRT) should be the radiation technique of choice for unresectable locally advanced non-small lung cancer (NSCLC), a secondary analysis of a randomized trial suggested.

In the study, IMRT resulted in similar survival outcomes compared with 3D conformal radiotherapy (3D-CRT), but with less severe lung toxicity and radiation exposure to the heart, reported Stephen Chun, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the World Conference on Lung Cancer (WCLC).

The new findings came from a long-term analysis (median follow-up 5.2 years) involving 482 patients from the NRG Oncology-RTOG 0617 trial.

Despite baseline characteristics that seemed to put IMRT at a disadvantage -- including more stage IIIB cancers and tumors in unfavorable cardiac locations -- no significant differences between the IMRT and 3D-CRT arms were seen for median overall survival (2.2 vs 2 years, respectively), progression-free survival (0.8 vs 1 year), distant metastasis-free survival (1.1 vs 1.2 years), or secondary cancer rates (6.6% vs 5.5%).

The analysis "likely represents the strongest evidence supporting intensity-modulated radiotherapy for locally advanced lung cancer that we will ever have, given that a randomized trial comparing the two techniques directly is unlikely to ever be performed," said Chun.

"It's been 20 to 30 years since we've turned the page on 3D conformal radiotherapy for prostate cancer, head and neck cancer, brain tumors," he said. "The time is here for us to turn the page on 3D conformal radiotherapy for locally advanced lung cancer in favor of IMRT."

Definitive concurrent chemoradiation is the standard of care for unresectable locally advanced NSCLC, but the optimal radiation technique "is controversial," Chun said, adding that IMRT is more labor intensive than 3D-CRT, which has historically been used for this patient population.

While an earlier analysis of RTOG 0617 showed less pneumonitis with IMRT, "there is sparse long-term data justifying the use" of the more costly radiation technique, which better sculpts and conforms radiation doses to tumors, Chun said.

RTOG 0617 was a randomized phase III trial assessing the role of radiotherapy dose escalation (60 vs 74 Gy) and the addition of cetuximab (Erbitux) to weekly carboplatin and paclitaxel for locally advanced NSCLC. Use of IMRT or 3D-CRT was one of the stratification factors. The showed worse survival with the higher radiation dose and no benefit with the addition of cetuximab.

When looking at long-term side effects in the new analysis, IMRT was associated with more than a two-fold reduction in grade ≥3 pneumonitis (3.5% vs 8.2% with 3D-CRT, P=0.03).

Additionally, despite historical concerns about IMRT generating a low-dose radiation bath (V5Gy) to a large area of normal lung tissue, Chun reported there were no excess cancers, increased adverse events, or effect on survival related to the approach.

"These findings do not support lung V5Gy constraints, which inevitably degrade planned conformity," he said.

WCLC discussant Matthew Hatton, MBChB, MSc, of the Weston Park Cancer Centre in Sheffield, England, agreed with Chun's conclusion that IMRT should be the standard choice for locally advanced NSCLC.

"And I would agree that this trial has been able to give us the evidence to support that conclusion," said Hatton. "RTOG 0617 confirms there is a real place for randomized trials to generate the evidence to guide our practice, and those trials need to embed transitional research, and there are opportunities to embed these technical radiotherapy questions within the trials."

Heart Dose and Survival

Chun and his fellow researchers also looked at factors predicting overall survival and showed on multivariable analysis that a heart V40Gy (the amount of heart receiving a radiation dose of 40 Gy) of 40% or greater was associated with worse survival compared with a heart V40Gy of less than 20% (HR 1.34, 95% CI 1.06-1.70, P=0.01).

Thus, "we validated a novel cardiac constraint -- specifically maintaining a heart V40Gy less than 20%," Chun said.

He also observed that radiation dose level and planning target volume were significantly associated with survival, while age -- along with lung V5Gy -- had no significant impact on survival. "For this reason, age in and of itself, should not be a contraindication or reason to discriminate against patients for curative intent chemoradiation," he said.

Chun concluded that the study "corroborates the importance of using IMRT for conformity, to minimize intermediate-risk doses to the lungs, and intermediate- and high-risk doses to the heart," and emphasized that IMRT should become standard in this setting.

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