Intensity-modulated radiation therapy (IMRT) reduced the risk of toxicity to the lungs and radiation exposure to the heart vs three-dimensional conformal radiotherapy (3D-CRT) for the treatment of locally advanced non–small cell lung cancer (NSCLC), according to a planned long-term prospective analysis of the NRG Oncology RTOG 0617 trial comparing the two techniques based on trial stratification.¹ The retrospective study, which was presented at the International Association for the Study of Lung Cancer 2023 World Lung Cancer Conference, suggested IMRT should be the preferred technique for this patient population.

Severe lung toxicity was significantly reduced by more than twofold with IMRT: pneumonitis occurred in 3.5% of patients treated with IMRT vs 8.2% of those who received 3D-CRT (P = .03). Additionally, exposure to the heart was also reduced with IMRT.

“IMRT spared more normal tissue than 3D-CRT, which translated into a clinically meaningful benefit to patients,” stated lead author Stephen G. Chun, MD, Associate Professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center, Houston. “Despite historical concerns of IMRT generating a low-dose radiation bath to a large area of normal lung tissue [ie, volume receiving 5 Gy or higher (V5Gy)], we found no excess cancers, increased adverse events, or survival detriment associated with the lung V5Gy.”

Stephen G. Chun, MD

Fiona Hegi-Johnson, MD

Dr. Chun continued: “IMRT should be the preferred choice for locally advanced NSCLC to mitigate severe pulmonary toxicity and minimize radiation exposure to the heart. The analysis emphasizes the importance of optimizing radiation planning, with special attention to reducing lung V20Gy and heart V20–60Gy, constraining the heart V40Gy < 20%.”

“This is an incredibly important study,” said press conference moderator Fiona Hegi-Johnson, MD, a radiation oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia, and Director of the Board of the Trans-Tasman Radiation Oncology Group. “This will transform the care of NSCLC across the world.”

Concurrent chemoradiation is an established standard of care for unresectable locally advanced NSCLC, but the optimal photon-based radiation technique is controversial because of a lack of prospective data comparing IMRT and 3D-CRT long term. “Although 3D-CRT has been widely used to treat unresectable locally advanced lung cancer, the technique is less precise than IMRT, which better sculpts and conforms to tumors than 3D-CRT,” Dr. Chun said, reducing radiation exposure to nearby organs. “As IMRT is more labor-intensive and costlier than 3D-CRT, it is important to justify IMRT use based on long-term prospective outcomes.”

The primary analysis of the phase III RTOG 0617 trial found there was no benefit in overall survival between high-dose (74 Gy) and standard-dose (60 Gy) radiation -therapy in advanced NSCLC. In the trial, radiation technique was a -preplanned stratification factor (ie, IMRT vs 3D-CRT).² A secondary analysis based on initial trial stratification was performed to compare directly the 5-year outcomes of patients treated with IMRT and 3D-CRT for locally advanced NSCLC. Outcomes analyzed included 5-year overall survival, progression-free survival, time to local failure, and distant metastasis–free survival.

RTOG 0617 Details

The NRG Oncology RTOG 0617 study enrolled 482 patients with locally advanced NSCLC from 2007 to 2011 and compared a high dose of radiation (74 Gy) with a standard dose (60 Gy). All patients were treated with concurrent chemotherapy (carboplatin or paclitaxel with or without cetuximab). Of these patients, 47% were treated with IMRT and 53% with 3D-CRT. The secondary analysis was based on a median follow-up of 5.2 years.

At baseline, the median heart V40Gy was 16.5% with IMRT vs 20.5% with 3D-CRT (P < 0.01), and lung V5Gy was 61.6% vs 54.8% (P < 0.01). At 5 years, the IMRT and 3D-CRT groups had similar outcomes in terms of overall survival, progression-free survival, time to local failure, and distant metastasis–free survival.

Long-Term Toxicity

Despite the similarity in outcomes between the two techniques, IMRT demonstrated a clear advantage in reducing the risk of lung toxicity over the longer term. The rate of pneumonitis at a median follow-up of 5.2 years was 3.5% vs 8.2%, respectively, for IMRT vs 3D-CRT (P = .03).

Survival was similar in the two treatment arms. However, a correlation was found between survival and radiation dose to the heart. IMRT significantly reduced radiation exposure to the heart.

On unadjusted analysis, the heart V20–60Gy was continuously associated with survival (P < .01); and a heart V40Gy ≤ 20% was associated with significantly improved survival than a heart V40Gy ≥ 20% (median survival, 2.5 vs 1.7 years, P < .01). Multivariable analysis showed a heart V40Gy ≥ 20% was significantly associated with worse survival (P = .01), whereas a lung V5Gy had no significant impact on long-term survival (P = .13).

“This was a key finding of the trial,” Dr. Chun stated. “Constraining the heart V40Gy less than 20% is an important and novel radiation planning objective that should be incorporated into international lung cancer treatment guidelines. Additionally, the findings do not support constraining the lung V5Gy low-dose bath because it degrades conformity and increases heart exposure,” he added.

Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to assess grade 3 and higher toxicities and development of second malignancies. The lung V5Gy was not associated with grade ≥ 3 pneumonitis, esophagitis, weight loss, cardiovascular toxicity, neurologic toxicity, or hematologic toxicity. The IMRT and 3D-CRT groups had similar rates of second malignancy development with long-term follow-up (6.6% vs 5.5%, respectively).

In addition, there was no evidence that age impacted long-term outcomes. “Age in itself should not be considered a contraindication for curative-intent chemoradiotherapy for locally advanced NSCLC,” explained Dr. Chun. “These findings provide a crucial contribution to the ongoing discourse on radiation techniques for NSCLC treatment, paving the way for more informed clinical decisions and improved patient outcomes.”

“The data from our study make a compelling argument that we should use IMRT for locally advanced lung cancer,” he continued. “As a randomized clinical trial comparing 3D-CRT and IMRT is unlikely to be performed, this study represents the strongest prospective evidence we will ever have in support of IMRT. We turned the page on 3D-CRT for head and neck cancers, brain tumors, and prostate cancer decades ago, and it is time for us to finally turn the page on 3D-CRT for locally advanced lung cancer.” 

DISCLOSURE: The study was funded by Eli Lilly, plus grants from the National Cancer Institute. Dr. Chun reported financial relationships with Curio Science, Norton Healthcare, AstraZeneca, Binaytara Foundation, Henry Ford Health, Hong Kong Precision Oncology, ViewRay, the American Board of Radiology, and the Japanese Society for Radiation Oncology. Dr. Hegi-Johnson has received funding, honoraria, and has served on advisory boards for AstraZeneca; has received honoraria from BeiGene and MSD; and her work is supported by the Peter Mac Foundation and the Victorian Cancer Agency.

REFERENCES

1. Chun SG, Hu C, Choy H, et al: Long-term outcomes by radiation technique for locally advanced non-small lung cancer: A secondary analysis of NRG Oncology-RTOG 0617 at 5 years. 2023 World Conference on Lung Cancer. Abstract OA17-04. Presented September 11, 2023.

2. Bradley JD, Paulus R, Komaki R, et al: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): A randomized, two-by-two factorial phase 3 study. Lancet Oncol 16:187-199, 2015.