IMRT for locally advanced NSCLC reduces risk for severe pneumonitis

Issue: November 25, 2015

Patients with stage III non–small cell lung cancer experienced less inflammation and a better tolerance to follow-up chemotherapy when they receive intensity-modulated radiation therapy rather than 3D-conformal radiotherapy, according to phase 3 study results presented at the ASTRO Annual Meeting.

Perspective from Henning Willers, MD

The standard of care for these patients with locally advanced NSCLC is concurrent chemotherapy and radiation therapy. The two types of radiotherapy used in this setting are the 3D-conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT).

Stephen Chun, MD, fellow in the department of radiation oncology at The University of Texas MD Anderson Cancer Center in Houston, and colleagues compared the two radiation modalities by performing a secondary analysis of the NRG/RTOG 0617 trial that was conducted from 2007 through 2011.

A cohort of 482 patients from this trial underwent radiotherapy. Fifty-three percent received 3D-CRT and 47% received IMRT. Because the original trial was not randomized for these modalities, the patients in the IMRT arm had larger and more advanced tumors — 38.6% of the patients in that group with stage IIIB tumors compared with 30.3% in the 3D-CRT group.

Despite having more advanced tumors, patients in the IMRT arm had a 44% lower occurrence of severe pneumonitis — defined as inflammation of the lung that required oxygen, steroids or a mechanical ventilation and/or led to death — than patients in the 3D-CRT group (HR = 0.44; P = .0653). This was especially evident in tumors that were larger than the 460 mL median (HR = 0.22; P = .02).

A total of 3.5% of patients in the IMRT arm experienced severe pneumonitis compared with 7.9% of the 3D-CRT group (P = .046).

IMRT also had a significantly lower dose of radiation to the heart, which was associated with higher rates of survival. A greater proportion of patients receiving IMRT also completed high-dose consolidative chemotherapy than those treated with 3D CRT (37% vs. 29%).

“These findings have the potential to fundamentally change the way we deliver radiation therapy for locally advanced lung cancer,” Chun said in a press release.

Chun added that reducing the prevalence of life-threatening pneumonitis, IMRT can improve a patient’s quality of life, reduce their admissions to hospitals and ICUs, and decrease use of supplemental oxygen.

“In our study, it seemed that IMRT might also facilitate patients being able to tolerate higher doses of consolidative chemotherapy which are standard after radiation,” he said. – by Anthony SanFilippo

For more information: Chun SG, et al. Abstract 2. Presented at: ASTRO Annual Meeting; Oct. 18-21, 2015; San Antonio, Texas.

Disclosure: The study was supported by grants from Bristol-Myers Squibb and Eli Lilly.

Perspective

Henning Willers, MD

Radiation therapy is the mainstay of treatment for patients with inoperable locally advanced non–small cell lung carcinoma. Unfortunately, with traditional radiation techniques and doses of approximately 60 Gy, at least 30% to 50% of patients experience tumor regrowth within the radiation field. This is to a great extent due to the often large size of tumors at time of diagnosis and unfavorable biology, highlighting the need for treatment intensification. However, the delivery of a radiation doses sufficient for local tumor eradication in conjunction with radiosensitizing drugs is limited by the proximity of critical normal organs in the chest.

Intensity-modulated radiation therapy (IMRT) has been developed more than 20 years ago. IMRT is an advanced mode of radiation therapy that “paints” radiation doses onto the tumor with high precision while minimizing high-dose exposure of nearby organs. This painting of dose is achieved by modulating, or controlling, the intensity of the radiation beam in numerous small volumes.

Despite the promise of IMRT to improve the therapeutic ratio and its use in other cancer types, there have been sparse data on its benefits in patients with NSCLC. Single-institution experiences, particularly from The University of Texas MD Anderson Cancer Center, have suggested that IMRT may decrease treatment side effects such as pulmonary toxicity. However, prospective data from well-designed clinical trials addressing this issue have been lacking to date.

The NRG/RTOG 0617 study is a large multi-institutional phase 3 clinical trial that randomized patients with locally advanced NSCLC to two different radiation doses (60 Gy vs. 74 Gy) and receipt of a biological agent (cetuximab [Erbitux, Lilly] vs. none) in conjunction with carboplatin/paclitaxel. Radiation modality — ie, IMRT vs. standard radiation (3D-CRT) — was at the discretion of the treating physician.

A secondary analysis of this landmark trial has recently been reported at the ASTRO Annual Meeting. The delivery of IMRT, which was given to almost 50% of patients, was associated with decreased rates of symptomatic pneumonitis, heart sparing, and a higher portion of patients receiving full-dose adjuvant chemotherapy. Although the choice of IMRT vs. 3-D CRT was not randomized and there may exist some institutional bias, the results confirm our expectation that IMRT is associated with fewer adverse events.

These results are especially remarkable when considering that optimal IMRT planning requires careful specification of multiple normal tissue dose constraints. In this trial — designed more than 10 years ago — there were relatively few dose constraints particularly with regard to heart and esophagus sparing to guide IMRT planning and high-dose delivery.

Thus, more work needs to be done to fully realize the potential of IMRT. This includes optimizing dose parameters to reduce rates of severe esophagitis, and enabling centers with less IMRT experience to execute these highly complex treatments.

Importantly, the new data highlight the need for high-precision radiation to facilitate the delivery of appropriate systemic therapies. The data also strongly argue that despite its cost, IMRT should become a standard option for the treatment of locally advanced NSCLC, something that many health insurance companies have been hesitant to embrace.

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Bradley J D, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(14)71207-0.

Chun SG, et al. Int J Radiat Oncol Biol Phys. 2015;doi:10.1016/j.ijrobp.2015.07.010.

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Willers H, et al. Cancer J. 2013;doi:10.1097/PPO.0b013e318292e4e3.

Henning Willers, MD

Massachusetts General Hospital

Harvard Medical School

Disclosures: Willers reports no relevant financial disclosures.