Practice Changing: High-Dose Radiation Not Superior in NSCLC

Surprise Results

Nick Mulcahy

October 04, 2011

October 4, 2011 (Miami Beach, Florida) — A landmark trial in nonsmall-cell lung cancer (NSCLC) has found that high-dose conformal radiotherapy (74 Gy) did not improve survival, compared with the standard dose (60 Gy), in patients with unresectable stage III disease.

In fact, median overall survival was better with the standard dose than with the high dose (21.7 vs 20.7 months; P = .02).

"I think it changes practice," said study chair Jeffrey Bradley, MD, from the Washington University School of Medicine in St. Louis, Missouri.

Dr. Bradley spoke at a press conference here at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting; he presented the results of a study of 423 patients with grade 3 NSCLC at the plenary session.

Dr. Bradley explained that high-dose radiation — not standard-dose radiation — is typically used in this setting in the United States.

These NSCLC stage III patients are "technically curable" and receive "aggressive" treatment because their cancer, although not operable, is limited to the lungs and lymph nodes and has not yet spread elsewhere, he explained.

A community-based clinician concurred that the high-dose radiation has been a community standard for an extended period of time. "We have been using 74 Gy at Boca Raton Hospital for the past 5 years," said Tim Williams, MD, a radiation oncologist at the Florida hospital and a past chair of ASTRO. He moderated the press conference.

However, another community-based radiation oncologist refuted the idea that a high dose is frequently used in stage III patients.

"A minority of our patients receive 74 Gy," said Christopher Koprowski, MD, from the Helen Graham Cancer Center of the Christiana Care Health System in Newark, Delaware. "We individualize treatment, and patients receive somewhere between 60 and 74 Gy," he told Medscape Medical News at the meeting. The determinant of the dose is the "hazards to the organs at risk," said Dr. Koprowski, referring to the lungs, esophagus, heart, and spinal cord. The patients who receive the high dose are "usually those with lower tumor bulk," he said. "Therefore, we are not violating normal tissue constraints."

Unexpected Finding

The trial, known as Radiation Therapy Oncology Group (RTOG) 0617, is the first randomized trial in 30 years to assess optimal radiation dose in lung cancer, said Dr. Bradley. Earlier smaller trials had found a survival advantage with high-dose radiotherapy.

We were surprised by the results.

The finding that high-dose radiation does not improve survival was unexpected. "We were surprised by the results," he told the ASTRO audience. Most clinicians have believed that higher doses of radiation cured more patients with lung cancer, Dr. Bradley said in a press statement.

But that is not what the study found.

At the initial planned interim analysis for overall survival, the investigators found that, after 90 deaths, the high-dose radiation groups had "crossed the futility boundary." The study was designed to detect a median overall survival improvement of 7 months in the high-dose radiation groups.

"High-dose radiation, as delivered in this trial, does not improve overall survival," Dr. Bradley and colleagues conclude.

An emphatic no to dose escalation.

"Level I evidence demonstrates no role for dose escalation" in stage III NSCLC, said Benjamin Mosvas, MD, from Henry Ford Hospital in Detroit, Michigan. Dr. Mosvas, who served as discussant of the paper at the plenary session. He also said the study results were "an emphatic no" to dose escalation.

More Study Details

The study was a 2 ₓ 2 design, with patients randomized to standard-dose or high-dose radiation with or without the targeted therapy cetuximab (Erbitux; Bristol-Myers Squibb). The high-dose regimen was 7 weeks and 37 fractions (2 Gy per day); the standard-dose regimen was 6 weeks and 30 fractions (2 Gy per day).

Concurrent chemotherapy for all patients included weekly paclitaxel (45 mg/m2) and carboplatin (area under the curve, 2). Patients were randomized to a 400 mg/m2 loading dose of cetuximab on day 1, followed by weekly doses of 250 mg/m2.

The high-dose radiation groups are now closed, but the study remains open to the standard-dose groups so that the addition of cetuximab can be examined.

Dr. Bradley said that he and his coinvestigators cannot explain the results and that the data are being carefully reviewed.

In the study, both 3-dimensional conformal radiation therapy (55% of patients) and intensity-modulated radiation therapy (IMRT; 45%) were used. However, there was no difference in outcome with the different technologies, said Dr. Bradley. RTOG is the first phase 3 lung cancer study to include IMRT, he noted.

There were no statistically significant differences in toxicities between the high-dose and standard-dose groups, Dr. Bradley pointed out.

On multivariate analysis, 3 factors were significantly associated with overall survival, noted Dr. Bradley: the 60 Gy dose; nonsquamous cell histology; and smaller gross tumor volume.

The trial, which has a goal of 500 patients, accrued 423 from November 2007 to April 2011.

Eligibility criteria included biopsy-proven stage IIIA/B NSCLC, a performance status of 0 or 1, and a forced expiratory volume in 1 second of at least 1.2 L/s. Exclusion criteria included supraclavicular or contralateral hilar disease, weight loss of at least 10%, and previous nonsurgical therapy for NSCLC.

This study was supported by the National Cancer Institute, Bristol-Myers Squibb, and ImClone. The authors have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting: Abstract LB2. October 3, 2011.

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