CHEMORADIATION FOR NSCLC

Survival outcomes for patients with unresectable, locally advanced non–small cell lung cancer (NSCLC) who undergo chemoradiation may be much higher than previously estimated.

Updated findings from the RTOG 0617 trial show 5-year survival rates that are more than double that expected. Five years after being treated with a standard dose of 60 Gy of radiation delivered in 30 fractions, the overall survival rate was 32%. Data from the National Cancer Institute indicate that 5-year survival rates in this population range from 5% to 14%.

This sets a new benchmark of survival. Dr Jeffrey Bradley

"This sets a new benchmark of survival for patients with inoperable stage III NSCLC treated with chemoradiation," said lead author Jeffrey D. Bradley, MD, FASTRO, a professor of radiation oncology and director of the S. L. King Center for Proton Therapy at the Washington University School of Medicine in St. Louis, Missouri.

The 5-year results also confirmed that standard-dose radiation therapy is preferable to higher-dose therapy and that adding cetuximab does not offer an additional survival benefit.

The findings were presented here at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.

Earlier results of this study demonstrated that standard-dose radiation therapy is associated with a survival advantage over high-dose therapy. As previouslyreportedby Medscape Medical News, a planned interim analysis presented at the 2011 ASTRO annual meeting showed that median overall survival was better with the standard dose than with the high dose (21.7 vs 20.7 months; P = .02) in 423 patients.

The final results of the RTOG 0617 were presented 2 years later at the annual meeting of the American Society of Clinical Oncology. Those results showed a median survival of 28.7% for standard dose vs 19.5% for high dose.

Dr Bradley noted that the results were subsequently published in the Lancet Oncology in 2015, and that their findings "really shook up the oncology community because a higher dose is usually better, but in this case it wasn't.

"We've done multiple secondary analyses and published on them, and today we are showing mature 5-year data," he said. "Our mature follow-up data confirm that a dose of 60 Gy was superior to 74 Gy."

The long-term survival rates from the RTOG 0617 are encouraging for lung cancer patients who are undergoing treatment, commented Kenneth Rosenzweig, MD, professor and system chair of the Department of Radiation Oncology at the Mount Sinai Health System in New York City.

"It has long been thought that if a patient was unable to undergo surgery for their tumor, the chance of long-term survival was extremely poor," said Dr Rosenzweig, who was not involved with the study. "But now we have learned that using just radiation therapy and chemotherapy provides survival rates that are vastly superior than anything that had been seen in history previously.

This is a testament that the improved treatment techniques, such as intensity-modulated radiation therapy, which was used in many patients on this trial, are resulting in better outcomes for our patients," he added.

Standard Dose Superior

RTOG 0617 was a multicenter phase 3 trial that compared high-dose conformal radiation therapy with standard-dose therapy in the setting of concurrent chemotherapy. A secondary analysis studied the effect of adding the targeted agent cetuximab to chemotherapy.

A cohort of 544 patients (496 eligible for analysis) with stage III inoperable NSCLC were randomly allocated to receive either standard-dose treatment of 60 Gy or high-dose treatment of 74 Gy, which was delivered in 2-Gy daily fractions through either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy.

Patients were also randomly assigned to receive cetuximab (400 mg/m ² loading dose of cetuximab on day 1, followed by weekly doses of 250 mg/m²) or placebo.

The median follow-up for surviving patients was 5.1 years (interquartile range, 4.6 - 6 years).

Median overall survival was higher for patients in the standard-dose cohort, at 28.7 months vs 20.3 months (hazard ratio [HR], 1.35; P = .004).

At 5 years, overall survival rates were significantly higher with standard-dose radiotherapy, at 32.1% vs 23% for the high-dose arm ( P = .004).

Progression-free survival (PFS) rates at 5 years also showed an advantage for standard-dose therapy, at 18.3% vs 13% (P = .055).

The authors found that on multivariate analysis, the differences observed on overall survival were driven by radiation dose, planning target volume (P = .022), the accrual volume of the treating institution ( P = .017), presence of esophagitis/dysphagia (P = .008), and V5 heart dose/volume (P = .005).

Rates of local, regional, and distant failure also favored the standard dose, although the differences did not reach significance. Rates of local failure were 38.2% vs 45.7% (P = .068); rates of regional failure, 35.7% vs 38.4% (P = .5); and distant failure, 52.3% vs 57.6% ( P = .3).

Not surprisingly, treatment-related toxicity was greater in the high-dose arm. There were three treatment-related deaths in the standard-dose arm vs nine in the high-dose group. Rates of toxicities of grade 3 or higher were also greater, including rates of dysphagia (3.2% vs 12.1%; P < .0001) and esophagitis (5% vs 17.4%; P < .0001).

No Benefit for Cetuximab

Median overall survival for those in the cetuximab arm was 24 months (95% confidence interval [CI], 20.4 - 30 months), vs 24 months (95% CI, 20.5 - 28.8 months) for patients who received placebo (HR, 1.0; P = .048). There was no benefit to adding cetuximab to the regimen of patients with EGFR H-scores higher than 200, which runs counter to earlier findings from the trial.

"The use of cetuximab was also of no benefit," said Dr Bradley.

How Can We Do Better?

Approached by Medscape Medical News for an independent comment, Henning Willers, MD, director of thoracic radiation oncology, Massachusetts General Hospital Cancer Center, and associate professor, Harvard Medical School, Boston, explained that this study sets an important benchmark, as it now has solid 5-year results. "The overall survival is 32% for the standard radiation dose arm of 60 Gy, which is among the best ever recorded in stage III NSCLC," he said.

"However, while 32% isn't bad, it is not earth shattering for this PET-staged patient population, and we have to do much better for our patients," Dr Willers continued. "The rate of local failure is close to 40%, and distant failure is in excess of 50% for patients treated with the standard dose, which is consistent with historical results.

"But the question is, how are we going to do better than that? This trial has established a baseline for forging a path forward," he said.

One avenue that the radiation oncology community has tried to follow in order to improve outcomes is to raise the dose of radiation, but this trial clearly shows "that we cannot give 74 Gy ― at least not within the normal organ constraints and the technology that was used in this trial."

He cautioned, however, that the fact that 74 Gy was not beneficial and that it can lead to detrimental outcomes does not mean that 60 Gy is the answer to the problem, because about 40% of patients still experience local failure.

In the future, it remains to be seen whether a more modest dose escalation, perhaps up to 70 Gy, with modern techniques and careful attention to heart and esophagus sparing would show more benefit.

Adding an immune checkpoint inhibitor to the treatment regimen is another, highly promising option to improve outcomes.

Dr Willers pointed to the recently reported findings from the PACIFIC study, which showed that giving the immunotherapy durvalumab (Imfinzi, AstraZeneca) after chemoradiotherapy in stage III, locally advanced NSCLC doubled progression-free survival (PFS) over placebo, increasing it by 11 months.

"It improved PFS dramatically, with a hazard ratio of 0.5, which is amazing," said Dr Willers. "This is important, because we are never going to go through the ceiling of about 30% survival with conventional chemoradiation, and cetuximab failed to achieve this, as 0617 shows. We need a new biology.

"The timing of the PACIFIC, together with the RTOG 0617 trial, gives us a path forward," he said. "We don't have the overall survival data yet from the PACIFIC trial, and especially the long-term data."

Once those data mature, he emphasized, "there is reason to hope that we will finally have broken through that ceiling of 30% survival."

The study is funded by the National Cancer Institute and Eli Lilly. Dr Bradley has relationships with ViewRay, Inc, and Mevion Medical Systems and organized ab NRG Oncology research agenda on lung cancer. He also has relationships with the American College of Radiology and organized oral board examinations for the American Board of Radiology. Several coauthors have disclosed relationships with industry, as noted in the abstract. Dr Willer has disclosed no relevant financial relationships. 

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract 227, presented September 25, 2017.