No Benefit With Boosted Radiation Dose in Esophageal Cancer

Roxanne Nelson, RN, BSN

January 24, 2020

San Francisco — Escalating the dose of radiation therapy does not appear to improve outcomes for patients with esophageal cancer who are receiving definitive chemoradiation, according to new findings.

Overall, patients who received a standard dose of 50.4 Gy to the primary tumor and regional lymph nodes, combined with an integrated boost of 0.4 Gy per fraction (total 61.6 Gy), had no improvement in local control as compared with those receiving the standard dose alone.

The 3-year local progression-free survival (PFS) was 71% in the standard therapy arm vs 73% in the boosted arm, and 3-year overall survival was 41% vs 40%, respectively.

Lead author Maarten C.C.M. Hulshof, MD, PhD, of the Amsterdam University Medical Center, Netherlands, explained that in 2002, a previous dose escalation trial did not find an improvement in survival or local/regional control.

And now after "years of hard work, we are back to where we started, and the standard dose remains at 50 Gy," he said.

The study results were presented here at the 2020 Gastrointestinal Cancers Symposium.

During his presentation, Hulshof pointed out that the standard dose for local regional control in esophageal cancer is about 50 Gy, which is low compared to the dose for other solid tumor sites. As an example, it is 60 Gy to 80 Gy for malignancies of the larynx, lung, bladder, and cervix.

Similarly, local regional control rates are also lower as compared to other tumor sites (50% for the esophagus vs 70%-85% for larynx, bladder, and prostate).

Nearly 20 years ago, the INT 0123 (Radiation Therapy Oncology Group 94-05) dose escalation trial compared high-dose (64.8 Gy) with standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer who were not undergoing surgery (J Clin Oncol. 2002;20[5]:1167-74). No significant difference was found in median survival, 2-year survival, or local/regional failure and local/regional persistence of disease.

"The trial was stopped prematurely, and negative results were never well understood," said Hulshof. "And so we thought there was a need for a dose-escalation trial, which we did in the Netherlands."

The same biological dose was compared "with some innovations," he noted.

Study Details

In this study, 260 patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus, and who were ineligible for surgery, were randomized to either a standard dose of 50.4 Gy or a high dose of 61.6 Gy.

The chemotherapy regimen was six concurrent cycles of carboplatin (AUC 2) and paclitaxel (50 mg/m2) for both arms.

The primary endpoint was to improve local PFS by 15%; secondary endpoints were locoregional PFS, overall survival, and toxicity. Patients were stratified for histological subtype, with squamous cell carcinoma comprising about 60% of tumors in both arms.

The trial was started in 2012 and ended in June 2018, and at the time of the analysis, there was a median follow-up of 48 months.

The 3-year locoregional PFS was 53% for the standard-dose group and 63% for the high-dose group.

When looking at results by histological subtype, 3-year local PFS was 77% for patients with squamous cell and 62% for adenocarcinoma — but by 5 years, the differences largely disappeared.

Overall grade 4 and 5 toxicity was higher in the boosted-dose arm: 10.8% vs 13.6% and 5% vs 8.5%. Hulshof noted that there was "a slight excess of fatal toxicity in the boosted arm."

"We had good local control of 72%," he concluded. "But the disappointing conclusion is that there was no improvement with boosted dose on progression free survival. The standard advised dose remains at 50.4 Gy."

Theory and Practice

In a discussion of the paper, Sara Lonardi, MD, of the Institute of Oncology Veneto, Italy, noted that the higher rate of toxicity seen in this trial was not observed in another recent study conducted at MD Anderson Cancer Center in Houston, Texas (JAMA Oncol. 2019;5[11]:1597-1604).

The results of that phase 1/2 study of chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose found the regimen to be well tolerated, with encouraging local control.

In the current study, "excessive toxicity led to a lower rate of compliance to therapy in the boosted arm," she said. "Compliance parameters were in favor of standard care."

Lonardi also questioned if the rational of "the boost" was strong enough to set up such a large trial with such an ambitious endpoint.

She noted that the benefit seen in this trial was due to hypofractionated radiation and not a boosted dose. Previous studies, including the INT 0123, failed to show superiority for the boosted dose.

"From a theoretical perspective, a boost should work and we should have seen positive results," she said. "This study used more modern radiation treatments and modern regimens of chemotherapy."

Quoting baseball great Yogi Berra, she noted that, "In theory there is no difference between theory and practice. But in practice, there is."

Making another reference to popular culture, this time the TV series Knight Rider, Lonardi pointed out that "it seems that the only turbo boost that works to have a jump ahead is that of David Hasselhoff's supercar."

The study was funded by the Dutch Cancer foundation KWF. Lonardi has disclosed relationships with Merck Serono, Amgen, Lilly, Servier, Bristol Myers Squibb, and Roche. Hulshof has disclosed no relevant financial relationships.

2020 Gastrointestinal Cancers Symposium: Abstract 281. Presented January 23, 2020. 

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