High-dose, accelerated radiotherapy brings better 2-year overall survival, with no added toxicity

In patients with limited stage, small-cell lung cancer (SCLC), hyperfractionated, accelerated, twice-daily thoracic radiotherapy (60 Gy) was feasible, and higher doses brought about significant improvements in two-year and median overall survival compared with the standard dose and schedule (45 Gy), with no additional toxicities, according to a study published in The Lancet Oncology.

“To our knowledge, the two-year overall survival in our trial is the highest reported in trials in limited stage SCLC, including all trials of high-dose, once-daily thoracic radiotherapy, and adds to the evidence suggesting that accelerated, hyperfractionated thoracic radiotherapy is the most effective approach in this disease,” wrote Bjørn Henning Grønberg, MD, of the Norwegian University of Science and Technology, Trondheim, Norway, and colleagues.

In patients with SCLC, twice-daily thoracic radiotherapy delivered at doses of 45 Gy in 30 fractions is currently considered to be the most efficacious.

In this open-label, randomized, phase II trial, Grønberg and fellow researchers enrolled 170 patients (median age: 65 years; 57% women; 31% aged ≥70 years; 98% current or former smokers) from 22 public hospitals in Norway, Denmark, and Sweden with treatment-naïve confirmed, limited stage SCLC. In all, 89% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, 84% had stage III disease, 8% had pleural effusion, and 20% had weight loss of >5% in the three months before enrollment.

All patients were treated with four courses of intravenous [IV] cisplatin (75 mg/m2) or carboplatin (area under the curve: 5-6 mg/mL x min, Calvert’s formula) on day one, followed by IV etoposide (100 mg/m2) on days 1-3 every three weeks. They were randomized to treatment with thoracic radiotherapy in doses of either 45 Gy in 30 fractions, or 60 Gy in 40 fractions to the primary lung tumor, and PET-CT positive lymph node metastases at 20-28 after initial course of chemotherapy. All patients then received two fractions per day, 10 fractions per week. Patients who responded had the option of prophylactic cranial irradiation (25-30 Gy).

At two years, 74.2% of patients treated with 60 Gy were alive, compared with 48.1% of those treated with 45 Gy (OR: 3.09; 95% CI 1.62-5.89; P=0.0005). Patients treated with 60 Gy had significantly longer median overall survival compared with those treated with 45 Gy (37.2 vs 22.6 months, respectively; HR: 0.61; 95% CI 0.41-0.90; P=0.012). Only female sex was associated with improved two-year overall survival.

Median progression-free survival was 18.6 months in the 60 Gy group, compared with 10.9 months in the 45 Gy group (HR: 0.75; 95% CI: 0.52-1.09; P=0.13), but upon multivariate analysis, no differences were seen (HR: 0.68; 95% CI 0.45-1.03; P=0.067).

Upon post-hoc analysis, researchers found that median time from disease progression to death was longer in the group treated with 60 Gy compared with 45 Gy (14.0 vs 8.2 months, respectively; P=0.0009).

Overall response occurred in 77.5% of the 60 Gy group versus 76.5% in the 45 Gy patients (P=0.88). No between-group differences were seen in local control, with relapse within the radiotherapy field seen in 21% versus 35% of patients, respectively. In addition, no between-group differences were seen in frequency of distant metastases (42% vs 46%; P=0.59).

The most common grade 3-4 adverse events included neutropenia (81% vs 81%, respectively), neutropenic infections (27% vs 39%), thrombocytopenia (24% vs 25%), anemia (16% vs 20%), and esophagitis (21% vs 18%). In patients treated with 60 Gy, 55 serious adverse events (SAEs) occurred in 38 patients, compared with 56 SAEs in 44 patients treated with 45 Gy. Three treatment-related deaths occurred in each group.

“To our knowledge, this is the first randomized trial comparing high-dose, hyperfractionated, accelerated, twice-daily thoracic radiotherapy with the established 45 Gy schedule. Our results show that administering 60 Gy is feasible, does not cause more toxic effects, and suggest that the higher dose provides a large survival benefit. As far as we know, the 2-year and median overall survival are the highest reported in any randomized trial of thoracic radiotherapy in limited stage SCLC. It is also one of few randomized trials limiting radiotherapy fields to ¹⁸F-fluorodeoxyglucose PET-CT positive lesions, omitting elective nodal irradiation, and allowing modern radiotherapy techniques,” concluded Grønberg et al.

In an accompanying editorial, Suresh Senan, MD, PhD, of Vrije Universiteit, Amsterdam, Netherlands, acknowledged the importance of these results—with a few caveats.

Senan first questioned the significance level set in the study: “Because recent studies investigating radiotherapy dose escalation in the thorax during chemoradiotherapy in NSCLC and esophageal tumors have reported more toxicity and a failure to improve survival, the use of a study design specifying a one-sided P of less than 0.10 significance level for the primary endpoint is questionable. No differences in severe toxicity were observed between the study groups; however, possible imbalances in tumor volumes between groups are suggested by the similar rates of radiation esophagitis,” he wrote.

Senan also noted the limitations of the study’s inclusion criteria.

“The feasibility of delivering 60 Gy twice daily to all eligible patients was not a prerequisite for study inclusion, and four patients in the high-dose group received only 45 Gy due to large tumor volumes. Patients aged 70 years or older comprised 31% of study patients, an age group previously reported to have lower treatment completion rates in limited stage SCLC, as well as more fatal complications. Unusually, women comprised the majority of patients (57%) enrolled in the present trial, whereas women comprised 47% of patients enrolled in 11 phase 2/3 trials for limited stage SCLC done by the National Clinical Trials Network,” he noted.

Nevertheless, he concluded, the results are of significance and call for a confirmatory phase III study.

“Unlike non-small-cell lung cancer (NSCLC), there has been little progress in the treatment of small-cell lung cancer (SCLC) in the past two decades,” Senan wrote. “However, Grønberg and colleagues’ study does provide more evidence to show that using modern delivery techniques, the 45 Gy twice-daily schedule can be delivered safely to many patients with limited stage SCLC,” he concluded.

According to the study authors, limitations included the sample size, the lack of data on tumor and irradiated surrounding normal tissue, and the lack of central quality assurance of radiotherapy. They also noted that because of the highly positive results for the primary endpoint—two-year overall survival—their use of two-sided instead of one-sided P values should not change interpretation of the results.

  1. Twice-daily thoracic radiotherapy of 60 Gy in 40 fractions may be a viable alternative to established schedules in patients with limited stage, small-cell lung cancer (SCLC), researchers found.

  2. In these patients, administering a higher dose (60 Gy) is feasible, did not cause more toxic effects, and provided a large survival benefit.

Liz Meszaros, Contributing Writer, BreakingMED™

The study was funded by the Norwegian Cancer Society, the Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.

Grønberg has received research funding from Roche and AstraZeneca, and honoraria from Roche, AstraZeneca, Pierre Fabre, Takeda, Eli Lilly, Bristol Myers Squibb, Bayer, and Novartis, all outside the submitted work.

Senan has received research grants and personal fees from Varian Medical Systems and AstraZeneca; research grants from ViewRay and Bristol Myers Squibb; and personal fees from Merck Sharp & Dohme and BeiGene, all outside the submitted work.

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Topic ID: 78,24,730,24,192,925