High-dose 70 Gy once-daily thoracic radiotherapy did not significantly improve OS compared with the current standard of 45 Gy twice-daily radiotherapy in patients with limited-stage SCLC, according to results of the CALGB 30610 (Alliance)/RTOG 0538 trial.
“Outcomes in the 70 Gy cohort do provide the best evidence available in support of high-dose once-daily thoracic radiotherapy for limited SCLC but the study was not designed to asses whether 70 Gy high-dose daily radiotherapy was non-inferior to 45 Gy BID,” said Jeffrey A. Bogart, MD, of SUNY Upstate Medical University, who presented the results at the 2021 ASCO Annual Meeting (Abstract 8505).
This trial showed that after a median follow-up of 4 years, once-daily 70 Gy compared with twice-daily 45 Gy did not significantly improve OS (hazard ratio [HR]=0.94; 95% CI, 0.75-1.17; P = 0.591). The median OS for the 70 Gy once-daily arm was 30.5 months compared with 28.5 months for 45 Gy twice-daily arm.
Study discussant Ramesh Rengan, MD, PhD, of University of Washington School of Medicine, pointed out that the Intergroup 0096 trial published in 1999 established twice-daily radiotherapy with concurrent chemotherapy and subsequent prophylactic cranial radiation as the standard for limited-stage SCLC.
“Why do we re-examine these standards? Because they are imperfect,” Dr. Rengan said. “Twice daily radiotherapy with concurrent chemotherapy is associated with significant morbidity and cost to our patients, as well as substantial time and resource commitment from the patient and the radiotherapy clinic.”
Dr. Rengan also pointed out the higher rate of grade-3 or higher esophagitis seen in the twice-daily arm of the INT 0096 trial and scientific concerns that the once-daily arm employed too low of a dose (a total of 45 Gy).
CALGB 30610/RTOG 0538 opened in 2008 and closed in 2019, accruing 638 patients. The phase-III trial had three arms originally, randomly assigning patients 1:1:1 to 45 Gy twice daily over 3 weeks, 70 Gy once daily over 7 weeks, or 61.2 Gy concomitant boost over 5 weeks. After an interim toxicity analysis eliminated the 61.2 Gy arm (dropped in March 2012), patients were randomly assigned 1:1 to the two remaining arms.
The median age of patients was 63 and the majority were Caucasian (86%) and female (52%).
The median 2-year and 5-year OS for the once-daily arm were 58% and 29%, respectively. For the twice-daily arm these rates were 56% and 34%, respectively.
Administration of once-daily radiotherapy also did not result in a significant difference in progression-free survival (PFS). Median PFS was 13.5 months for twice-daily arm compared with 14.2 months for once-daily arm (HR=0.98; 95% CI, 0.8-1.2; P = 0.857).
Overall toxicity rates were similar in both arms although Dr. Bogart noted that more in-depth analysis is pending. There were similar rate of grade-3 or worse dehydration, febrile neutropenia, esophageal pain, and dysphagia. Severe pulmonary toxicity and reported pneumonitis were low in both arms.
In the twice-daily arm there were 4 total deaths, 2 of which were thought to be possibly, probably, or definitely related to treatment. In the high-dose, once-daily arm there were 11 total deaths and 5 possibly, probably, or definitely related to treatment.
Dr. Rengan pointed out that the rate of grade-3 or higher esophagitis of 16.7% was substantially lower than what was reported in the original INT 0096 trial.
“This may be due to using more limited involved field approaches, or advances in treatment delivery techniques employed in this trial compared with the original INT 0096 study,” Dr. Rengan said.
He also emphasized that the CALGB 30610/RTOG 0538 trial was designed to test superiority not non-inferiority or equivalence.
Putting Results in Context
Dr. Rengan said when evaluating these data, it is important to consider when the standard is not actually the standard.
“I would argue it is when Level 1 evidence does not impact practice patterns,” he said.
He pointed to research showing that from 1999-2012 the rate of utilization of twice-daily radiotherapy for limited-stage SCLC was surprisingly low at 11.3%, a rate that is essentially unchanged from the utilization rate before the report of INT 0096 (10% in 1998).
“This suggests that these current standards simply do not have traction with oncologic providers,” Dr. Rengan said, adding that this means the standard needs to evolve.
Ideally, Dr. Rengan said, once-daily radiotherapy would be tested for non-inferiority against the current standard in a pragmatic, prospective, randomized trial.
“That is indeed a challenging endeavor,” he said. “The CALGB trial had multiple protocol modifications and required 11 years to complete accrual.”
Until then, Dr. Rengan said, twice-daily radiotherapy should continue to be considered the standard of care, when feasible, for limited-stage SCLC.
Bogart JA, et al. Phase 3 comparison of high-dose once-daily (QD) thoracic radiotherapy (TRT) with standard twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC): CALGB 30610 (Alliance)/RTOG 0538. Abstract 8505. Presented at: 2021 ASCO Annual Meeting.