Journal and News Scan

This expert opinion editorial is published in JTCVS in response to the article by Chang and colleagues. Meyers and colleagues begin by emphasizing that a large randomized controlled trial (RCT) would be the best way to answer the question of whether SABR or lobectomy is superior treatment for patients with early stage NSCLC. This editorial highlights the limitations of analyzing and publishing data from failed trials and demonstrates how this contributes little to the ongoing debate. First, neither the STARS trial nor the ROSEL trial achieved 4% of the target sample size which leads to inaccurate results especially since the outcome of interest, death, occurred in an exceedingly small number of patients. Second, this cohort of patients differs significantly from the full cohort, had accrual been successful; early planned analyses in RCTs (when accrual is low) are conservative to prevent false positive results (Type I error). Third, the mortality rate in the surgical arm is 2-4 times the expected mortality for patients with stage I NSCLC undergoing resection. Fourth, the low accrual limits the external validity of these data. Fifth, the fact that there was one treatment-related death in the surgical arm, none in the SABR arm, and no difference with regard to recurrence does not seem to add up to the original article's claim that there is a statistically significant difference in survival favoring SABR. Sixth, the degree of surgical risk for these patients was unclear and it is difficult to account for variation in surgical treatment at different centers. Seventh, in Figure 2, A (overall survival) the hazard ratio is 0.14 in favor of SABR with a confidence interval that includes 1.0 (insignificant), but the p-value listed is 0.037 (significant). Lastly, the authors point out that equipoise existed prior to these RCTs and is still very much present as this controversy continues.

This is a letter in response to the article by Chang and colleagues. The authors focus on two key points: the difference in 3-year survival between the two treatment groups and the proposed use of endobronchial ultrasound (EBUS) in combination with SABR to decrease the likelihood of false-negative results from imaging for clinical staging of lymph nodes. First, the original article found a 3-year survival rate of 79% in the surgical arm and 95% in the SABR arm. They point out that this survival difference is driven by the small sample size of the STARS trial in which all 20 patients in the SABR arm survived and 5 of 16 patients in the surgical arm died. Furthermore,  although basic baseline characteristics were similar, differences in comorbidities between the two groups were not accounted for. Second, they disagree with using EBUS in the hopes of reducing the false-negative results associated with staging by PET/CT. A recent study demonstrated that the sensitivity of EBUS is 35% in patients with NSCLC who have negative CT and PET/CT. They conclude by disagreeing that surgery can be replaced by SABR and EBUS as staging would likely be inaccurate and for those who are understaged, adjuvant therapy would not be offered thereby worsening prognosis.

This is a letter in response to the article by Chang and colleagues. The authors begin by stating that the data from this study should be graded according to an internationally accepted system, GRADE. In terms of overall mortality, the study should be downgraded by two points to low quality, because the two trials had different results and the pooled estimate is inaccurate. Moreover, given the small sample size, it is likely that the two groups differed with regards to risk of mortality, perhaps with higher risk patients randomised to the surgical arm as evidenced by the unacceptably high mortality rate in that group. They also point out that only 27% of patients in the SABR arm of the ROSEL trial had biopsy proven NSCLC. In addition, Figure 2, A (overall survival) has a hazard ratio of 0.14 in favor of SABR, but the 95% CI (0.017-1.190) is discrepant with the p-value of 0.037. Lastly, the original article concluded that the two treatments were equally effective although the two trials were not designed as equivalence trials. The authors state that no conclusions can be drawn from the data of these trials. 

This is the authors' reply to the letters submitted to The Lancet Oncology. They begin by stating that the strength of their analysis was that patients were randomised, thereby avoiding selection bias. With regards to low accrual, one major factor was failure of thoracic surgeons to participate. In addition, stage I NSCLC is relatively uncommon. They state that the median follow-up was long enough to discover recurrences and that there were enough patients to accurately analyze the data from a statistical standpoint. For patients in the ROSEL trial who did not undergo biopsy, clinical staging via PET scan has been shown to have a low false positive rate in the Netherlands. When considering VATS versus thoracotomy, cancer outcomes are not improved by VATS, readmission for complications of VATS is similar to thoracotomy, and nodal upstaging for clinical stage I NSCLC is more common after thoracotomy, although extent of lymph node dissection does not affect outcomes. Therefore the possible superiority of VATS may not lead to a clinically significant improvement in the surgical treatment of these patients. With regards to comorbidities, all patients underwent cardiopulmonary testing to determine their surgical candidacy. Zhang and colleagues had disagreed with the use of SABR and EBUS for concern that lymph node involvement would be understaged and those patients would miss out on adjuvant therapy. The original article showed no difference in regional recurrence between the two groups. Opitz and colleagues graded the original article, but Chang and colleagues replied that the randomised design of the two trials translates to a higher level of evidence than prior studies. Chang clarifies that the 30-day surgical mortality was 0%, but the 90-day mortality was 3.7% which is less than recent published literature. The authors respond to Dearman and colleagues' suggestion regarding NHS England and CtE by stating that there is already a considerable amount of data comparing SABR versus surgery. The authors finish by stating that they continue to support their conclusion that SABR is a non-invasive standard treatment alternative to surgery for patients unable to undergo surgery and should also be considered a viable treatment option for patients who are surgical candidates.