Christopher Anker, MD
Christopher Anker, MD, a radiation oncologist at The University of Vermont Medical Center and Associate Professor at the Larner College of Medicine at the University of Vermont, Burlington, told The ASCO Post that although the benefit to overall survival disappeared with time likely due to a power issue, the research published by Dr. Yakoub and colleagues is the first meta-analysis to show an overall survival improvement at any time point with the addition of radiotherapy. Only network meta-analyses have had the power to find this recently, with one noting a 97.5% probability based on Bayesian analysis of neoadjuvant chemoradiation as the best treatment with regard to overall survival compared to other treatments including neoadjuvant chemotherapy, with the caveat of comparatively increased risks for postoperative mortality1 similar to Dr. Yakoub’s findings. Nevertheless, said Dr. Anker, these two abstracts do not advance the current understanding of what might be the optimal neoadjuvant regimen, as they lack the ability to address important nuances of the data.
“Quite simply, we need new prospective randomized controlled trial data to guide us,” said Dr. Anker. “Conducting further meta-analyses and National Cancer Database analyses is not going to move the needle much, as they are really only hypothesis-generating.”
Key Endpoints and Radiation Dose
According to Dr. Anker, the only two endpoints that “really matter” are overall survival and quality of life, and all other endpoints are surrogates for these outcomes, although pathologic complete response for gastroesophageal cancer has been found to be associated with neither.2 Therefore, although this pathologic finding alone does not justify the use of radiation, said Dr. Anker, both of these studies likely involved older radiation techniques and, at least for the NCDB analysis, higher-than-necessary radiation doses, possibly adding to the morbidity that can be avoided with modern radiotherapy plans. The NCDB analysis included a significant portion of patients with proximal gastric cancer and adds support to the current preferred regimen for this anatomic subsite of perioperative chemotherapy without radiation. Solid quality-of-life data are needed from ongoing randomized controlled trials, he added, as perioperative chemotherapy comes with plenty of toxicity, and many patients do not receive planned adjuvant treatment.
In addition, concurrent chemoradiation plans using a lower radiation dose of 41.4 Gy might actually be better tolerated than perioperative chemotherapy, suggested Dr. Anker. Results from a National Cancer Database study showed that, compared to 50 to 50.4 Gy, a lower dose of radiotherapy (41.4 Gy) was “associated with increased rates of esophagectomy without negatively impacting overall survival, R0 resection, or complete pathologic response.”3 Although it is an National Cancer Database study, he continued, it supports the already strong rationale for using 41.4 Gy in the neoadjuvant setting established by the CROSS randomized controlled trial.4
As providers await data from several ongoing prospective randomized trials to determine the optimal neoadjuvant regimen, the best published outcomes for esophageal cancer come from the CROSS group, said Dr. Anker. So, that is what is preferred by many in the United States. Although appropriately not included in the meta-analysis by Dr. Yakoub, network meta-analyses include nondirect as well as direct treatment comparisons, and the CROSS study was the main driver for chemoradiation having superior overall survival compared to all other neoadjuvant regimens.1
“We need to keep doing prospective, randomized trials to help us better match the right treatment to the right patient. Thus, we can limit the use of radiotherapy (and/or adjuvant chemotherapy if perioperative chemotherapy is planned) to those who truly will benefit,” Dr. Anker concluded.
DISCLOSURE: Dr. Anker reported no conflicts of interest.
1. Chan KKW, Saluja R, Delos Santos K, et al: Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis. Int J Cancer 143:430-437, 2018.
2. Petrelli F, Tomasello G, Barni S: Surrogate end-points for overall survival in 22 neoadjuvant trials of gastro-oesophageal cancers. Eur J Cancer 76:8-16, 2017.
3. Ising MS, Marino K, Trivedi JR, et al: Influence of neoadjuvant radiation dose on patients undergoing esophagectomy and survival in locally advanced esophageal cancer. J Gastrointest Surg Off J Soc Surg Aliment Tract 23:670-678, 2019.
4. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al: Neoadjuvant chemoradiotherapy plus surgery vs surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial. Lancet Oncol 16:1090-1098, 2015.
Improved local-regional tumor control may not be enough to justify the increased morbidity of adding neoadjuvant radiation to chemotherapy in esophageal and gastroesophageal junction cancers, according to a pair of studies presented during the 2020 Society of Surgical Oncology (SSO) International...