Neoadjuvant radiotherapy for esophageal cancer: is a higher dose better? (2023)

Neoadjuvant chemoradiotherapy (CTR) is currently a standard treatment for locally advanced esophageal cancer.1). The data demonstrating the effectiveness of neoadjuvant CRT over surgery alone is supported by several randomized trials, the largest of which was the CROSS trial, which showed that in patients with locally advanced esophageal cancer, treatment with 41.4 Gy in 23 fractions can be performed simultaneously Carboplatin/Taxol results in better overall survival (OS) compared to surgical treatment alone (2). The CALGB 9781 study randomized patients to neoadjuvant treatment with 50.4 Gy in 28 fractions with concomitant cisplatin and fluorouracil or surgery alone and demonstrated superior OS in the group of patients receiving neoadjuvant treatment, but this study was due to less Accumulation terminated prematurely (3). Other randomized trials have used neoadjuvant radiotherapy (RT) doses between 35 and 50 Gy along with chemotherapy with mixed results (4-6). Therefore, the optimal dose of neoadjuvant RT is controversial, and current NCCN guidelines recommend a radiation dose of 41.4 to 50.4 Gy.

Now that neoadjuvant CRT has become established as the standard of care for patients with locally advanced esophageal cancer, it is important to determine the optimal dose of neoadjuvant RT, as this can have a significant clinical impact on treatment outcome. Higher dose neoadjuvant RT has been shown to increase the turnaround of negative margin surgical resection and thereby prolong OS (2,6). However, increasing the dose should be done with caution, as higher doses of neoadjuvant RT have also been associated with poor healing of the gastroesophageal anastomosis and postoperative morbidity.7). Dose escalation studies for esophageal cancer in the neoadjuvant setting have not been performed. Studies comparing 64.8 Gy to 50.4 Gy as the definitive treatment for esophageal cancer have shown no benefit with increasing dose.8,9).

In this regard, Semenkovitchand another(10) performed a large retrospective study using a recent national dataset to provide more clarity on tumor response, perioperative mortality, and OS differences in patients with locally advanced esophageal cancer who received neoadjuvant RT followed by esophagectomy when they were stratified by neoadjuvant RT dose. Patient records were obtained from the National Cancer Database (NCDB) and inclusion criteria included patients with esophageal squamous cell carcinoma or adenocarcinoma diagnosed between 2004 and 2014 and treated with induction RT and esophagectomy. Patients were included if the start of induction therapy and surgery were less than 6 months apart and the radiation dose was 30 to 70 Gy. Patients were divided into three cohorts based on neoadjuvant RT dose: low-dose RT (lRT) patients received < 40 Gy, standard-dose RT (sRT) patients received 40 to 50.4 Gy, and high-dose RT ( sRT). 40 Gy. at 50.4 Gy high (hRT) > 50.4 Gy obtained. The primary endpoints evaluated were OS, 90-day postoperative mortality and pathologic complete response rate (pCR). Univariate and multivariate analyzes were performed to identify factors and outcomes related to the three radiation dose groups, and Kaplan-Meier curves were constructed to compare OS.

A total of 12,675 patients met the selection criteria and were enrolled in the study. Of these, 10.5% (n=1329) received lRT, 84.7% (10,738) received sRT and 4.8% (n=608) received hRT. Of the patients treated with photon-based treatment, 58% received intensity-modulated radiation therapy (IMRT) treatment, while 42% received 3D treatment. Neoadjuvant chemotherapy was administered to 98.3% of patients and concomitant chemotherapy to 85.3% of patients. In all patients, CRP rates increased with increasing neoadjuvant radiation dose, with 11.7%, 16.2%, and 21.0% (P<0.001) of patients achieving CRP at the doses of lRT, sRT, and hRT, respectively. Higher doses of neoadjuvant RT were also associated with a higher rate of downstage disease (52.0% in lRT, 56.4% in sRT, and 63.1% in hRT patients, P=0.001). Importantly, when comparing different cohorts receiving neoadjuvant RT dose, no significant differences in surgical margin status were observed. In the regression analysis, the use of IRT was associated with a lower probability of PCR compared to the standard dose [odds ratio (OR) 0.67; p<0.001], as well as a lower probability of pathologic downstaging (OR, 0.85, p=0.04) compared to using sRT, but no statistically significant differences were observed between CPA rate or pathologic downstaging in patients who were treated with sRT were compared to those who were treated with hRT. Comparisons of postoperative mortality showed that 90-day postoperative mortality was significantly increased in the hRT group (hRT 12.7%, sRT 7.9%, and lRT 7.9%; P<0.001) and in regression logistic hRT with an increase was associated at 90 days. postoperative mortality compared to sRT (OR, 1.59, 95% CI, 1.21-2.09). No differences in 90-day postoperative mortality were observed when comparing patients treated with ESRD with patients treated with RT. No difference in long-term OS was observed between the three radiation dose cohorts.

The investigators also performed subgroup analyzes between patients treated with a neoadjuvant RT dose of 45 Gy and those treated with 50.4 Gy, and between patients with squamous cell carcinoma or adenocarcinoma histology. Patients treated with a neoadjuvant RT dose of 50.4 Gy had higher CRP rates than patients treated with 45 Gy (17.3%against15.0%, p=0.003), although no differences in OS or 90-day postoperative mortality were observed between the two dose groups. In patients with esophageal squamous cell carcinoma, higher rates of CRP were observed with increasing doses of neoadjuvant RT: 18.1% for lRT, 26.3% for sRT, and 33.9% for hRT, P=0.003. Importantly, patients in the hRT groups (19.4% in the hRT cohort, 9.9% in the sRT cohort, and 11.8% in the hRT cohort) had poorer 90-day postoperative mortality from lRT, P=0.0003) was observed. In addition, an improved median OS was observed in patients treated with neoadjuvant sRT (42.6against34.8 months for hRT and 30.7 months for lRT, P=0.03). In the adenocarcinoma histology cohort, higher PCR rates were again observed with increasing neoadjuvant RT dose (10.0% for lRT, 14.0% for sRT, and 16.8% for hRT, P<0.001), although when compared No statistically significant differences were found in median OS or 90-day postoperative mortality between different neoadjuvant RT dose groups.

The researchers concluded that while hRT may lead to higher rates of CRP, it was also associated with increased 90-day postoperative mortality and no median OS benefit. Therefore, the authors suggested that a neoadjuvant RT dose between 40 and 50.4 Gy could maximize tumor response without increasing perioperative morbidity and that this should be the standard neoadjuvant RT dose.

This study had several strengths that make its findings generalizable to the general US population: First, because this study used the NCDB as its database, it was able to use and support cancer statistics from approximately 70% of the US population their conclusions on a large number of patients. Second, the authors were meticulous in stratifying patients by neoadjuvant RT dose. The three dose cohorts were appropriately selected, allowing the investigators to observe statistically significant differences in CPA rates and postoperative morbidity. Finally, the authors used postoperative mortality as an indicator of morbidity during surgery, allowing for treatment-emergent toxicity associated with increasing the neoadjuvant RT dose. A concern with using higher doses of neoadjuvant RT is increased toxicity to the patient during irradiation, as well as increased perioperative morbidity. The NCDB does not contain information on patient morbidity during irradiation or in the immediate postoperative period per se, but does contain information on 30- and 90-day postoperative mortality. This is a reasonable predictor of surgical morbidity, and investigators were able to demonstrate worse 90-day postoperative mortality in the hRT cohort, suggesting that this RT dosage may cause excess toxicity.

This study also had some weaknesses that may limit the generalizability of its results. First, the authors only used neoadjuvant RT as entry criteria, not neoadjuvant CRT. The standard neoadjuvant treatment based on the CROSS study is neoadjuvant CRT (2), as this is the treatment group that has superior OS compared to surgery alone. While it is true that approximately 90% of patients in each dose group received chemotherapy, there were significant differences in patients receiving multi-drug chemotherapy. The differences in the CRP rate in the different dose cohorts might not have been observed if the authors had restricted the analysis to patients receiving cRT. In addition, there were significant differences in the distance from radiation to surgery in the various dose cohorts. For example, 43.6% of patients receiving high-dose RT underwent surgery > 105 days post-radiation, whereas only 24.1% of patients receiving standard-dose RT underwent surgery > 105 days post-radiation. It is possible that the longer interval between surgery and RT in the high-dose RT arm resulted in a higher rate of CRP in these patients. Finally, as this was a retrospective review, an intention-to-treat analysis could not be performed and the rationale for the specific dose selected could not be explained.

El estudio de Semenkovichand another(10) is a good attempt to further explore the dose-response effect observed when comparing different doses of neoadjuvant RT. As expected, higher doses of neoadjuvant RT were associated with higher PCR rates. Interestingly, the hRT dose cohort was also found to have the worst 90-day postoperative mortality, suggesting that this dose range may result in unacceptable levels of perioperative morbidity. Unfortunately, the study neither controlled for chemotherapy use nor attempted to standardize the time from radiation to surgery, which could have skewed the results. Notwithstanding, the conclusion that neoadjuvant RT doses of 40 to 50.4 Gy are optimal for use in the neoadjuvant setting to maximize benefits of RT and minimize harm is reasonable based on the data presented here. Further investigation is needed to determine whether this is also true in the context of concomitant chemotherapy and whether a dose of 40-41.4 Gy is sufficient or whether an increase to 50.4 Gy is required to achieve the beneficial effects of neoadjuvant therapy achieve.

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Ethical statement:The authors are responsible for all aspects of the work and for ensuring that questions about the accuracy or completeness of any part of the work are properly investigated and resolved.

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