Neoadjuvant PD-1 blockade combined with chemotherapy is not superior to neoadjuvant chemotherapy alone in resectable locally advanced esophageal carcinoma

Globally, cancer remains a significant health issue for humanity, with esophageal cancer being the sixth leading cause of cancer-related deaths [1]. The 5-year overall survival rate of patients with esophageal cancer was between 12 and 20%, and esophageal cancer treatments faced enormous challenges [2, 3].

Neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) before surgery had a better prognosis than those who received surgery alone for patients with locally advanced esophageal cancer (LAEC) [4]. Based on a large number of clinical evidence [4‐8], nCT or nCRT has been recommended as standard treatment in patients with LAEC [9]. However, although the prognosis of patients was improved to some extent, patients still faced the risk of cancer recurrence [9]. A multicentre Phase III trial (NEOCRTEC5010) showed that the 5-year cumulative total recurrence rate of patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with nCRT was 32.2%, the local recurrence rate was 15.3%, and the distant recurrence rate was 24.3%, respectively [7, 9]. On the other hand, a meta-analysis demonstrated that nCRT had a higher 3-year survival benefit than nCT including local recurrence rate and distant metastasis rate; however, there was no increase in 5-year survival [10]. Radiotherapy was limited by patient compliance, and many patients refused or abandoned radiotherapy because of the intolerable adverse effects in China [11]. Therefore, developing a new treatment model was necessary to improve the prognosis of patients with LAEC.

Recently, neoadjuvant immunochemotherapy (nICT), such as camrelizumab, sintilimab, or tislelizumab combined with chemotherapy, has shown acceptable safety and high efficacy in patients with LAEC [12‐14]. In addition, Xu et al. demonstrated that nICT and nCRT had comparable R0 resection rates (90.9% vs. 89.0%, P=0.302) and pathological complete remission (pCR) rate (29.8% vs. 34.0%, P=0.167) in ESCC [15]. Of note, there was still no clear evidence of the prognostic difference between nCT and nICT. More clinical evidence was needed to support the feasibility of nICT.

Several studies have found that pathological tumor response (PTR), such as tumor regression grade (TRG) and downstaging, was a prognostic factor for patients with esophageal cancer who received neoadjuvant treatment [16‐19]. This study compared the differences in pCR rate, major pathological response (MPR) rate, TRG, downstaging, and event-free survival (EFS) between nICT and nCT groups to investigate whether neoadjuvant immunochemotherapy was superior to chemotherapy alone in patients with esophageal cancer.

In this retrospective study, patients with esophageal cancer who received nICT showed higher pCR and downstaging rates compared with the nCT arm; however, the differences were not statistically significant. Patients who achieved downgrading showed better MPR and pCR rates. Finally, the nICT group did not show significantly better EFS than the nCT group. This suggested that neoadjuvant immunochemotherapy was not superior to chemotherapy alone in esophageal cancer treated with neoadjuvant therapy.

Recently, immunotherapy has become a popular field for treating solid tumors, including esophageal cancer [20]. In multiple Phase II clinical studies, neoadjuvant immunochemotherapy demonstrated safety and efficacy in treating esophageal cancer [12, 14, 21]. And in Phase III clinical study by Sun et al., objective response rates (ORR) were significantly higher in the group treated with pembrolizumab combined with chemotherapy than in the group treated with chemotherapy alone (45.0% vs. 29.3%, P<0.001) [22]. At first sight, these observations seemed to be contradictory to our results. However, there were two reasons that can explain why the EFS of the nICT group was not significantly better than the nCT group. Firstly, EFS has been influenced by postoperative adjuvant therapy. Over time, the selection of appropriate postoperative adjuvant therapy may shorten the difference in tumor recurrence or progression time between nICT and nCT groups. It was worth mentioning that further studies were needed to determine whether patients with esophageal cancer needed further adjuvant therapy after surgery. Evidence showed that esophageal cancer patients with residual lymphatic invasion after surgery needed adjuvant therapy [23]. Secondly, some patients with esophageal cancer receiving neoadjuvant therapy may not be sensitive to immunotherapy. It was essential to look for biomarkers that predicted a high response to immunotherapy in patients with esophageal cancer. Unfortunately, this study did not include relevant predictive indicators, including PD-L1. Liu et al. confirmed that ESCC patients with up-regulation of ABCC3, CBR1, and TALDO1 were not sensitive to immunotherapy [24]. In contrast, ESCC patients with enriched immune-related functional pathways (such as NK cells and B cell activity) were sensitive to immunotherapy and had a better prognosis [24].

The prognosis of patients with esophageal cancer receiving neoadjuvant therapy was analyzed according to pathology. Pathological reactions have been used to predict the efficacy of neoadjuvant therapy [17]. Among patients receiving neoadjuvant therapy, those who achieved pCR or MPR had a better prognosis [25, 26]. At present, CT, positron emission tomography/computed tomography (PET-CT), and endoscopic ultrasound (EUS) cannot be adequate to accurately assess pCR in patients with esophageal cancer after neoadjuvant therapy [27]. To a certain extent, the combination of endoscopy and biopsy determined the pathological response of esophageal cancer patients receiving neoadjuvant treatment [28]. In this study, postoperative specimens were used for pathological reaction assessment, 17 patients (TRG 0 or TRG 1) achieved MPR and 7 (TRG 0) pCR. Subgroup analysis confirmed a significant correlation between TRG and pCR/MPR in either the nCT or nICT groups, suggesting that TRG was also a prognostic factor for neoadjuvant therapy. On the other hand, patients who achieved downgrading had higher MPR and pCR rates, and the difference was significant, suggesting that downgrading can also be used as a good prognostic indicator for esophageal cancer patients receiving neoadjuvant therapy and it's consistent with previous research [19].

Other methods have also been found to predict the prognosis of esophageal cancer patients treated with neoadjuvant therapy. It was worth mentioning that metabolic response was superior to histopathology in assessing the prognosis of patients receiving neoadjuvant therapy [29]. A study by Buck et al. proved that using the binary classifier trained on spatial tumor metabolite data for stratification of esophageal adenocarcinoma patients receiving neoadjuvant therapy had an accuracy of 89.7% was better than 70.5% using histopathology [29]. In addition, another study demonstrated that the quantitative response evaluation criteria in solid tumors with multiparametric MRI can assess the prognosis of ESCC patients receiving neoadjuvant therapy [30].

In the future, more clinical trials are needed to confirm our conclusions. ECOG conducted a phase II/III trial to evaluate the efficacy of nivolumab and ipilimumab in perioperative patients (n=278) with esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma [3]. The primary endpoints included pCR rates and EFS, which were expected to be completed in 2023 [3]. Yan et al. proposed a phase III clinical trial to further evaluate the role of toripalimab plus chemotherapy in the neoadjuvant setting for patients with resectable ESCC [31]. In addition, improving the efficacy of immunotherapy in patients with esophageal cancer was also the direction of future research. The animal experiment showed that the expression of PD-L1 increased from 45.16 to 77.42% in a dose-dependent manner in a mouse model of esophageal adenocarcinoma induced by chemoradiotherapy (P=0.001) [32]. Another study found that trastuzumab can increase tumor PD-L1 expression, and the combination of anti-PD-1 antibodies and trastuzumab can play a synergistic antitumor effect [33]. These suggested that immunotherapy combined with chemoradiotherapy or targeted therapy may bring a higher pathological response rate to patients with esophageal adenocarcinoma.

This study lacked an adequate sample size, and our findings were not statistically significant. The follow-up time was not long enough to see more considerable relapsed events between the nICT and the nCT groups. The retrospective study lacked analyses of markers that predicted the efficacy of neoadjuvant immunotherapy. This study was based on the Chinese population, and the results may not apply to populations in other countries.

Neoadjuvant PD-1 blockade combined with chemotherapy was not superior to chemotherapy alone for resectable locally advanced esophageal carcinoma patients. However, more studies with long-term follow-up were needed to confirm this result.