A step forward to the era of immunotherapy in resectable esophageal cancer: 2021 NCC/CATS/CSTCVS/STM expert consensus on perioperative immunotherapy for esophageal cancer

Esophageal cancer is prevalent in the Asian population and is notorious for being highly lethal in both locally advanced and metastatic settings. With the advancement in multimodal perioperative therapy, the overall survival (OS) after esophagectomy has been improved remarkably. Neoadjuvant chemoradiation is practiced worldwide as a standard of care that increases pathologic complete response (pCR) rate and improves OS (1). Nevertheless, the disease recurrence rate is still substantial. Immune checkpoint inhibitors (ICIs) have shown promising efficacy in the adjuvant and palliative settings in several landmark phase III randomized controlled studies including the CheckMate 577 study (2), the KEYNOTE-590 study (3), the CheckMate 649 study (4), the ATTRACTION-4 study (5), and the recently published CheckMate 648 study (6). It is therefore potentially very advantageous to boost the chance of cure for esophageal cancer by adding ICIs in the perioperative settings.

This editorial highlights the recent Consensus jointly developed by the National Cancer Center (NCC), Chinese Association of Thoracic Surgeons (CATS), Chinese Society for Thoracic and Cardiovascular Surgery (CSTCVS), and Esophageal Disease Panelists of Society for Translational Medicine (STM) (7). In the absence of robust phase III data, a recent cross-sectional survey, as quoted in the introduction of the Consensus, has already reported an astonishing rate (82.6%) of perioperative immunotherapy combined with chemoradiation or chemotherapy being implemented in the 69 major centers for esophageal cancer in China. It is understood that most of the implementations are within clinical trial settings, but the proliferating trend implicates an unmet need to make the current Consensus timely and highly anticipated. The group is to be congratulated for the effort in bringing together a panel of world-renowned experts in esophageal cancer and arrived at recommendations with the modified Delphi method and GRADE approach (8,9).

The Consensus contains 11 recommendations which are based on variable qualities of evidence and levels of consensus among the experts. Recommendation 1 states that preoperative immunotherapy should be limited to the framework of clinical trials because of insufficient evidence (quality of evidence: medium; consensus level: 100%). This is a modest, yet practical, recommendation to avoid too liberal use of immunotherapy preoperatively in the real world. Although studies like the PALACE1 (10) and the PERFECT study (11) have shown an early signal of feasibility, further larger scale prospective studies are warranted for not only the efficacy/safety data but the mechanistic rationale of the optimal regimen. Tables 1,2 summarize the ongoing global and China studies, respectively. Recommendation 4 suggests that when neoadjuvant immunotherapy is being considered, 2–4 cycles of immunotherapy with chemotherapy or chemoradiation are recommended (quality of evidence: low; consensus level: 91.9%). However, for whom and when neoadjuvant immunotherapy should be considered remains ambiguous with this recommendation. Regarding the question for “whom”, it is assumed that those with bulky tumor or significant nodal burden are potential candidates but whether adding immunotherapy could lead to significant downstaging or not, in the specified time window, is still uncertain. Concerning “when”, vast data on immunotherapy in gastroesophageal cancer suggests that the median time to response is around 6–10 weeks and late-responders are also seen (3-6). So, the jury is still out for the optimal number of cycles and the picture is even more complicated if postoperative immunotherapy is to be added.

As expected, the highest quality of evidence and level of consensus is that surgery remains the standard of care regardless of the modality that patients are treated preoperatively. According to recommendations 7 and 8, esophagectomy performed in either open or minimally invasive method with 2- or 3-field lymph node dissection (depending on the tumor site and supraclavicular lymph node involvement) should be the first-line approach in all esophageal cancer patients after neoadjuvant immunotherapy (quality of evidence: high; consensus level: 97.3%). Following preoperative immunotherapy, the transthoracic and transabdominal surgical approaches are recommended for patients with Siewert type I and III esophagogastric junction tumors respectively. and for Siewert type II cancer it should be decided by thoracic or gastrointestinal surgeons (quality of evidence: high; consensus level: 94.6%). Notably, most experts in the panel believe that preoperative immunotherapy would not significantly add to surgical morbidity and mortality. Perhaps this should be heeded with caution, especially in the setting of immunotherapy combination with chemoradiation. Lee and associates reported a single-arm phase II study that added pembrolizumab concurrent with preoperative chemoradiation (12). While the pCR rate reached 46.1%, there were two postoperative deaths primarily attributed to acute lung injury. Without further safety data from well-designed prospective studies, acute lung injury as a potential sequela of concurrent radiotherapy and immunotherapy should always be assumed until proven otherwise. This is particularly true in Asia where thoracic esophageal squamous cell carcinoma is predominant and the radiotherapy field encompasses a substantial volume of lung parenchyma.

A predictive biomarker is a holy grail for immunotherapy to guide proper patient selection and maximize therapeutic ratio. Recommendation 3 suggests that programmed cell death-ligand 1 (PD-L1) expression, as measured by combined positivity score (CPS) may be helpful in decision making (quality of evidence: low; consensus level: 75.7%). Microsatellite instability resulting from mutations causing DNA mismatch-repair protein deficiency is a strong predictor of immunotherapy benefit but it is only relevant in less than 1% of patients with esophageal cancer. Alternative biomarkers such as tumor mutational burden (TMB), neurotrophic tyrosine receptor kinase (NTRK), and infiltrating immune cells still require clinical validation. Innovation is all that is required here. The PERFECT-trial suggests that it is promising to explore the IFN-γ signature (11). The AuspiCiOus study from Netherland [NCT05177133] quantifies RNA level and infiltrating immune cells in biopsies, blood, and faeces to determine IFN-γ expression before and during treatment. Moreover, the changes in RNA expression and phenotype of peripheral blood mononuclear cells (PBMCs), expression level of ADAM12 in tumor tissue, the concentration of circulating tumor (ct) DNA in blood, and cytokine/chemokine profile in blood before and during treatment are obtained. This hopefully will provide a very comprehensive panel of markers, including the fecal microbiome, for response prediction and disease monitoring in the future.

If there is anything that the Consensus could be improved, it could stratify for adenocarcinoma and squamous cell carcinoma individually as their tumor biology and response to immunotherapy are different. It is anticipated that a reasonable bulk of evidence specific to squamous cell carcinoma will be available in the coming 2–4 years and most of these will be coming from China (Table 2). Studies in China but not yet recruiting also include “Neoadjuvant Immunotherapy to ESCC, a phase 2 randomized control trial comparing Sintilimab Injection plus Paclitaxel and Cisplatin and Paclitaxel plus Cisplatin combined chemotherapy” [NCT04625543] and is expected to be completed in 2023. “Neoadjuvant immunotherapy Combined With Chemoradiotherapy Versus Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (cT1b-3N1-2M0, cT3-4aN0M0): A Multi-center Prospective Randomized Clinical Trial also on Tislelizumab” [NCT04973306] is expected to be completed in 2027. Their results will be valuable in supplementing previous trials such as NICE and KEEP-G 03 (13,14).

In summary, the Consensus is both timely and practical at this point of time when the treatment algorithm for resectable esophageal cancer is rapidly evolving. In light of limited evidence available, especially in the area of neoadjuvant immunotherapy, the Consensus should not be regarded as the definitive answer but instead as a proper framework to steer the academic community in the right direction for good clinical practice and trial design towards the era of immunotherapy in resectable esophageal cancer !

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-22-4/coif). LKO receives the speaker honorarium from Amgen, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Roche, Sanofi-Aventis, Taiho, sits on the Advisory Board of Amgen, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Roche, Sanofi-Aventis, Taiho and Data Safety Monitoring Board of LintonPharm, and is a site PI for studies Checkmate 577, Checkmate 648 and Checkmate 649, mentioned in the manuscript, at Queen Mary Hospital, Hong Kong. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
2. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
3. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759-71. [Crossref] [PubMed]
4. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40. [Crossref] [PubMed]
5. Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2022;23:234-47. [Crossref] [PubMed]
6. Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
7. Kang X, Qin J, Zhang R, et al. 2021 NCC/ CATS/CSTCVS/STM expert consensus on perioperative immunotherapy for esophageal cancer. Ann Esophagus 2021;4:33. [Crossref]
8. Dalkey NC, Helmer-Hirschberg O. An experimental application of the Delphi method to the use of experts. Santa Monica, CA: RAND Corporation, 1962. Available online: https://www.rand.org/pubs/research_memoranda/RM727z1.html.
9. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6. [Crossref] [PubMed]
10. Li C, Zhao S, Zheng Y, et al. Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J Cancer 2021;144:232-41. [Crossref] [PubMed]
11. van den Ende T, de Clercq NC, van Berge Henegouwen MI, et al. Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase II feasibility trial (PERFECT). Clin Cancer Res 2021;27:3351-9. [Crossref] [PubMed]
12. Lee S, Ahn BC, Park SY, et al. A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC). Ann Oncol 2019;30:v747-v55. [Crossref]
13. Liu J, Li Z, Fu X, et al. A prospective phase II clinical trial exploring neoadjuvant immunotherapy combined with chemotherapy in resectable thoracic esophageal squamous cell cancer (TESCC) with multi-station lymph node metastases (NICE study): Preliminary results. Ann Oncol 2020;31:S1292. [Crossref]
14. Gu Y, Chen X, Wang D, et al. A study of neoadjuvant sintilimab combined with triplet chemotherapy of lipo- paclitaxel, cisplatin, and S-1 for resectable esophageal squamous cell carcinoma (ESCC). Ann Oncol 2020;31:S1307-8. [Crossref]