The role of neoadjuvant immunotherapy in nonsurgical candidates with locally advanced esophageal squamous cell carcinoma

The primary treatment for local staged squamous cell esophageal carcinoma incorporates neoadjuvant chemoradiation followed by surgical resection for those who are considered medically fit for surgery. Those who are not deemed fit for surgery are often treated with chemoradiotherapy alone. Current studies focus on survival and outcomes of patients treated with standard of care consisting of neoadjuvant chemoradiation followed by surgery, but there is less knowledge surrounding patients who undergo neoadjuvant chemoimmunotherapy followed by radiotherapy. As studies have started to show benefit for immunotherapy in the adjuvant and neoadjuvant setting in several disease types, it is an important time to dive deeper into whether these agents may provide benefit in the neoadjuvant and adjuvant setting in certain patient populations.

Kong’s paper “Radiotherapy for patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunotherapy combined with chemotherapy” is a retrospective analysis that aims to investigate this population of patients who do not undergo surgery and are treated with chemoimmunotherapy followed by radiotherapy for definitive treatment (1). The study analyzed T1-3N+M0 or T3-4aNanyM0 with ECOG PS 0–1 who were ineligible for surgery after receiving neoadjuvant chemoimmunotherapy (1). After receiving chemoimmunotherapy, these patients received radiotherapy with chemotherapy or radiotherapy alone. Initially all patients received PD-1 inhibitors in combination with chemotherapy every 3 weeks for 2–4 cycles. Notably, patients who received subsequent radiotherapy alone had a 2-year overall survival (OS) that was 37.8% less compared to those receiving chemoradiotherapy (1). These findings hint that certain populations of patients with esophageal cancer may be insensitive to chemotherapy, radiotherapy, or immunotherapy which is further due to the tumor microenvironment (1). This population of patients unfortunately are more difficult to treat and suffer from greater side effects when given combination therapy (1). Additionally, it is important to note that those who had a poor response to chemoimmunotherapy did not seem to have the same level of efficacy with radiotherapy as those who had a robust response to neoadjuvant chemoimmunotherapy (1). This further causes concern for insensitivity to radiotherapy as previously mentioned. This study highlights the need for more neoadjuvant chemoimmunotherapy studies to better understand the overall outcomes and progression-free survival (PFS) and OS that may be possible by incorporating in these novel therapies.

When looking at multiple other studies that have been performed for locally advanced esophageal squamous cell carcinoma, there are many that focus on response after standard of care in those medically fit for surgery. Wu conducted a study that assessed complete response rates, long term survival, and recurrence rates for patients treated with chemotherapy vs. chemoradiotherapy following surgery (2). This study overall favored chemotherapy for long term survival and reported that local recurrence was more common than distant metastases. The rate of recurrence was also found to be lower in the chemotherapy group (2). Another study by Liu assessed locally advanced esophageal squamous cell carcinoma and patients who did not receive surgical intervention due to refusal of surgery (3). These patients received chemoradiotherapy alone and had poorer outcomes as these patients had the chance of achieving complete remission with surgical intervention.

When focusing specifically on immunotherapy in the neoadjuvant setting, there have been several studies that analyze its use in local staged squamous cell esophageal carcinoma, but these studies need greater exploration. Cheng investigated several studies regarding unresectable locally advanced esophageal cancer. The TENERGY trial by ESMO offered atezolizumab maintenance therapy following chemoradiotherapy. The TENERGY trial was a phase II multicenter study that started in 2022 and studied atezolizumab following chemotherapy with 5-FU with cisplatin in locally advanced esophageal squamous cell carcinoma. With a median OS of 31 months, this trial showed promise, but the median PFS was only 3.2 months (4). The phase II trial, ImpactCRT looking into chemoimmunotherapy before chemoradiotherapy for unresectable disease which showed promise, but a larger trial would be needed to further support the results given this study only included 46 patients (4). This study focused on using induction chemotherapy with camrelizumab followed by concurrent chemoradiotherapy. There are still many ongoing trials involving immunotherapy for unresectable esophageal cancer.

There are also several studies that have focused on immunotherapy in the neoadjuvant setting when patients have resectable esophageal squamous cell carcinoma. These studies show promise for immunotherapy combined with chemoradiotherapy when approaching patients with resectable disease, but the pathological response needs to be weighed against the toxicities to better understand the use of these regimens (5). Some trials that study the role of neoadjuvant immunotherapy with chemoradiation includes PALACE-1. PALACE-1 looked at pembrolizumab preoperatively with carboplatin and paclitaxel with concurrent radiation. The pathological complete response was found to be ~56% for this study. Along the same lines, immunotherapy given concurrently with chemoradiation, before chemoradiotherapy, or after chemoradiotherapy has shown promise in patients with unresectable disease, but with the adverse effects noted in these trials need longer follow-up and larger trials (6). A clinical trial conducted in 2020 showed promise of treating locally advanced esophageal squamous cell carcinoma with karelizumab with concurrent chemoradiation. Patients received chemoimmunotherapy initially followed by maintenance therapy with immunotherapy after completion of radiation. At 1-year PFS rate was 80% and 1-year OS rate was 86.4% with the rate of at least grade 3 side effects being 35%. The most common adverse effect noted was radiation esophagitis. Similarly, a phase II trial for durvalumab and tremelimumab with chemoradiotherapy had common side effects of rash and thyroid abnormalities (6).

Locally advanced esophageal squamous cell carcinoma that is deemed unresectable has been studied for many years. Kong’s paper addresses an important role of immunotherapy in its treatment and the possibility of neoadjuvant chemoimmunotherapy followed by definitive radiation treatment as an appropriate option (1). Several clinical trials have taken place that study similar efficacy as Kong, but their limitations are related to toxicities and small population sizes. Kong’s study also acknowledges its limitations, including the small sample size resulting in low power to provide definitive data (1). Other limitations include this study being a single center study, along with lack of data regarding OS in these patients. It is also important to note the significant toxicities that were found in this study and the need to explore this further, along with OS, with clinical trials to further implement the findings (1). Overall, the study shows promise for chemoimmunotherapy followed by definitive radiation for unresectable esophageal squamous cell carcinoma.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Esophagus. The article has undergone external peer review.

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-45/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-45/coif). The 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. Kong Y, Su M, Fang J, et al. Radiotherapy for patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunotherapy combined with chemotherapy. Sci Rep 2024;14:16495. [PubMed]
2. Wu YY, Dai L, Yang YB, et al. Long-Term Survival and Recurrence Patterns in Locally Advanced Esophageal Squamous Cell Carcinoma Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy Followed by Surgery. Ann Surg Oncol 2024;31:5047-54. [PubMed]
3. Liu YW, Lee JY, Wang YK, et al. Comparison of therapeutic outcomes in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A prospective observational cohort study. J Formos Med Assoc 2024;123:106-15. [PubMed]
4. Cheng S, Li B, Yu J, et al. Update of latest data for combined therapy for esophageal cancer using radiotherapy and immunotherapy: A focus on efficacy, safety, and biomarkers. Chin J Cancer Res 2023;35:483-500. [PubMed]
5. Park D, Jeon WJ, Yang C, et al. Advancing Esophageal Cancer Treatment: Immunotherapy in Neoadjuvant and Adjuvant Settings. Cancers (Basel) 2024;16:318. [Crossref] [PubMed]
6. Wang FM, Mo P, Yan X, et al. Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy. World J Gastrointest Oncol 2024;16:1-7. [Crossref] [PubMed]