Prospects of immune checkpoint inhibitor in combination with chemotherapy or chemoradiation in esophago-gastric cancers

Recent trends in neoadjuvant immunotherapy for esophageal squamous cell carcinoma (ESCC)

Recent studies have highlighted the effectiveness and safety of neoadjuvant immunotherapy (preoperative immunotherapy) for patients with ESCC (1,2). Frequently combined with chemotherapy or chemoradiotherapy, this approach has shown potential in improving pathologic complete response (pCR) rates and survival outcomes (3,4).

The study in question was designed with pCR and survival as its primary endpoints. Given the significant differences observed in pCR rates, the findings have been presented as noteworthy results. The combination of immunotherapy with chemoradiotherapy has demonstrated approximately 48% pCR, a significant improvement compared to 29% with chemotherapy alone. Studies like JUPITER-06 and KEYNOTE-590 underscore the potential of immune checkpoint inhibitors (ICIs) to enhance survival outcomes and improve long-term prognosis for locally advanced ESCC (5,6). Moreover, the synergistic effects of ICIs with chemotherapy and radiotherapy, which expose tumor antigens, have been shown to strengthen tumor control and reduce recurrence (7-9).

Regarding this insight, another important study is ESCORT-NEO/NCCES01 trial (10). The results of the ESCORT-NEO/NCCES01 trial suggest that neoadjuvant chemotherapy combined with camrelizumab improves the pCR rate in resectable ESCC. However, several challenges remain. First, the improvement in pCR may not necessarily translate into extended overall survival (OS) or disease-free survival (DFS), and further research is needed to confirm the long-term effects. Additionally, the management of immune-related adverse events (irAEs) is crucial, as they may cause delays in surgery or lead to complications. Furthermore, the optimal timing and sequencing of immunotherapy, as well as the role of immunotherapy after surgery, require further evaluation in future studies.

The timing of surgery following an ICI-containing regimen, lymph node dissection strategies, and the duration of preoperative chemoimmunotherapy

The timing of surgery following an ICI-containing regimen is unlikely to differ significantly from that following non-ICI regimens from an oncological perspective. However, irAEs induced by ICIs can sometimes lead to uncontrollable complications, resulting in significant delays in transitioning to surgery, and in rare cases, making surgical intervention unfeasible, as reported in JCOG1804E.

Theoretically, given the anti-tumor effects, the optimal approach would be to inhibition tumor immune evasion at the earliest possible stage of treatment. However, considering the impact of irAEs, it is anticipated that future treatment strategies will need to take into account the potential effects of specific regimens on surgical feasibility. While ICIs will undoubtedly play a pivotal role in future cancer treatments, it is also conceivable that the fundamental approach to surgery itself may require reevaluation.

In the field of head and neck cancer, there have already been reports highlighting the drawbacks of excessive lymph node dissection performed beyond necessity, particularly in the context of optimizing the local immune environment following surgery (Nature Medicine). To reduce the risk of postoperative local recurrence, activating the anti-tumor function of lymphocytes in the surrounding tissue is considered a crucial strategic approach. However, the complete eradication of this immune environment with radical lymph node dissection is not theoretically ideal in the other aspect.

Discrepancy between pCR and prognosis

While pCR and major pathological response (MPR) are recognized as important indicators for predicting prognosis in thoracic ESCC, recent global randomized controlled trials (RCTs) involving ICIs in the neoadjuvant setting have shown that pCR does not always correlate with improvements in OS or DFS. This phenomenon has also been observed in gastroesophageal junction (GEJ) cancers, where higher pCR rates achieved with ICI-chemotherapy regimens have not necessarily translated into OS benefits. Although this study reports promising pCR results, the connection between these findings and long-term survival improvements warrants further observation.

Given that the mechanisms underlying responses to neoadjuvant therapy remain insufficiently understood, Qin et al. (2) conducted a systematic review and meta-analysis comparing neoadjuvant immunotherapy with conventional neoadjuvant therapy in patients with locally advanced esophageal cancer. Their findings suggest that neoadjuvant immunotherapy may offer improved pathological response rates and survival benefits. However, variability in patient responses and the potential impact of irAEs highlight the need for further investigation.

Building upon these insights, careful consideration must be given to the timing of surgery following ICI-containing regimens, as irAEs may lead to significant delays or, in rare cases, render surgical intervention unfeasible. Additionally, the role of lymph node dissection strategies and the preservation of the local immune environment postoperatively require further evaluation. These aspects emphasize the necessity of refining treatment approaches to optimize both oncological outcomes and surgical feasibility.

Several key clinical trials have provided valuable insights into the evolving treatment landscape. The CheckMate 577 trial demonstrated an improvement in DFS with nivolumab following chemoradiotherapy for esophageal and GEJ cancers. The JUPITER-06 trial presented initial findings on the use of toripalimab in neoadjuvant settings, while the KEYNOTE-590 trial analyzed the role of pembrolizumab in ESCC treatment. Furthermore, the PALACE-1 trial explored the relationship between pCR rates and prognosis in ESCC and GEJ cancers. These studies collectively contribute to a deeper understanding of the clinical benefits and limitations of neoadjuvant immunotherapy in esophageal cancer.

The role of pCR in survival outcomes for esophageal and GEJ cancers: a literature-based analysis

pCR defined as the absence of viable tumor cells in resected specimens following neoadjuvant therapy, is often heralded as a surrogate endpoint for survival in cancer treatment. However, its predictive value for OS and DFS in esophageal and GEJ cancers has been called into question. This article reviews the current evidence, citing key studies, to elucidate the complex relationship between pCR and survival outcomes (11,12).

Evidence supporting the link between pCR and survival

Meta-analysis of esophageal cancer trials

A large meta-analysis by Samson et al. evaluated survival outcomes in patients with pCR after neoadjuvant chemoradiotherapy (nCRT). The study included 24 trials and reported that patients achieving pCR had a significantly lower recurrence risk [hazard ratio (HR) =0.44; 95% confidence interval (CI): 0.38–0.51]. Additionally, pCR was associated with improved 5-year OS rates compared to non-pCR patients (55.9% vs. 38.2%). These findings suggest that pCR may serve as a positive prognostic marker but highlight variability in survival outcomes across studies (13).

Cross-trial comparisons [National Clinical Cancer Network (NCCN) clinical practice guidelines]

The NCCN guidelines highlight that pCR is often associated with reduced lymphovascular invasion and better local tumor control. While it generally corresponds to favorable outcomes, the extent of this correlation varies depending on tumor histology (adenocarcinoma vs. squamous cell carcinoma) and therapeutic regimen (14).

Contrasting evidence: pCR is not always predictive of long-term survival

Post-neoadjuvant studies in adenocarcinoma

Research by von Döbeln et al. showed that in GEJ adenocarcinoma patients, achieving pCR after nCRT did not correlate with a proportional survival benefit. Despite a higher pCR rate (24%) with intensified regimens, OS rates were not significantly different between pCR and non-pCR groups after R0 resection. These findings underline the importance of surgical outcomes and tumor biology in survival determinations (15).

JCOG9907 trial (Japan)

The JCOG9907 trial, focusing on ESCC, revealed a discrepancy between pCR rates and survival. Patients treated with nCRT had higher pCR rates compared to those receiving chemotherapy alone, but DFS and OS did not consistently align with pCR achievements. These results suggest that factors such as micrometastases and immune evasion mechanisms may influence survival, independent of local tumor eradication (16).

Role of emerging therapies in shaping the pCR-survival paradigm

Integration of immunotherapy

A trial by Kelly et al. demonstrated that the addition of ICIs to nCRT increased pCR rates in locally advanced ESCC patients (48% vs. 29% with nCRT alone). However, improved pCR did not translate into a statistically significant OS benefit, raising questions about pCR as a reliable endpoint for novel therapies. This underscores the need for complementary biomarkers, such as circulating tumor DNA (ctDNA), to predict long-term outcomes (8).

Neoadjuvant durvalumab (KEYNOTE-590 analysis)

The KEYNOTE-590 trial demonstrated that adding durvalumab (PD-L1 inhibitor) to nCRT improved pCR but failed to show significant OS gains in adenocarcinoma patients. These results reflect tumor heterogeneity and underscore the necessity of identifying molecular subgroups that derive maximal survival benefit (6).

Why pCR may fail to predict survival

Residual micrometastatic disease

Even in cases of pCR, undetectable micrometastases may lead to distant recurrence, particularly in patients with aggressive tumor biology or insufficient systemic control during neoadjuvant treatment (17).

Immune microenvironment influence

Studies suggest that nCRT may modulate the tumor immune microenvironment, enhancing immune suppression in some cases. While achieving pCR, the immunological shifts may paradoxically increase relapse risk (18).

Clinical implications and future directions

The inconsistent relationship between pCR and survival outcomes highlights the need for individualized treatment strategies. Key areas of focus include:

• Refining biomarkers: ongoing research into biomarkers like ctDNA and PD-L1 expression could improve patient stratification, ensuring therapies are tailored to those likely to benefit most.
• Combination strategies: exploring the synergy between immunotherapy, chemotherapy, and targeted agents holds promise for improving outcomes beyond pCR. Further trials such as PERFECT and PALACE-01 are expected to shed light on these combinations.
• Surgical optimization: quality of surgery, including lymphadenectomy extent and margin status, remains a crucial determinant of survival, independent of pCR achievement.

While pCR remains a valuable marker of treatment response, its role as a predictor of survival in esophageal and GEJ cancers is not absolute. Integrating molecular diagnostics, refining therapeutic combinations, and focusing on systemic disease control will be pivotal in bridging the gap between pCR and survival outcomes. Future trials are essential to solidify the prognostic relevance of pCR in the context of rapidly evolving treatment paradigms.

Treatment-related adverse events (TRAEs)

Attention must also be paid to treatment-related complications. While most TRAEs are manageable, the combination therapies increase the incidence of severe adverse events (grade 3–4), especially with radiotherapy, where risks of pneumonia and dermatitis rise. Additionally, long-term postoperative complications such as aspiration pneumonia may become more prominent, particularly when extensive lymphadenectomy, such as three-field dissection for upper thoracic ESCC, is performed.

Clinical trials targeting squamous cell carcinoma, including ICI-based neoadjuvant treatments like the PERFECT trial and PALACE1 trial (3,4), occasionally report severe complications like acute respiratory distress syndrome (ARDS) and interstitial pneumonia, though at low frequencies. Similar events have been noted in lung cancer studies, emphasizing the need for vigilance as preoperative chemoimmunotherapy becomes more widespread. Notably, ARDS has been identified as a severe complication in studies where definitive surgery was performed following preoperative chemoradiotherapy combined with ICIs. This highlights the critical need for appropriate management of patients receiving ICI-based therapies, as it will play a key role in future treatment strategies. Additionally, addressing and mitigating severe adverse events when they occur is essential for improving overall treatment outcomes.

Critical considerations

Certain aspects of the present study require closer scrutiny. First, the surgical approaches (Ivor Lewis versus McKeown) and their respective lymph node dissection strategies remain unclear. Given that most cases in this East Asian study likely involve squamous cell carcinoma, differences in postoperative complication rates between these surgical techniques must be examined. For upper thoracic ESCC, thorough lymphadenectomy around the bilateral recurrent laryngeal nerves and supraclavicular nodes is critical for achieving radical cure but increases risks of recurrent laryngeal nerve paralysis and related complications like aspiration pneumonia.

Future directions

The ICI used in this study has not yet gained widespread international usage but holds significant promise as it progresses towards global adoption. Further randomized trials are needed to determine the optimal dosage, timing, and combination strategies for ICI-based therapies. Additionally, biomarker research to predict immunotherapy response could play a crucial role in advancing personalized treatment approaches.

In conclusion, neoadjuvant immunotherapy presents a promising avenue for ESCC treatment. Particularly when combined with chemoradiotherapy, it yields favorable outcomes. However, to establish its broader clinical application, further validation through ongoing and future trials will be essential.

Acknowledgments

We greatly appreciate the members of the Division of Esophageal Surgery for their critical discussion of our manuscript. We thank the members of the Division of Esophageal Surgery, and Division of Gastric Surgery for reviewing and discussing the study.

Footnote

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

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2157/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2157/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/.

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