Induction immunotherapy plus chemotherapy followed by definitive chemoradiation therapy in locally advanced esophageal squamous cell carcinoma: a propensity-score matched study

Esophageal cancer (EC) ranks as the sixth leading cause of cancer-related death worldwide, resulting in approximately 5.4 million deaths annually [1, 2]. Substantial variations exist in the incidence, mortality, and histopathology of esophageal cancer across different geographic regions [3, 4]. China exhibits a high prevalence of EC with over 50% of new cases reported globally each year; more than 90% of these cases are attributed to squamous cell carcinoma [5, 6].

Surgery is the preferred treatment modality for patients with locally advanced EC [7]; however, at the time of diagnosis, approximately 50–60% of EC patients are ineligible for radical resection [8]. Concurrent chemoradiotherapy (CCRT) currently serves as the standard therapeutic approach for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) [9‐12]. Despite advancements in treating this population, a considerable number of patients eventually experience local recurrence or distant metastases, leading to a disappointing prognosis [4, 13‐15]. Previous studies have attempted to optimize CCRT regimens in order to enhance patient survival; nevertheless, altering chemotherapy agents or increasing radiotherapy dosage have not yielded significant improvements in survival rates [11, 15, 16]. The efficacy of induction chemotherapy in improving survival outcomes for patients with unresectable locally advanced ESCC remains controversial based on existing research findings [17‐20]. Therefore, it is imperative to identify a novel and effective regimen for managing unresectable locally advanced ESCC.

In recent years, the clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of various malignant tumors, including EC [21‐25]. Multiple randomized clinical trials have consistently demonstrated that anti-programmed cell death-1 (PD-1) inhibitors, as first- or second-line agents, substantially enhance overall survival in patients with advanced EC [21‐28]. The combination of anti-PD-1 immunotherapy and chemotherapy has emerged as the new standard first-line treatment for advanced EC [21, 22, 25, 29, 30]. Furthermore, several clinical studies have reported favorable outcomes in terms of effectiveness and safety when neoadjuvant immunotherapy plus chemotherapy for operable locally advanced ESCC in the short term [31‐36]. However, there is currently a lack of reports on the efficacy of immunotherapy plus chemotherapy in patients with unresectable locally advanced ESCC.

The combination of immunotherapy and chemoradiotherapy has emerged as a novel strategy for the treatment of EC, potentially exhibiting synergistic action and enhanced efficacy [37]. Although preliminary data from small-scale studies have demonstrated promising efficacy and reliable safety of immunotherapy combined with concurrent radiotherapy/chemoradiotherapy in unresectable locally advanced ESCC [38‐42], there is still a lack of results from prospective phase III clinical studies to confirm the effectiveness of these combination treatments, leaving the optimal strategies unclear. At present, most of the clinical research on combination therapy in unresectable locally advanced ESCC focuses on concurrent administration of immunotherapy with CCRT or/and maintenance therapy after CCRT. However, no studies have reported on the use of induction immunotherapy plus chemotherapy prior to CCRT for this patient population. In this retrospective study, we aimed to evaluate the efficacy and safety profile of induction immunotherapy plus chemotherapy followed by definitive chemoradiotherapy in patients with unresectable locally advanced ESCC.

To the best of our knowledge, this study represents the first investigation comparing the efficacy and safety of induction immunotherapy in combination with chemotherapy followed by concurrent chemoradiotherapy for managing unresectable locally advanced ESCC. Our findings demonstrate a significant improvement in OS among patients who received induction immunotherapy plus chemotherapy compared to those who underwent definitive concurrent chemoradiotherapy alone, with 1-year OS rates of 86.7 and 81.7%, and 2-year OS rates of 76.0 and 50.7%, respectively. This retrospective analysis provides novel evidence supporting the potential adoption of an alternative treatment paradigm involving induction immunotherapy plus chemotherapy followed by concurrent chemoradiotherapy for patients with unresectable locally advanced ESCC.

In the pre-immunotherapy era, the efficacy of induction chemotherapy in improving survival outcomes for patients with unresectable locally advanced ESCC was a subject of controversy based on existing research findings [17‐20]. A randomized phase II trial demonstrated no significant improvement in response rate or survival when induction chemotherapy was added to CCRT in unselected ESCC patients [20]. One possible reason for the failure of this study could be attributed to the limited effectiveness of the induction chemotherapy regimen. Interestingly, post-hoc analysis revealed that responders to induction chemotherapy had significantly better survival compared to nonresponders among EC patients treated with CCRT. In the current era of immunotherapy, combination therapy with immunotherapy and chemotherapy has shown ORR as high as 70% in advanced ESCC cases [21, 22, 25, 29, 30]. Furthermore, neoadjuvant immunotherapy plus chemotherapy in operable ESCC cases resulted in a pooled pathological complete response (pCR) rate of 32.4% and major pathological response (MPR) rate of 49.4% [43]. Our findings demonstrated that induction immunotherapy plus chemotherapy achieved CR or PR in a remarkable proportion of patients within the induction IC group (81.97%), highlighting its substantial role within the comprehensive treatment plan. This is likely one key factor contributing to the significant survival benefit observed in our study.

Furthermore, tumors exhibited shrinkage following induction immunotherapy plus chemotherapy, thereby rendering them more susceptible to radiation therapy due to an enhanced tumor microenvironment characterized by reduced hypoxia and promoted normalization of tumor blood vessels, along with increased infiltration of T cells into the tumor tissues [44]. Consequently, the sequential application of immunotherapy plus chemotherapy has resulted in improved sensitivity toward radiotherapy. This represents a second potential explanation for the observed efficacy of concurrent chemoradiotherapy following prior administration of immunotherapy plus chemotherapy in our current study.

The combination of immunotherapy with CCRT holds significant potential for future applications in the management of unresectable locally advanced ESCC. Various modalities exist for combining immunotherapy with radiotherapy to treat esophageal cancer, including pre-radiotherapy immunotherapy, concurrent radiotherapy immunotherapy, post-radiotherapy immunotherapy, or different combinations thereof. Radiotherapy plays a crucial role in releasing tumor antigens and modulating immune pathways favorably, thereby enhancing tumor antigen presentation, priming of tumor-specific cytotoxic T cells, as well as improving T cell homing, engraftment and function within tumors, which may improve the response of the tumor to immunotherapy [45]. Consequently, current clinical research on combination therapy in unresectable locally advanced ESCC predominantly focuses on CCRT combined with concomitant or/and adjuvant immunotherapy [38‐42].

Several studies have suggested that the combination of CCRT with concomitant or/and adjuvant immunotherapy extended the survival benefit for patients with unresectable locally advanced ESCC. Park et al.'s investigation demonstrated impressive 2-year OS rates of 75% among individuals with locally advanced ESCC when durvalumab and tremelimumab were combined with definitive chemoradiotherapy [38]. Similarly, another phase Ib clinical trial evaluating camrelizumab combined with concurrent chemoradiotherapy reported high 1-year and 2-year OS rates of patients up to 85.0 and 69.6%, respectively [39]. On the other hand, Zhu et al.’s results revealed that more than 60% of patients achieved clinical CR rates when treated with toripalimab combined with concurrent chemoradiotherapy; the corresponding 1-year OS rate was 78.4%, while 1-year PFS was 54.5% [42]. Although preliminary data from these small-scale studies have shown promising efficacy and safety profiles of CCRT in combination with concomitant or/and adjuvant immunotherapy in unresectable locally advanced ESCC [38‐42, 46], there is still a lack of results from prospective phase III clinical trials (such as ESCORT-CRT, KEYNOTE-975, KUNLUN, RATIONALE-311, KYSCRAPER-07) [47‐50] to confirm the effectiveness of these combination treatments, leaving the optimal strategies unclear. Notably, our retrospective study's 2-year OS rate was comparable or even superior to those observed in these previous small-scale prospective studies; this further emphasizes the need for additional clinical trials investigating the efficacy of induction immunotherapy plus chemotherapy followed by CCRT.

There were some differences observed in treatment-related adverse events between the two groups in this study. Notably, patients in the induction IC group exhibited a lower incidence of adverse events such as leukopenia, neutropenia, nausea, and vomiting. This favorable outcome could potentially be attributed to the utilization of long-acting recombinant human granulocyte colony-stimulating factor and novel anti-emetic drugs like neurokinin-1 (NK-1) receptor antagonists that have emerged in recent years. Conversely, patients in the induction IC group experienced a higher incidence of hepatic dysfunction; however, most cases were classified as grade 1–2 and showed improvement with liver protective agents. No significant disparities were observed regarding radiation pneumonitis between the two groups, suggesting that induction immunotherapy plus chemotherapy may not exacerbate radiation-induced lung inflammation. Overall, the treatment approach involving sequential concurrent chemoradiotherapy following induction immunotherapy plus chemotherapy demonstrates acceptability.

As a retrospective, single-center study, our investigation was limited by a small sample size and selection bias; therefore, further prospective, randomized controlled clinical trials are warranted to elucidate the efficacy of this treatment model. Moreover, the follow-up duration in our study remained relatively short, with median PFS and OS not yet reached in the induction IC group. Consequently, an extended follow-up period is necessary to ascertain the long-term effectiveness of this combination therapy approach. Additionally, due to immunotherapy being a novel anti-tumor treatment modality introduced later on, there exists a notable disparity in treatment timing between the two patient groups included in our study. Notably, patients in the induction IC group initiated treatment slightly later than those receiving CCRT. The potential impact of this factor on patient prognosis remains unclear; hence, more prospective randomized controlled studies are imperative. Furthermore, as a retrospective study, there were differences in the immune checkpoint inhibitors and chemotherapy drugs selected by patients in treatment, which may also affect the efficacy, and more prospective studies are needed to clarify the impact of different drugs on efficacy.

In this retrospective study, we first have demonstrated the efficacy and safety of induction immunotherapy plus chemotherapy followed by concurrent chemoradiotherapy for the management of unresectable locally advanced ESCC. These findings highlight the potential of this novel treatment approach, emphasizing the need for further investigation through prospective clinical trials.