Immune Therapy in Esophageal Cancer: A Rationale and Current Status

Special Article - Esophageal Cancer

Gastrointest Cancer Res Ther. 2016; 1(2): 1011.

Immune Therapy in Esophageal Cancer: A Rationale and Current Status

Giuroiu I and Leichman L*

Perlmutter Cancer Center, New York University School of Medicine, New York, USA

*Corresponding author: Lawrence Leichman, MD, Perlmutter Cancer Center, 160E. 34th St, Room 8-941, New York, NY10016, USA

Received: October 25, 2016; Accepted: November 17, 2016; Published: November 21, 2016


Esophageal adenocarcinoma; Esophageal squamous cell carcinoma; Immune checkpoint inhibition


Esophageal cancer carries a poor prognosis within the United States and worldwide, with adenocarcinoma (EA) prevailing in the U.S. and the West as it is etiologically tied to rising obesity rates, associated acid reflux, and Barrett esophagus. However, the number afflicted with squamous cell carcinoma (ESCC) throughout the world is far greater than adenocarcinoma. ESCC is most prevalent in the Far East, including Japan and China, as well as in South Africa, Turkey, and Iran as it is etiologically tied to tobacco use, diets low in fresh fruit and vegetables, chemical preservatives in food, and exposure to the human papillomavirus (HPV) [1]. Surgical resection remains the gold standard of treatment for early tumors, but the addition of chemotherapy and radiation therapy has proven necessary for the control and enhanced survival of those presenting with locally advanced disease. While systemic cytotoxic chemotherapy is the chief option for the palliation of metastatic disease, immune checkpoint inhibitor therapy has emerged as a promising new therapeutic option as it has for several other malignancies. The theoretical basis for testing immune checkpoint inhibitor therapy for those with esophageal cancer rests with the tumor’s association with mutagenic toxins and its increased mutational burden. Herein we review current results and ongoing studies seeking improved outcomes in patients with esophageal cancer treated with immune therapy.

Esophageal Cancer

Esophageal cancer represents one percent of all new cancer diagnoses in the United States but carries a dismal average survival rate of less than 20 percent at 5 years [2]. An estimated 16,980 cases were diagnosed in the U.S. in 2015, with an estimated 15,590 patients expected to die from this disease [2]. Worldwide, approximately 455,800 cases are diagnosed each year, with 400,200 deaths per year representing the 6th most common cause of cancer death [3]. In spite of advances in combining chemotherapy, radiation therapy, and surgery, the 5-year overall survival rate ranges from 4.2% for those presenting with distant metastases at diagnosis to 40.4% for those presenting with locally advanced cancer at diagnosis [4].

Histologically, esophageal cancer can be divided into adenocarcinoma (EA) and squamous cell carcinoma (ESCC). These differ in etiology, precursor lesions, molecular properties, and epidemiology. While the incidence of EA has surpassed that of ESCC in the U.S., ESCCs represent 80 percent of esophageal cancer cases worldwide [5]. Inspite of these statistics, clinical trials and the treatment guidelines they helped establish have not distinguished between patients with the two different histologies. Specifically, clinical trials based in the U.S. largely reflect the performance of patients with EA, leaving ESCC an understudied disease [1].

Current Standard of Care for Esophageal Cancer

Multiple randomized controlled trials and meta-analyses have demonstrated survival benefit for patients with EA and ESCC treated with neoadjuvant chemoradiation [6]. The current standard of care for both EA and ESCC was established after publication in 2012 of the chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), in which patients with both histologies were treated with weekly carboplatin AUC 2 and paclitaxel 50 mg/m2 administered concurrently with 41.4 Gy external-beam radiation prior to surgery versus surgery alone [7]. At initial publication, after a median follow-up of 45.4 months, the median overall survival (OS) was 49.4 months in the chemoradiotherapy-surgery group versus 24 months in the group undergoing surgery alone (P=0.003); notably, patients with ESCC had not yet reached a median OS [7]. Subsequently, at a median follow-up of 84 months, patients treated with neoadjuvant chemoradiotherapy followed by surgery still showed significant benefit in median progression-free survival (PFS) and OS as compared to those undergoing surgery alone [8]. Furthermore, among the patients treated neoadjuvantly, those with ESCC experienced near doubling of PFS and OS [8]. It is worth noting, however, that in spite of these significant gains, only 41% of the patients originally enrolled in the chemoradiotherapy plus surgery group were still alive at this median follow-up period of 7 years [8].

Even before the establishment of neoadjuvant chemoradiotherapy and surgery as the new standard of care for patients with esophageal cancer, studies explored the benefit of surgery in patients who achieved a complete pathologic response to neoadjuvant chemo radiotherapy. RTOG 85-01, a randomized trial comparing chemoradiotherapy to radiotherapy alone, without subsequent surgery, showed a 21% 5-year OS in patients with ESCC and a 27% 5-year combined OS for EAs and ESCCs [9,10]. The degree of pathologic response to neoadjuvant chemoradiotherapy was then shown to correlate with survival [11]. Subsequently, two randomized trials compared definitive chemoradiation to chemoradiation followed by surgery in patients with ESCC [12,13].

Neither trial showed an overall survival advantage for the addition of surgery to chemoradiation, although surgery was associated with a lower rate of local progression at 2 years [12]. Ultimately, these studies support the currently accepted practice of treating ESCC patients with definitive chemoradiation and foregoing surgery for patients who demonstrate a clinical complete response (cCR) by endoscopic clearance and 18F-fluorodeoxyglucose (FDG)-PET scan resolution of all FDG-avid areas.

Taken together, the above data underscore the need for novel local and systemic treatment modalities to improve upon the progress achieved with current chemoradiation for those with locally advanced esophageal cancer. The overarching goal, as with most neoadjuvant therapy, is to achieve a complete clinical response that can be translated into a complete pathologic response with attendant improved survival.

Immune Checkpoint Blockade and PD-L1 Expression in Esophageal Cancer

By evolving from a series of mutations arising in healthy cells, often as a result of extrinsic toxic insults, some cancers can be characterized as being “foreign” to their hosts. More specifically, they escape immune editing, a process by which tumors find a way to overcome their host’s natural immune defenses [14-16]. Most of these tumors have been shown to carry a relatively high mutational burden, thus presenting a larger variety of novel antigens to the immune system [15]. The classic example of a tumor with a high mutational burden that has demonstrated the property of overcoming immune editing is melanoma. Cancers that do not appear “foreign” to their host use immune editing to bypass the host’s immune defenses, and tumor growth proceeds largely unimpeded as a result of immune tolerance toward cancer cells [16].

The immune system’s attack against foreign antigens is highly regulated by stimulatory and inhibitory mechanisms that evolved to prevent overly destructive immune responses to pathogen invasion. Cancer cells exploit immune checkpoints to avoid recognition [17,18]. To date, two inhibitory receptors, programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), have been successfully employed in the clinic for therapeutic inhibition that releases the breaks on immune attack against tumor cells. PD-1 and CTLA-4 are expressed on tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment, while PD-L1 and PD-L2 are expressed on the surface of tumor cells [19-21]. Monoclonal antibodies against PD-1(nivolumab and pembrolizumab) and its ligand, PD-L1 (atezolizumab), as well as against CTLA-4 (ipilimumab) are currently selectively approved in the treatment of melanoma, small cell and non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, Hodgkin lymphoma, and head and neck squamous cell carcinoma. These tumors generally feature high numbers of somatic mutations and neoantigens, which may be recognized as “foreign” to their host (Figure 1). In general, these are the tumors that have been associated with better clinical outcomes following PD-1 blockade [15,22]. Therefore, we can hypothesize that esophageal cancer and ESCC in particular, ranking high among mutation-bearing tumors, would also present promising targets for immune checkpoint inhibitors [15,23].

Citation: Giuroiu I and Leichman L. Immune Therapy in Esophageal Cancer: A Rationale and Current Status. Gastrointest Cancer Res Ther. 2016; 1(2): 1011.