The incidence of esophageal carcinoma in the Western world has increased more than 600% since the 1970s, mainly due to the rising incidence of adenocarcinoma.¹ Therapeutic improvements in both early and locally advanced esophageal adenocarcinoma have been in part based on an understanding that gastroesophageal reflux (GER) is a precursor to esophageal cancer leading to a sequence of epithelial changes from metaplasia to progressive dysplasia, ultimately culminating in adenocarcinoma. This understanding coupled with technological advancements in endoscopic and radiographic imaging, have enhanced the surveillance and staging accuracy of esophageal cancer allowing us to both identify patients at an early stage more often, and to select patients with potentially curable disease more reliably.

Although resection of the esophagus was the mainstay of esophageal cancer treatment in the past, we have learned that even very radical resections combined with other forms of local or regional therapy are not adequate to cure advanced disease in the majority of cases. Distant recurrence continues to be the main cause of death in patients with esophageal cancer.

The late 19th and early 20th centuries were marked by Billroth’s² and Halstead’s³ pioneering developments in the surgical treatment of gastric and breast cancer, respectively. The first successful esophagectomy was performed by Franz Torek in Germany on March 14, 1913, under chloroform and ether anesthesia.⁴ In situ reconstruction was not performed and enteral continuity was achieved via extracorporeal esophago-gastrostomy utilizing a plastic tube. The patient survived for 12 years, ultimately dying not of cancer but from pneumonia. This landmark event translated into the recognition of the potential for cure of localized esophageal cancers utilizing surgical extirpation. With improvements in perioperative care, surgery became a supplement to radiation as the treatment of choice for localized esophageal cancer in the early 20th century. Over time, more extensive en bloc esophageal resections and lymphadenectomy became favored with the hope that radical resection of disease would result in a cure more frequently. This was similar to Halsted’s approach to radical mastectomy for breast cancer at a time when many patients were dying of poorly controlled local-regional disease. However, we have learned that while this approach may lead to better locoregional control, it fails to achieve cure in a cohort of patients who are ultimately destined to succumb to systemic disease.

Increased understanding of cancer biology led to the development of nonsurgical treatment strategies for solid organ malignancies combining radiation therapy for local effect and chemotherapy for systemic effect. Intuitively, this strategy addresses both local disease and “sterilizes” potential micrometastases. The demonstrated efficacy of this treatment paradigm has stimulated interest in combining surgery, radiation therapy, and chemotherapy to maximize the treatment effect, and this combination has become the focus of several clinical trials investigating the role and timing of each method.

Neoadjuvant therapy is based on the principles of increased patient tolerance and compliance with therapy compared to administration after surgical resection. Importantly, the response to neoadjuvant therapy can be directly observed via imaging and pathologically assessed after resection. In contrast, advocates of adjuvant (postsurgical) therapy promote its administration only to patients with indications based on final pathologic analysis, thus sparing patients unnecessary toxic effects of treatment in addition to avoiding toxic effects that may impact resection.

Initially, radiation was considered the primary treatment modality for esophageal cancer. Early experiences with radium bougies and later use of external beam radiation demonstrated esophageal tumor regression with rare complete tumor responses. With the evolution of surgical care, radiation became a part of a multidisciplinary approach to esophageal cancer therapy with the goal of sterilizing areas within or around the operative field.⁵

Neoadjuvant Radiation Therapy and Surgery

Initial randomized trials of neoadjuvant radiation therapy for esophageal cancer focused on administering radiation doses of 20 to 40 Gy prior to resection in an attempt to decrease local recurrence and improve survival rates (Table 90-1). With one exception, all of these trials included patients with squamous cell carcinoma (SCC) only, and none of the trials demonstrated significant benefits of adding radiation therapy to resection.^6–9 A meta-analysis of 1147 patients by Arnott et al (1998)¹⁰ reiterated that neoadjuvant radiation alone does not improve survival in resectable esophageal cancer. However, grouping of patients with different tumor histologies and locations for the analysis may have confounded the results. Also, the studied radiation doses (20 to 40 Gy) may have been biologically inadequate to achieve a tumor-killing effect.

Surgery and Adjuvant Radiation Therapy

The vexing problem of locoregional recurrence following resection alone combined with the toxicity of radiation therapy in the neoadjuvant setting led to the consideration of adjuvant radiation therapy for esophageal cancer. The rationale for this approach was the ability to deliver a high dose (40 to 60 Gy) of radiation postoperatively without worsening perioperative complications. Postoperative radiation therapy (PORT) was first tried in the 1960s, but not until the 1980s did some prospective trials demonstrate that PORT could achieve better local control and perhaps improve survival compared to surgery alone. As shown in Table 90-2, PORT for esophageal cancer appeared to be potentially beneficial in several trials.^11–14 However, most of the data in those trials are conflicting and subject to selection bias. Notably, these trials did not examine new radiation techniques such as intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton therapy, which have become more widely available than they were at the time of these studies.

The cause of death from esophageal cancer is mainly attributed to metastatic disease. Intuitively, administering systemic chemotherapy even in seemingly localized disease state “destroys” potential micrometastatic deposits. Moreover, chemotherapy at times down-stages marginally resectable tumors resulting in improved complete (R0) resection rates and decreased incidence of locoregional recurrence.¹⁵ Chemotherapy also acts synergistically with radiation, further strengthening arguments for its use. Importantly, when chemotherapy is administered preoperatively, the biologic response can be evaluated and quantified pathologically. The magnitude of this response can then serve as an indicator for outcomes potentially influencing further treatment. Current chemotherapeutic regimens are based on platinum compounds (cisplatin and carboplatin) in combination with 5-fluorouracil (5-FU) or taxanes as a doublet.¹⁶ This approach has had encouraging results in early phase II trials, in some instances producing clinical responses in up to 50% of patients, with occasional complete pathologic responses.

Neoadjuvant Chemotherapy and Surgery

In several prospective randomized trials, researchers compared chemotherapy followed by surgery with surgery alone for both esophageal adenocarcinoma and SCC (Table 90-3).^17–25 The landmark trial of neoadjuvant chemotherapy for esophageal cancer was performed by Roth et al (1988);¹⁷ the trial compared cisplatin-based chemotherapy followed by esophagectomy with esophagectomy alone in patients with mid to distal esophageal SCC. The major contribution of this small study was the observation of significantly longer median survival durations in patients with major (47%) or complete (5%) responses to chemotherapy than in nonresponders (20 months vs. 6 months; p = 0.008). This study demonstrated the biological heterogeneity of esophageal cancers and their varied susceptibility to chemotherapy and paved the way for current translational efforts in personalized cancer therapy.

One of the largest randomized trials of preoperative and postoperative chemotherapy versus surgery alone in esophageal cancer patients was the North American Intergroup Trial (INT 0113) (Kelsen et al, 1998).²¹ This trial failed to demonstrate significantly better survival with chemotherapy plus surgery than with surgery alone in either adenocarcinoma or SCC patients. The caveats of the trial included outdated staging and response evaluation based on use of barium swallows alone and low compliance in completion of both the preoperative (66%) and postoperative (38%) chemotherapy regimens. Interestingly, the R0 resection rate was similar in the two groups (~60%), as was the 3-year survival rate (23% for chemotherapy plus surgery vs. 26% for surgery alone; p = 0.74). Importantly, those patients who achieved an R0 resection had a statistically significant and a marked improvement in overall survival compared to those patients having an R1, R2, or no resection. The notable locoregional recurrence rate of 30% in this trial was an impetus for adding radiation therapy to the regimen in future trials and performing more radical surgery.

In contrast to Kelsen trial, a phase III Medical Research Council (MRC) trial in the United Kingdom (2002) of chemotherapy plus surgery versus surgery alone in locally advanced esophageal cancer demonstrated a benefit for chemotherapy.²³ The largest trial of its kind, it included 802 patients randomized to receive chemotherapy plus esophagectomy versus esophagectomy alone. Cisplatin and 5-FU were the chemotherapeutic agents administered in a regimen of two cycles given 3 weeks apart, with an 86% compliance rate. At a median follow-up duration of 37 months, the 2-year survival rate was better in the neoadjuvant chemotherapy group than in the surgery-alone group (43% vs. 34%; p = 0.004). Likewise, the R0 resection rate was higher with than without chemotherapy (60% vs. 54%; p <0.001). The survival benefit of chemotherapy persisted even at the updated median follow-up duration of 6 years with 5-year survival rates of 23% with chemotherapy plus surgery and 17% with surgery alone (p = 0.03). This benefit was observed in both adenocarcinoma and SCC patients.²⁴

Another commonly referenced trial that demonstrated a survival advantage of neoadjuvant chemotherapy and surgery over surgery alone was the MRC Adjuvant Gastric Infusion Chemotherapy (MAGIC) trial by Cunningham et al (2006).²⁵ In this randomized trial, one arm consisted of patients who received treatment with cisplatin, 5-FU, and epirubicin in three cycles before and after surgery, whereas the other consisted of patients who underwent surgery alone. Patients in the chemotherapy plus surgery arm had better overall (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60 to 0.93; p = 0.009) and progression-free (HR, 0.66; 95% CI, 0.53 to 0.80; p <0.001) survival than did those in the surgery-alone arm. The majority of the enrolled patients had gastric carcinoma, with only a subgroup having esophageal or gastroesophageal junction tumors. The long-term follow-up of MRC and MAGIC trials indicate that the addition of chemotherapy to esophagectomy for resectable esophageal cancer is beneficial. However, completeness of resection in these trials is also clinically relevant. Considering that R0 resection is a significant predictor of survival in the majority of patients with solid organ malignancies, the question arises whether chemotherapy combined with radical en bloc surgery or chemoradiotherapy and surgery would achieve better R0 resection rates.

Surgery and Adjuvant Chemotherapy

Despite significant improvements in imaging modalities (e.g., positron emission tomography/computed tomography, endoscopic ultrasound), accurate clinical staging of esophageal cancer continues to be a formidable challenge, resulting in the potential for understaging or overstaging in a large number of patients.²⁶ Pathologic assessment of surgical specimens and “adequate” numbers of lymph nodes is the ultimate method of determining the disease stage.²⁷ Advocates of adjuvant chemotherapy favor its use only for patients who have pathologic stage characteristics associated with a high recurrence rate (e.g., tumor length and depth, nodal positivity, lymphovascular invasion, poor tumor differentiation), potentially sparing other patients from toxic effects (Table 90-4).