Esophageal cancer is estimated to be the eighth most common cause of cancer death among men in the United States and the fifth most common cause of cancer death worldwide (75). In 2015, the estimated numbers of new cases and deaths from esophageal cancer in the United States are 16,980 and 15,590, respectively (2). Esophageal cancer is three to four times more common in men than in women (76), with a mean age of 67 years (77). Lifetime risk of developing esophageal cancer is 1 in 125 for men and 1 in 435 for women (76). For classification purposes (AJCC staging version 7), primary tumors of the GEJ and proximal gastric cancer extending 5 cm into the stomach are included with esophageal cancers. The incidence of GEJ cancer has continued to increase over the last several decades. In recent years, this trend reached a new plateau, coinciding with the increased incidence of distal esophageal adenocarcinoma since the mid-1990s, a phenomenon confined to North America and other non-Asian countries. Overall, the prognosis of patients with esophageal/GEJ cancer remains poor. Histologic type makes a difference, because squamous cell cancer has a poorer prognosis than adenocarcinoma. Surgery is still the only chance for cure, and survival can be improved with multimodality therapy.
Although squamous cell cancer is the most common histologic type in many parts of the world, it is relatively uncommon outside of Asian and middle-Eastern countries. Squamous cell cancer is 20 times more common in China than in the United States (78). Esophageal cancer has a poor survival rate; only 17.5% of patients in the United States (3) and 10% of patients in Europe (79) survive at 5 years.
Etiologic Characteristics and Risk Factors
The most significant risk factors associated with almost 90% of esophageal squamous cell cancers are tobacco use, alcohol use, and a diet low in fruits and vegetables (9,80). Smoking and alcohol can synergistically increase the risk of esophageal squamous cell cancer. Dietary associations with esophageal squamous cell cancer, such as foods containing N-nitroso compounds, have long been implicated (81). Betel nut chewing, widespread in certain regions of Asia (82), and the ingestion of hot foods and beverages (such as tea) (83) in other endemic regions, such as Iran, Russia, and South Africa, have been associated with esophageal squamous cell cancer. Long-standing achalasia increases the risk of squamous cell cancer by 16 times (84). On average, squamous cell cancer develops 41 years after ingestion of lye. Tylosis, a rare disease associated with hyperkeratosis of the palms of the hands and soles of the feet, is associated with a high rate of esophageal squamous cell cancer (85).
Unlike squamous cell cancer, the risk factors for esophageal adenocarcinoma remain elusive. The strongest and most consistent risk factors include gastroesophageal reflux disease (GERD), smoking, obesity (86), and dietary exposure to nitrosamines; these are found in almost 80% of cases in the United States (87). According to a Denmark study, more than 50% of esophageal adenocarcinoma cases were found to have no history of symptomatic reflux disease (88). However, a large study conducted in Sweden demonstrated an association between reflux symptoms and esophageal adenocarcinoma (odds ratio, 7.7) and adenocarcinoma of gastric cardia (odds ratio, 2.0) (89). A high-fat, low-protein, high-calorie diet can also increase the risk. Some data have suggested that interactions between risk factors may be more important than individual risk factors. A study was performed on 305 esophageal adenocarcinoma patients and 339 age- and sex-matched controls; the strongest individual risk factor identified was reflux (90).
Barrett esophagus (BE) is generally believed to be a consequence of severe and chronic GERD. The presence of BE is associated with an increased risk of esophageal adenocarcinoma. The median age of BE diagnosis is 40 to 55 years, and it is most common in men (91).
The presenting symptoms of esophageal cancer usually include dysphagia, weight loss, bleeding, throat pain, and hoarseness. Early symptoms are usually nonspecific, and the patient may present with subtle symptoms, for example, food “sticking” transiently and reflux/regurgitation of food or saliva. This may precede frank dysphagia, which by all accounts is the most common complaint and becomes apparent when the esophageal lumen is narrowed to one-third of its normal diameter. For proximal esophageal tumors, increasing cough may be a sign of tracheoesophageal fistula. Chronic GI blood loss resulting from esophageal cancer may result in iron deficiency anemia.
Esophageal cancer includes adenocarcinoma, squamous cell cancer, mucoepidermoid carcinoma, small cell cancer, sarcoma, adenoid cystic carcinoma, and primary lymphoma. Adenocarcinoma is now more prevalent than squamous cell cancer in non-Asian countries and mostly develops in the distal esophagus (92). In general, squamous cell cancer is found in the upper half of the esophagus, whereas adenocarcinoma predominates closer to the GEJ. This chapter will focus on carcinomas of the esophagus/GEJ, whereas other chapters in this book will be dedicated to other types of malignancy of the esophagus/GEJ.
Esophageal cancer is a treatable disease but is rarely curable. Since the mid-1990s, the histologic type and location of cancer of the upper GI tract have changed. The incidences of proximal gastric, GEJ, and distal esophageal adenocarcinomas have steadily increased up until the last several years, where it now appears to have reached a steady state. The most current version of the AJCC TNM staging (version 7, Table 20-6) now includes primary tumors of the GEJ or proximal gastric cancer extending 5 cm into the stomach as part of esophageal cancer staging (26).
Table 20-6American Joint Cancer Committee TNM Staging System for Gastroesophageal Junction and Esophageal Cancers ||Download (.pdf) Table 20-6 American Joint Cancer Committee TNM Staging System for Gastroesophageal Junction and Esophageal Cancers
|Primary Tumor (T) |
|TX ||Primary tumor cannot be assessed |
|T0 ||No evidence of primary tumor |
|Tis ||High-grade dysplasia |
|T1 ||Tumor invades lamina propria, muscularis mucosae, or submucosa |
|T1a ||Tumor invades lamina propria or muscularis mucosae |
|T1b ||Tumor invades submucosa |
|T2 ||Tumor invades muscularis propria |
|T3 ||Tumor invades adventitia |
|T4 ||Tumor invades adjacent structures |
|T4a ||Resectable tumor invading pleura, pericardium, or diaphragm |
|T4b ||Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc. |
|Regional Lymph Nodes (N) |
|Nx ||Regional nodes cannot be assessed |
|N0 ||No regional nodal metastasis |
|N1 ||Metastasis in 1-2 regional lymph nodes |
|N2 ||Metastasis in 3-6 regional lymph nodes |
|N3 ||Metastasis in ≥7 regional lymph nodes |
|Distant Metastases (M) |
|M0 ||No distant metastases |
|M1 ||Distant metastases |
|Grade (G) |
|GX ||Grade cannot be assessed—stage grouping as G1 |
|G1 ||Well differentiated |
|G2 ||Moderately differentiated |
|G3 ||Poorly differentiated |
|G4 ||Undifferentiated—stage group as G3 squamous |
|Upper ||15 to <20 cm |
|Middle ||25 to <30 cm |
|Lower ||30-45 cm |
|Squamous Cell Cancer Stage Grouping |
|Stage ||T ||N ||M ||Grade ||Tumor Location ||5-Year Survival Rates (%) |
|0 ||Tis ||N0 ||M0 ||1, X ||Any ||>80 |
|IA ||T1 ||N0 ||M0 ||1, X ||Any ||>80 |
|IB ||T1 ||N0 ||M0 ||2-3 ||Any ||60 |
| ||T2-3 ||N0 ||M0 ||1, X ||Lower, X || |
|IIA ||T2-3 ||N0 ||M0 ||1, X ||Upper, middle ||53 |
| ||T2-3 ||N0 ||M0 ||2-3 ||Lower, X || |
|IIB ||T1-2 ||N1 ||M0 ||Any ||Any ||40 |
| ||T2-3 ||N0 ||M0 ||2-3 ||Upper, middle || |
|IIIA ||T1-2 ||N2 ||M0 ||Any ||Any ||25 |
| ||T3 ||N1 ||M0 ||Any ||Any || |
| ||T4a ||N0 ||M0 ||Any ||Any || |
|IIIB ||T3 ||N2 ||M0 ||Any ||Any ||17 |
|IIIC ||T4a ||N1-2 ||M0 ||Any ||Any ||13 |
| ||T4b ||Any ||M0 ||Any ||Any || |
| ||Any ||N3 ||M0 ||Any ||Any || |
|IV ||Any ||Any ||M1 ||Any ||Any ||5 |
|0 ||Tis ||N0 ||M0 ||1, X ||83 || |
|IA ||T1 ||N0 ||M0 ||1-2, X ||77 || |
|IB ||T1 ||N0 ||M0 ||3 ||65 || |
| ||T2 ||N0 ||M0 ||1-2, X || || |
|IIA ||T2 ||N0 ||M0 ||3 ||50 || |
|IIB ||T1-2 ||N1 ||M0 ||Any ||40 || |
| ||T3 ||N0 ||M0 ||Any || || |
|IIIA ||T1-2 ||N2 ||M0 ||Any ||25 || |
| ||T3 ||N1 ||M0 ||Any || || |
| ||T4a ||N0 ||M0 ||Any || || |
|IIIB ||T3 ||N2 ||M0 ||Any ||17 || |
|IIIC ||T4a ||N1-2 ||M0 ||Any ||15 || |
| ||T4b ||Any ||M0 ||Any || || |
| ||Any ||N3 ||M0 ||Any || || |
|IV ||Any ||Any ||M1 ||Any ||<5 || |
Clinical staging uses EGD with EUS, CT, and FDG-PET. In patients with proximal esophageal cancer, additional bronchoscopy is recommended to evaluate potential tracheal invasion or document and palliate tracheoesophageal fistula. Among patients with disease extending into the gastric cardia, most experts agree that laparoscopic peritoneal staging is also necessary to evaluate occult peritoneal seeding that is not well visualized with noninvasive modalities (Figs. 20-4,20-5,20-6,20-7,20-8,20-9).
Barrett esophagus, endoscopic view. (Used with permission from Klaus Monkemuller, MD, University of Alabama at Birmingham, Birmingham, AL.)
Esophageal mass, endoscopic view. (Used with permission from Klaus Monkemuller, MD, University of Alabama at Birmingham, Birmingham, AL.)
In various studies, FDG-PET has been consistently shown to have better specificity than CT at diagnosing metastatic disease and LN status. Positron emission tomography serves the primary purpose of detecting occult metastases that are present in 15% to 20% of newly diagnosed esophageal cancer patients (93,94). Multiple studies have been performed in esophageal cancer patients after preoperative treatment, with PET being examined for predicting prognosis (93,95) and treatment response (96). Other studies have shown conflicting results. For example, one study showed that complete response by PET was prognostic of the outcomes of patients receiving definitive chemoradiotherapy (97); however, another study found no correlation of posttreatment PET with survival or pathologic response (98). Fluorodeoxyglucose PET can better reveal bone metastasis than bone scans (99) and commonly reflects images of multiple foci of intense uptake. Studies have shown significant correlations between FDG uptake and tumor invasion depth and LN metastasis and survival rates, with a high degree of accuracy in the neck and upper thoracic and abdominal regions (100). Unlike with gastric cancer, FDG-PET results have been found to be important predictors of response and prognosis. In a retrospective analysis, Swisher et al reported the results of FDG-PET use in 103 consecutive patients with locally advanced esophageal cancer who underwent preoperative chemoradiotherapy (101). At surgery, 58 patients (56%) had experienced a pathologic response to chemoradiotherapy (surgical pathologic results ≤10% viable residual cancer cells). Pathologic response was associated with FDG-PET standardized uptake value (SUV) (3.1 vs 5.8, P = .01). A postchemoradiotherapy FDG-PET SUV ≥4 had the highest accuracy and was an independent predictor of survival (HR, 3.5; P = .04) on multivariate analysis (101).
Perhaps the strongest endorsement for using FDG-PET as predictor of response came from the Metabolic Response Evaluation for Individualization of Neoadjuvant Chemotherapy in Esophageal and Esophagogastric Adenocarcinoma (MUNICON-1) trial. Lordick et al (34) evaluated the feasibility and applicability of FDG-PET in clinical practice in 110 evaluable patients with locally advanced esophageal adenocarcinoma. Patients with adenocarcinoma of the esophagogastric junction types I and II (tumors extending to the esophagus 5 cm above and 2 cm below the GEJ) underwent 2 weeks of induction chemotherapy with FLP. Fluorodeoxyglucose PET scans were obtained for all patients at baseline and after induction chemotherapy. Metabolic response was defined as an SUV decrease by ≥35%. Responders underwent more chemotherapy with FLP or folinic acid, 5-FU, and oxaliplatin (FOLFOX) for 12 weeks followed by surgery. Nonresponders discontinued further chemotherapy after the 2 weeks of initial induction chemotherapy and underwent surgery. In this study, there were 54 responders (metabolic response rate, 49%). One hundred four patients (54 responders and 50 nonresponders) underwent surgery. At 2.3 years of follow-up, the median OS was not reached for responders and was 25.8 months (HR, 2.13; P = .015) for nonresponders. The median event-free survival durations for responders and nonresponders were 29.7 months and 14.1 months, respectively (HR, 2.18; P = .002). Major pathologic remissions (<10% residual tumor) were noted in 58% of responders and 0% of nonresponders (34). In the MUNICON-1 study, the response to induction therapy was valuable for stratifying patients to appropriate therapy, further establishing the clinical utility of FDG-PET in limiting exposure to unnecessary toxicity and maximizing therapeutic benefits. The MUNICON-2 and -3 trial results might be useful in establishing the role of PET in restaging esophageal cancer patients undergoing induction therapy (102).
The role of tumor markers (N-cadherin , activin A, nuclear factor-κB ) and cytogenetics in esophageal cancer staging and prognosis is another subject of active investigation. Esophageal cancer has certain molecular markers that may be predictive. Large population-based studies to validate these preliminary results remain incomplete. Until then, the clinical interpretation of currently available data should be done with caution.
The gold standard for treating high-grade dysplasia (HGD) and early or superficial esophageal cancer is esophagectomy. However, endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESMD), with or without photodynamic therapy (PDT), has become a popular alternative to surgery for early esophageal disease. Despite the recognized epidemiologic and clinical differences between esophageal squamous cell cancer and adenocarcinomas, there is still inadequate evidence that treatment for esophageal cancer should be based on histologic type. Locally advanced cervical esophageal cancer is preferably managed with definitive chemoradiotherapy. For all other esophageal cancers, current evidence supports the use of preoperative chemoradiotherapy to enhance surgical survival outcome in patients with locally advanced resectable disease. Surgery remains the best chance for long-term survival. Ongoing international clinical research with novel cytotoxic and targeted agents will continue to further define and improve survival outcomes of patients with locally advanced curable esophageal and GEJ cancers. Unfortunately, the main therapeutic goal is symptom palliation in patients with locally advanced, unresectable disease.
Endoscopic mucosal resection has gained popularity in Asia for the treatment of superficial or early esophageal cancer as well as BE with HGD. By providing large tissue specimens that can be examined to determine the characteristics and extent of the lesion and the adequacy of resection, EMR is both therapeutic and diagnostic. Endoscopic mucosal resection has been reported in several small prospective case series to be effective, with an initial complete remission (CR) rate of 59% to 99% (105,106). The ideal clinical characteristics for EMR are small (<2 cm diameter), solitary, flat lesions that are confined to the mucosa (T1a). Because EMR has a relatively high recurrence rate, it is recommended that BE and HGD or early esophageal cancer patients be followed up endoscopically every 3 months during the first year and annually thereafter. Complications associated with EMR are bleeding (4%-46%), perforation (1%), and stricture (20%) (107).
Only 23% of patients with esophageal cancer present with clinically resectable localized disease (108). Surgical resection is the mainstay of treatment for these patients (109) and should only be recommended as upfront treatment in T1b/T2 tumors without nodal involvement by EUS. Recent data indicate that the overall 5-year survival rate of esophageal cancer patients after curative surgery is about 25% (38,39,110). Therefore, preoperative chemotherapy or preoperative chemoradiotherapy have become the mainstay strategies for treatment to improve surgical outcome, whereas definitive chemoradiotherapy has been recommended for patients with cervical tumors or unresectable disease.
Cancers of middle or lower third of the esophagus (squamous cell carcinoma or esophageal adenocarcinoma, except GEJ cancers) generally require total esophagectomy, which is a challenging procedure with a high complication rate. No uniform surgical approaches to curative resection exist, but the most common procedures in North America include transhiatal, transthoracic (Ivor-Lewis), and tri-incisional esophagectomy. Transhiatal esophagectomy involves anastomosis of the stomach to the cervical esophagus (111). Ivor-Lewis transthoracic esophagectomy involves abdominal mobilization of the stomach and transthoracic excision of the esophagus, with anastomosis of the stomach to the upper thoracic or cervical esophagus. Limitations of the Ivor-Lewis procedure include a limited proximal resection margin and a higher risk of bile reflux because of the intrathoracic location of the anastomosis (112). The modified Ivor-Lewis procedure involves a left thoracoabdominal incision with a gastric pull-up into the left chest (113). Another surgical approach is tri-incisional esophagectomy in which transhiatal and transthoracic approaches are combined, allowing for transthoracic esophagectomy with node dissection and cervical esophagogastric anastomosis (114). For patients with potentially resectable disease, R0 resection is generally believed to be necessary to achieve durable survival (115). R0 resection is defined as resection of the primary tumor with negative proximal, distal, and circumferential margins. In one retrospective case-control analysis, 220 patients underwent limited transhiatal or extensive mediastinal lymphadenectomy with transthoracic esophagectomy. At a median of 4.7 years of follow-up, there was a trend toward higher DFS (39% vs 27%) and OS (39% vs 29%) rates in patients with more extensive nodal dissection (39,116). Despite a lack of prospective randomized studies, there is a growing consensus that more extensive nodal dissection is needed; including the removal of all cancerous tissue from the mediastinum improves DFS and OS durations through better control of locoregional recurrence. Also, aggressive lymphadenectomy is generally recommended to increase the accuracy of pathologic staging. In the latest version of the AJCC staging manual, an adequate number of LNs is required for defining stage of disease. In the United States, en bloc resection of the mediastinal and upper abdominal LNs is considered standard for transthoracic esophagectomy, and three-field lymphadenectomy is not considered a standard treatment for patients with esophageal cancer.
Preoperative chemotherapy theoretically increases the curative resection rates by downsizing and downstaging the primary tumor and LN metastases, reducing the local and distant relapse rates through suppression and elimination of micrometastases, improving tumor-related symptoms with early initiation of antineoplastic therapy, and appraising in vivo the chemosensitivity of the primary tumor that will influence the choice of chemotherapy in the adjuvant setting. Preoperative therapy is hypothesized to result in tumor downstaging, which allows for higher R0 resection and pathCR rates (117).
The two largest studies evaluating the role of preoperative chemotherapy were the US Intergroup trial (INT0113) (118,119) and UK Marsden Royal College (MRC)-OEO-2 randomized controlled trials (120). Both studies determined the survival benefit of preoperative chemotherapy compared with surgery alone in patients with resectable esophageal squamous cell cancer and adenocarcinoma. Cisplatin plus 5-FU (CF) was administered in both studies. The two studies had completely divergent findings. INT0113 found no clinical/pathologic benefit or survival improvement with preoperative chemotherapy followed by surgery compared with surgery alone (118). The median survival was 14.9 months for patients who received preoperative chemotherapy and16.1 months for those who underwent immediate surgery (P = .53). The recent updated analysis of INT0113 confirmed the lack of benefit of preoperative chemotherapy (119). The MRC-OEO-2 trial, however, reported a statistically significant improved R0 resection rate (78% vs 70%) and median OS time (17.2 vs 13.3 months) in patients who underwent preoperative chemotherapy (120). Results of both INT0113 and OEO-2 studies did not help determine the role of preoperative chemotherapy in patients with resectable esophageal cancer. In the United Kingdom and other countries in Europe, preoperative chemotherapy has become the acceptable standard of care.
The two most recent randomized studies of preoperative and perioperative chemotherapy, the French Actions Concertées dans les Cancer Colorectaux et Digestifs (ACCORD) 7 (58) and UK MAGIC trials (39), are the strongest validations of the benefits of preoperative and perioperative chemotherapy. These two studies are described in detail in the “Gastric Cancer” section of this chapter. In addition to the MAGIC and FRENCH trials, a third Japanese trial on squamous cell carcinoma patients (JCOG 9907) deserves mention because it was positive. Patients were given two cycles of CF preoperatively. Postoperatively, CF was administered to node-positive patients only. Of the above mentioned three trials, this one showed the highest 5-year survival rate in both arms (121).
Investigators at MRC are currently conducting two large phase III randomized controlled studies. MRC-OEO-5 is evaluating the use of preoperative chemotherapy, comparing two preoperative chemotherapy regimens, CF versus ECX (epirubicin, cisplatin, and capecitabine) (122). Meanwhile, other researchers in the United Kingdom are evaluating the addition of targeted therapy to perioperative chemotherapy. The MRC ST03 trial will determine whether the addition of bevacizumab to perioperative ECX improves survival. Table 20-7 lists the ongoing studies of locally advanced resectable gastric, GEJ, and distal esophageal adenocarcinomas.
Table 20-7Key Esophageal Cancer Trials ||Download (.pdf) Table 20-7 Key Esophageal Cancer Trials
|Study ||No. of Patients ||Treatment Arm Control Arm ||HR for OS (P value) ||OS (%) |
|Pre- and perioperative chemotherapy |
|Kelsen et al (119) (INT-113) ||467 || |
3 × CF → S
|0.75 (NR) ||5-year OS: 36% vs 23% |
|Allum et al (120) (MRC-OEO-2) ||802 || |
2 × CF → S
|0.84 (.03) ||5-year OS: 23% vs 17.1% |
|Ychou et al (58) (ACCORD 7) ||169 || |
2/3 × CF → S
|0.69 (.02) ||5-year OS: 38% vs 24% |
|Cunningham et al (122) (MRC-OEO-5) ||897 || |
2 × CF → S
4 × ECX → S
|Survival data not mature |
|1,100 || |
3 × ECX → S
ECX, B → S
|Survival data not mature |
Ando et al (121)
|380 || |
S → 2 × CF
2 × CF → S
|0.73 (.04) ||5-year OS: 43% vs 55% |
|Preoperative chemoradiotherapy |
|Tepper et al (125) (CALGB 9781) ||56 || |
2 × CF; 50.4 Gy → S
|1.46-5.69 (NR) ||5-year OS: 39% vs 16% |
|van Hagen et al (127) (CROSS) ||366 || |
5 × carboplatin/paclitaxel; 41.4 Gy → S
|0.657 (.003) ||5-year OS: 47% vs 34% |
|Preoperative CT vs preoperative CRT |
|Stahl et al (131) (POET) ||119 || |
2.5 × CF, Leu → S
2 × CF, Leu → CE 30 Gy → S
|0.67 (.07) ||3-year OS: 27.7% vs 47.4% |
|Postoperative CT |
|Ando et al (134) (JCOG 9204) ||242 || |
S → 2 × CF
|(.13) ||5-year OS: 52% vs 61% |
Preoperative radiotherapy was studied in the early 1980s. However, in several phase III studies, a benefit similar to that of surgery alone was not shown. In a recent quantitative meta-analysis comprising five randomized trials and 1,147 patients, it was again demonstrated that there is no improvement in survival with preoperative radiotherapy alone in potentially resectable esophageal cancer (123,124).
In the United States, pre- or perioperative chemotherapy is not as common as preoperative chemoradiotherapy for locally advanced esophageal and GEJ cancer. Preoperative chemoradiotherapy has the goal to improve pathCR rate, locoregional control, and survival.
The CALGB 9781 trial provided additional support for preoperative chemoradiotherapy, although it was stopped early because of a slow accrual rate. Fifty-six patients were randomly assigned to surgery alone (n = 26) or CF chemotherapy and concurrent radiotherapy (n = 30). At a median follow-up of 6 years, an intent-to-treat analysis showed a median OS duration of 4.5 versus 1.8 years (P = .002) in favor of trimodality therapy. The 5-year OS rates were 39% (95% CI, 21%-57%) versus 16% (95% CI, 5%-33%) in favor of trimodality therapy (125). Gebski et al (126) reported improved survival with preoperative chemotherapy and chemoradiotherapy. The HR for all-cause mortality with preoperative chemoradiotherapy versus surgery alone was 0.81 (95% CI, 0.70-0.93; P = .002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histologic tumor types (squamous cell cancer: HR, 0.84, P = .04; adenocarcinomas: HR, 0.75, P = .02). The HR for preoperative chemotherapy was 0.90 (95% CI, 0.81-1.00; P = .05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality for preoperative chemotherapy in squamous cell cancer (HR, 0.88; P = .12), but there was a benefit in adenocarcinoma (HR, 0.78; P = .014) (126). With chemoradiotherapy, evidence seems to suggest that treating physicians can expect a pathCR rate of 20% to 30%, a median OS duration of 16 to 24 months, and a therapy-related mortality rate of 5% to 10%.
The Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial was a well-executed study that established level 1 evidence for preoperative chemoradiotherapy. Three hundred sixty-eight localized esophageal cancer (adenocarcinoma or squamous) patients were randomly assigned to receive either preoperative paclitaxel and carboplatin with concurrent radiation 41.4 Gy (n = 178) or surgery alone (n = 188). With a median follow-up time of 45.4 months, the median OS for preoperative chemoradiotherapy group was 49.4 months versus 24.0 months for the surgery-alone group (HR, 0.657; 95% CI, 0.495-0.871; P = .003). Five-year OS was again in favor of the chemoradiotherapy group (47%) versus the surgery-alone group (34%) (127). The complete resection rate was higher in the chemoradiotherapy group (92%) versus the surgery-alone group (69%), and 29% of patients in the chemoradiotherapy group had pathCR. In a subgroup analysis, the patients with squamous cancer demonstrated the best outcomes (HR was 0.453 for squamous cancer vs 0.732 for adenocarcinoma) (127,128).
Preoperative Chemotherapy Versus Preoperative Chemoradiotherapy
Meta-analyses have been performed to further support the available evidence for preoperative therapy (126,129,130). Cumulatively, these three meta-analyses determined that the most consistent significant survival benefit resulted from the combination of surgery and preoperative chemoradiotherapy and, to a lesser extent, preoperative chemotherapy.
Since these studies, results from the Preoperative Chemotherapy or Radiochemotherapy in Esophagogastric Adenocarcinoma (POET) trial, presented by Stahl et al (131), have provided further support for three-step preoperative therapy, although the study was closed prematurely because of slow accrual. The POET trial was designed to evaluate the survival outcomes of patients treated with preoperative chemotherapy compared with preoperative chemoradiotherapy. One hundred nineteen patients were randomly assigned to chemotherapy followed by chemoradiotherapy and surgery (n = 59) or chemotherapy followed by surgery (n = 60); the R0 resection rates were 72% and 70% (P = not significant), the pathCR rates were 16% and 2% (P < .001), and the N0 rates were 64% and 38% (P < .001), respectively. The 3-year OS rate trended toward improvement with induction chemotherapy, chemoradiotherapy, and surgery (47% vs 28% with chemotherapy and surgery; P = .07) (131). Patients in the chemoradiotherapy arm had a significantly higher probability of a pathCR (15.6% vs 2.0%). Postoperative mortality rates did not differ between the chemoradiotherapy and chemotherapy arms (10% vs 4%; P = .26). These results suggest that preoperative chemoradiotherapy confers a survival advantage over preoperative chemotherapy in distal esophageal and GEJ adenocarcinoma. Maximizing duration and amount of therapy before surgery theoretically could improve the ability to deliver all planned effective therapies and initiate palliative therapy early and improve pathCR, local control, cure, and survival rates.
The use of induction chemotherapy before chemoradiotherapy and surgery has been evaluated in several phase II studies. Ajani et al (73) performed a feasibility study of preoperative induction combination chemotherapy with chemoradiotherapy to improve curative resection, local control, and survival in 2001. Thirty-seven potentially resectable cancers of the esophagus and GEJ were treated with induction chemotherapy followed by chemoradiotherapy and curative surgery. Induction chemotherapy consisted of two cycles of CF plus paclitaxel (CFP). After chemoradiotherapy, consisting of 45 Gy of radiation and concurrent CF, patients underwent surgery. Thirty-five (95%) of the 37 patients underwent surgery (R0 resection). The pathCR rate was 30% (11 of 37 patients); an additional five patients (14%) had only microscopic cancer. Downstaging was significant; the rates of T3 before surgery and at surgery were 89% and 9%, respectively (P = .01), and the rates of N1 were 66% and 20%, respectively (P = .01) (73). Patient selection is important because the current three-step strategy exchanges moderate toxicity for modest survival improvement.
In Europe and the United Kingdom, the treatment approach varies accordingly to tumor histology. For resectable squamous cell carcinoma, patients are commonly treated with preoperative chemoradiotherapy (132), whereas for resectable adenocarcinomas, either preoperative CRT or perioperative chemotherapy is administered. In the United States, preoperative chemoradiotherapy is the standard of care irrespective of histology.
Few studies have been performed to evaluate postoperative chemotherapy versus surgery alone. Reflecting the incidence of esophageal cancer during the 1980s and 1990s, these studies included more patients with squamous cell cancer than with adenocarcinoma; this is a shortcoming of these early studies. In a study by Pouliquen et al, no survival improvement was found in the patients who were administered postoperative chemotherapy (CF) (133).
The second study, a randomized trial, JCOG 9204, compared the outcomes of patients who underwent surgery alone versus patients who underwent surgery followed by adjuvant CF. The 5-year DFS rates favored the postoperative chemotherapy group (55% vs 45%; P = .037). However, the difference in the 5-year OS rate was not statistically significant (61% vs 52%; P = .13). The duration of adjuvant therapy was suboptimal, and approximately 25% of patients assigned to the postoperative chemotherapy group failed to receive the full course of therapy (134).
Another retrospective case-control study was designed to evaluate the effect of postoperative chemotherapy in 211 patients who underwent R0 esophagectomy with radical lymphadenectomy. Of 211 patients, 94 received postoperative chemotherapy, whereas the other 117 patients received surgery alone. The OS was compared between the two groups after they were stratified by the numbers of metastasis-positive LNs. In the subgroup of patients with more than eight positive LNs, postoperative chemotherapy significantly improved the OS compared with surgery alone. Therefore, the authors suggested that postoperative chemotherapy was beneficial only in patients with more than eight metastatic LNs (135), reducing the risk of relapse. However, postoperative chemotherapy did not improve the OS compared with surgery alone.
Many studies have been performed to evaluate the role of postoperative radiotherapy versus surgery alone. In two studies, conducted by Teniere et al (136) and postoperative radiotherapy did not improve survival. Results from two other randomized studies revealed conflicting findings. Xiao et al (137) demonstrated that postoperative radiotherapy improved the 5-year OS in esophageal cancer patients with stage III disease. In contrast, Fok et al found shorter survival durations in patients who underwent postoperative radiotherapy as a direct result of irradiation-related death and the early appearance of metastatic disease (138). Thus, the utility of postoperative radiotherapy may be limited. Of these studies, only the one by Zieren et al evaluated quality of life, which was found to be better in the surgery-alone group.
Malthaner et al (139) performed a meta-analysis of 34 randomized controlled trials and six meta-analyses in which patients with locally advanced esophageal cancer underwent pre- or postoperative chemotherapy, radiotherapy, or chemoradiotherapy. No significant difference in survival was observed in the postoperative radiotherapy group.
The available evidence suggests that postoperative chemotherapy or radiotherapy does not result in a benefit. However, few randomized comparisons have been performed with surgery alone versus surgery and postoperative treatment. In the INT-0116 study (38), 556 patients with resected GEJ and gastric adenocarcinoma were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. Adjuvant treatment consisted of 5-FU plus LV for 5 days, followed by 45 Gy of radiation with modified doses of 5-FU/LV on the first 4 and the last 3 days of radiotherapy. One month after radiotherapy, two 5-day cycles of 5-FU/LV were given 1 month apart. The median OS improved with postoperative chemoradiotherapy from 27 to 36 months (HR, 1.35; 95% CI, 1.09-1.66; P = .005), and the HR for relapse was 1.52 (95% CI, 1.23-1.86; P < .001). INT-0116 included 111 patients (20%) with GEJ or lower esophageal adenocarcinoma (38). Extrapolation of these results as supporting evidence for postoperative chemoradiotherapy in esophageal cancer should be performed with caution.
On the basis of the available evidence, patients with esophageal cancer gain limited survival benefit with postoperative chemotherapy and chemoradiotherapy after R0 resection. The limited contribution of postoperative therapy is probably due to the moderate toxicity, which leads to treatment-related complications or an inability to complete therapy.
The limited ability to deliver therapy after surgery, as demonstrated by results from both the INT-0116 and MAGIC studies (38,39), suggests that all effective therapy should be administered before surgery.
The potential activity of chemotherapy against micrometastases and its ability to act as a radiotherapy-sensitizing agent formed the basis for combining chemotherapy and radiotherapy to treat locally advanced cancer. In the RTOG 85-01 study, patients with locally advanced esophageal adenocarcinoma or squamous cell cancer were randomly assigned to chemoradiotherapy with CF or radiotherapy alone. The 5-year OS rates were 0% and 26% for radiotherapy and chemoradiotherapy, respectively (140).
A comprehensive review of the pattern of care for esophageal cancer in the United States from 1992 to 1994 surveyed 400 patients with locally advanced esophageal cancer treated at 63 institutions (141). The study confirmed that using combined concurrent chemoradiotherapy as a nonoperative strategy to achieve superior survival and local tumor control was better than radiotherapy alone (141). The report also suggested a trend toward survival improvement with chemoradiotherapy before surgery compared with chemoradiotherapy or surgery alone.
In the INT-0123 (RTOG 94-05) study, patients (n = 236) were administered concurrent CF (similar to RTOG 85-01) but were assigned randomly to different radiation doses, either 50.4 or 64.8 Gy. No association was found between higher radiation doses and higher median survival (13 vs 18 months for 50.4 vs 64.8 Gy, respectively) or 2-year survival (31% vs 40%, respectively). Higher radiation dose was also more toxic (142). The reason for the failure of the higher radiation dose to improve survival is unclear.
The multi-institutional RTOG 0113 trial evaluated induction chemotherapy followed by definitive chemoradiotherapy in patients with localized unresectable esophageal cancer. The primary goal was to determine whether any approach would result in a >78% 1-year OS, surpassing the historical 66% rate from RTOG 94-05. Seventy-two evaluable patients were randomly assigned to induction with CFP followed by CFP and 50.4 Gy of radiation (CFP arm, n = 37) or induction with paclitaxel plus cisplatin (PP) followed by PP and 50.4 Gy of radiation (PP arm, n = 35). The median OS durations for the CFP and PP arms were 28.7 and 14.9 months, respectively (18.8 months in RTOG 9405). The study did not reach its preset objective because the 1-year OS rates of the CFP and PP arms did not meet or surpass 78% (CFP 1-year OS, 76%). The 2-year OS rates for the CFP and PP arms were 56% and 37%, respectively. Toxicity was quite high in both arms (43% to 54% and 27% to 40% of patients experienced grade 3 and 4 toxicities, respectively). Therefore, neither combination (CFP or PP) was recommended for further evaluation (143).
Definitive Chemoradiotherapy Versus Chemoradiotherapy Plus Surgery
Stahl et al (131) performed a randomized comparison of chemotherapy followed by chemoradiotherapy and then surgery (surgical arm, n = 86) and chemotherapy followed by chemoradiotherapy and no surgery (nonoperative arm, n = 86) in 172 patients with locally advanced esophageal squamous cell cancer. The median follow-up duration was 6 years. The OS rates were similar for the surgical and nonsurgical arms (P < .05). The 2-year local PFS rate was higher in the surgical arm than the nonsurgical arm (64% vs 41%; HR, 2.1; 95% CI, 1.3-3.5; P = .003). The treatment-related mortality rate was significantly higher in the surgical arm (12.8% vs 3.5%; P = .03). The clinical tumor response to induction chemotherapy was the only independent prognostic factor for OS (HR, 0.30; 95% CI, 0.19-0.47; P < .0001). The results of this study suggested that adding surgery to chemoradiotherapy improves local tumor control but not survival in patients with locally advanced esophageal squamous cell cancer. Tumor response to induction chemotherapy is associated with a favorable prognostic group in these high-risk patients, regardless of treatment. Of course, the difficulty of incorporating these results into clinical practice is detecting residual disease or response after preoperative therapy.
Another randomized comparison in only responders to chemoradiotherapy (45 Gy conventional or 60 Gy split-course radiation) was conducted by Bedenne et al (144). Patients with resectable esophageal squamous cell cancer were treated with two cycles of CF along with concurrent radiotherapy (conventional/split course). Patients who experienced a response (n = 259) were then randomly assigned to surgery or more chemoradiotherapy. The 2-year OS rates were 34% and 40% (HR, 0.90; P = .44), the median OS durations were 18 and 19 months (P = not significant), the 2-year local control rates were 66% and 57% (P < .01), and the 3-month mortality rates were 9.3% and 0.8% (P = .002), respectively. The authors concluded that in patients who experience a response to chemoradiotherapy, surgery after chemoradiotherapy results in no added benefit over continued chemoradiotherapy (144).
Most data are not yet sufficiently mature to allow conclusions about optimal therapy for locally advanced squamous cell cancer of the noncervical esophagus. In a phase III study by the Chinese University Research Group for Esophageal Cancer (CURE), investigators from China are comparing the survival benefits of esophagectomy versus chemoradiotherapy. From 2000 to 2004, 80 patients were randomly assigned to esophagectomy (n = 44) or chemoradiotherapy (n = 36). A two- or three-stage esophagectomy with two-field lymphadenectomy was performed. Chemoradiotherapy consisted of CF and concurrent 50 to 60 Gy of radiation. Tumor response was assessed by EGD, EUS, and CT. Salvage esophagectomies were performed for incomplete response or recurrence. The median follow-up time was 1.4 years. No difference in the early cumulative survival rate was found between the two groups (Relative risk, 0.89; 95% CI, 0.37-2.17; P = .45), nor was there a difference in DFS. Patients treated with surgery only had a slightly higher recurrence rate in the mediastinum, whereas those treated with chemoradiotherapy had a higher rate in the cervical or abdominal region (145).
Surgery is the foundation of treatment for locally advanced resectable esophageal cancer. Early results from European studies suggested that patients with esophageal squamous cell cancer will not benefit from surgery after chemoradiotherapy (146). The caveat of the nonsurgical approach to solid tumors is detecting minimal residual disease. Therefore, until more confirmatory evidence and clinical tools become available for detecting minimal residual disease or molecular or imaging predictive markers in patients who require surgery after preoperative therapy, the treatments for squamous cell cancer and adenocarcinoma will remain similar.
The University of Texas MD Anderson Cancer Center Approach to Resectable Esophageal and Gastroesophageal Junction Cancers
All patients with newly diagnosed invasive cancer undergo careful staging, which includes endoscopic assessment of the location and size of the primary tumor and EUS staging, CT, and PET/CT. Patients with cervical or proximal esophageal cancer also undergo bronchoscopy as part of a recommended staging workup. For distal esophageal disease or gastric cardia cancer, staging laparoscopy is performed in some patients, but the decision is made on a case-by-case basis. Again, as in locally advanced gastric cancer, all patients with only localized disease are further evaluated by a multidisciplinary team that includes thoracic surgeons and radiation oncologists. Furthermore, patients with localized disease are discussed at the weekly Esophageal Multidisciplinary Tumor Board.
Currently, at the MDACC, treatment modalities for locally advanced resectable esophageal cancer include chemoradiotherapy and then surgery. For GEJ adenocarcinoma, postoperative chemoradiotherapy and perioperative chemotherapy are additional options available to patients. Patients with locally advanced cervical esophageal cancer are treated with primary definitive chemoradiotherapy, even those with resectable disease. Salvage surgery is considered only in patients with persistent or locally recurrent disease. Results from the RTOG 85-01 and 94-05 studies established that adding chemotherapy to radiotherapy improved survival and local relapse rates and that the optimal radiation dosage is 50.4 Gy in 28 fractions. With the results of the CROSS trial, we now recognize that a minimum dose of 41.4 Gy may be sufficient in the preoperative setting, although our preference is to use a higher dose. If at all possible, all locally advanced resectable esophageal cancers are treated on protocol at the MDACC or with preoperative chemoradiotherapy followed by surgical resection. Figure 20-3A summarizes the MDACC approach to resectable gastroesophageal cancer.
Advanced and Metastatic Gastric, Gastroesophageal Junction, and Esophageal Cancers
The prognosis of patients with advanced or metastatic gastric, GEJ, and esophageal cancers is poor; thus, clinicians should be cognizant of the patient’s quality of life and weigh the risks and benefits of therapy. The overall 5-year survival rate of upper GI cancer patients is less than 5%. The standard of care for advanced disease is chemotherapy. Many frontline combination chemotherapy regimens are available, but no head-to-head comparison has been performed for most of these; thus, the optimal choice is not obvious, and treatment remains regionally variable. However, with the advent of molecular targeted therapy, it may be possible to select therapy based on the disease’s molecular characteristics. The results of the Trastuzumab in Gastric Cancer (ToGA) study (147) raised the exciting possibility of personalized treatment for upper GI cancers; however, other results have since been disappointing. Until more specific and accurate molecular markers of response and prognosis become available, patient outcome with systemic therapy is best predicted by clinical characteristics, such as performance status.
The medical treatment of metastatic gastric cancer is primarily palliative and confers a modest effect on OS. Multiple agents are active in the treatment of gastric cancer, including fluoropyrimidines (5-FU, capecitabine, and S-1), anthracyclines, platinum agents, taxanes, irinotecan, and some targeted therapies such as trastuzumab for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancers. Combination regimens are associated with higher response rates and, according to one meta-analysis, are also associated with increased survival when compared with single-agent chemotherapies (148). By and large, the trials addressing the value of targeted therapies, for example targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), were done in unselected (not biomarker enriched) populations and have, not surprisingly, yielded disappointing results.
Only a minor amount of level 1 evidence exists for the treatment of gastric cancer in the first-line setting. In fact, only docetaxel (149), cisplatin/oxaliplatin (150), and trastuzumab (147) are supported by high level evidence.
A phase III trial involving 445 patients with metastatic cancer randomized patients to receive CF or CF plus docetaxel. The investigators found that the addition of docetaxel was superior in terms of response rate (37% vs 25%; P = .01), time to tumor progression (5.6 vs 3.7 months; P < .001), and OS (9.2 vs 8.6 months; P = .02) (149). One could question the clinical significance of a less than 1 month absolute improvement in OS, particularly in the context of significant toxicities, most notably a high rate of febrile neutropenia (30%). Importantly, this regimen should not be used in patients who have a reduced performance status.
Another randomized phase III trial including 1,002 patients tried to improve on the regimen of ECF by substituting oral capecitabine for infusional 5-FU and by using the nonnephrotoxic oxaliplatin rather than cisplatin. The combination of epirubicin/oxaliplatin/capecitabine (EOX) was found to be less toxic and at least as effective as ECF. The median survival times in the ECF (control), ECX, EOF (epirubicin/oxaliplatin/5-FU), and EOX arms were 9.9, 9.9, 9.3, and 11.2 months, respectively. The 1-year survival rates were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, OS was longer with EOX than with ECF, with an HR for death of 0.80 in the EOX group (95% CI, 0.66-0.97; P = .02). Progression-free survival and response rates did not differ significantly among the regimens (150).
The third randomized phase III trial enrolled 305 patients in Japan to either S-1 alone or S-1 and cisplatin. Median OS was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months) than in those assigned to S-1 alone (11.0 months; HR for death, 0.77; 95% CI, 0.61-0.98; P = .04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median PFS, 6.0 vs 4.0 months; P < .0001) (151). This trial provided evidence for the superiority of the addition of cisplatin when compared to a fluoropyrimidine alone and established the use of a fluoropyrimidine in addition to a platinum as a reasonable treatment option.
Trastuzumab was the first targeted agent with documented clinical activity in the advanced gastric and gastroesophageal cancer setting. This treatment is useful in the HER2-enriched population; however, approximately 20% of gastric cancers and 30% of gastroesophageal cancers overexpress HER2, so that a relatively small proportion of patients benefit from the treatment. The ToGA trial randomized 584 patients whose tumors overexpressed HER2 by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to receive a fluoropyrimidine (5-FU or capecitabine) plus cisplatin with or without trastuzumab. The chemotherapy was administered every 3 weeks for six cycles, and trastuzumab was administered every 3 weeks until disease progression (147). The investigators found that the addition of trastuzumab to chemotherapy increased OS from 11.1 to 13.8 months (HR, 0.74; 95% CI, 0.60-0.91; P = .0046). The secondary end points of PFS (6.7 vs 5.5 months; P = .0002) and response rate (47.3% vs 34.5%; P = .0017) were also improved. On extended follow-up, the HR of OS for the addition of trastuzumab has decreased to 0.80 (152), indicating that although real, the response to trastuzumab may be short lived. The difference in median OS was reduced from 2.7 months to merely 1.4 months, representing an approximate 50% decrease in the effect of trastuzumab, which suggests that only a few patients benefit. Based on this trial, the combination of trastuzumab and chemotherapy has become the standard of care in patients whose tumors overexpress HER2.
In contrast to the positive results with trastuzumab in HER2-overexpressing gastroesophageal cancers, bevacizumab failed to demonstrate an OS benefit when it was added to a combination of cisplatin and fluoropyrimidine in patients with advanced gastric and GEJ adenocarcinoma (153). A total of 774 patients were randomized, and the median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (HR, 0.87; 95% CI, 0.73-1.03; P = .1002). Both median PFS (6.7 vs 5.3 months; HR, 0.80; 95% CI, 0.68-0.93; P = .0037) and overall response rate (46.0% vs 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo (153). In a preplanned subgroup analysis, the investigators were able to show that a benefit in terms of OS existed for “Pan-American” patients but not for European and Asian patients. This might point to differences in tumor biology, but is also dependent on other factors. A subsequent retrospective biomarker analysis of the AVAGAST trial showed that patients with high baseline plasma VEGF-A levels and low baseline expression of neuropilin-1 seemed to have an improved OS. For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions (154). It is important to note that neither of these biomarkers has been validated. Unlike the ToGA trial, the AVAGAST trial did not use a biomarker-enriched patient population, underscoring the importance of appropriate patient selection in randomized controlled trials and the use of predictive biomarkers to direct care. Similarly, the AVATAR trial, which included an all Asian patient population, did not show any survival benefit of adding bevacizumab to the cisplatin-capecitabine combination (155).
Equally disappointing results were also reported from two EGFR-targeting trials: the Erbitux (cetuximab) in Combination with Xeloda (capecitabine) and Cisplatin in Advanced Esophagogastric Cancer (EXPAND) and Revised European American Lymphoma (REAL-3) trials (156,157). The EXPAND trial randomized 904 patients to receive capecitabine and cisplatin, with or without cetuximab. This study did not achieve its primary end point, with the median PFS for 455 patients allocated to capecitabine-cisplatin plus cetuximab being 4.4 months compared to 5.6 months for 449 patients who were allocated to receive capecitabine-cisplatin alone (HR, 1.09; 95% CI, 0.92-1.29; P = .32) (156). The REAL-3 study was terminated prematurely because a statistically significant lower OS was noted in patients treated with modified epirubicin/oxaliplatin/capecitabine (EOC) and panitumumab. The final analysis of this study, which randomized patients with advanced gastroesophageal adenocarcinoma, was published (157). Median OS of patients allocated to EOC was 11.3 months (95% CI, 9.6-13.0 months) compared with 8.8 months (95% CI, 7.7-9.8 months) in 278 patients allocated to modified EOC and panitumumab (HR, 1.37; 95% CI, 1.07-1.76; P = .013). There was a nonsignificant trend to worse outcomes in patients treated with panitumumab, again highlighting the importance of patient selection in randomized controlled trials. A biomarker analysis of the REAL-3 trial did not identify any biomarkers whose presence predicted resistance to modified EOC and panitumumab; however, only a few biomarkers were evaluated in this study (158).
The role of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor (TKI), was investigated in combination with capecitabine plus oxaliplatin (CapeOx) in 545 patients with HER2-positive advanced/metastatic gastroesophageal adenocarcinomas in the TRIO-013/LOGiC trial. The addition of lapatinib to CapeOx did not improve efficacy (OS and PFS) among untreated HER2-positive metastatic gastric cancer patients (159).
In summary, the standard of care in the first-line setting remains a combination of fluoropyrimidine and platinum-containing chemotherapy, with the addition of trastuzumab in the HER2-enriched population. The results of targeted therapy trials have mostly been disappointing, but none of these trials looked at an appropriately biomarker-enriched population.
The validity of the use of second-line chemotherapy and its benefit in gastric cancer has long been questioned; however, all recently published trials demonstrated an OS prolongation, albeit very modest, when chemotherapy was compared to best supportive care (BSC) (160,161,162,163). Arbeitsgemeinschaft Internistische Onkologie (AIO), a small German phase III study, compared the efficacy of irinotecan plus BSC to BSC alone in patients with advanced gastric or GEJ adenocarcinoma (161). Only 40 patients were randomized, and the study closed early due to poor accrual. The HR for death was 0.48, with a 95% CI of 0.25 to 0.92, favoring the active treatment with irinotecan (P = .023). The median survival time was 4.0 months (95% CI, 3.6-7.5 months) in the irinotecan arm and 2.4 months (95% CI, 1.7-4.9 months) in the BSC arm (161). There were no documented responses to irinotecan in this trial.
The second trial, COUGAR-02, randomized 186 patients to docetaxel plus BSC versus BSC alone. Docetaxel significantly improved OS compared with BSC alone, with a median OS of 5.2 months (95% CI, 4.1-5.9 months) for docetaxel and 3.6 months (95% CI, 3.3-4.4 months) for BSC (HR, 0.67; 95% CI, 0.49-0.92; P = .01) (162).
The role of angiogenesis inhibition as a target in gastric cancer was investigated in the Ramucirumab Monotherapy for Previously Treated Advanced Gastric or Gastro-Oesophageal Junction Adenocarcinoma (REGARD) trial, which randomized 355 patients to receive ramucirumab or placebo (160). This study demonstrated a marginal improvement in median OS (5.2 months in patients in the ramucirumab group and 3.8 months in patients in the placebo group; HR, 0.776; 95% CI, 0.603-0.998; P = .047). Interestingly, the average patient on study treated with ramucirumab received treatments for 2 weeks longer than the average patient on placebo. In the recently published Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW) trial, ramucirumab was added to weekly paclitaxel as a second-line therapy in 665 patients with advanced or metastatic gastric cancer, demonstrating a significant improvement in both PFS and OS over paclitaxel alone (163). A statistically significant prolongation of OS was demonstrated (HR, 0.81; 95% CI, 0.68-0.96; P = .017). Median OS times were 9.6 and 7.4 months in the ramucirumab-plus-paclitaxel arm and placebo-plus-paclitaxel arm, respectively. The PFS was also significantly longer for patients receiving ramucirumab plus paclitaxel (HR, 0.64; 95% CI, 0.54-0.75; P < .001) with an overall good safety profile, further supporting its role in combination with chemotherapy.
Another study that demonstrated an OS benefit for patients treated with chemotherapy (either docetaxel or irinotecan) versus BSC was published by Kang et al (164). Median OS was 5.3 months among 133 patients in the chemotherapy arm and 3.8 months among 69 patients in the BSC arm (HR, 0.657; 95% CI, 0.485-0.891; one-sided P = .007). There was no median OS difference between docetaxel and irinotecan (5.2 vs 6.5 months; P = .116).
In the randomized phase III Taiwan Cooperative Oncology Group (TCOG) GI-0801/Biweekly Irinotecan Plus Cisplatin (BIRIP) trial, BIRIP was compared to irinotecan alone after S1-based chemotherapy failure in patients with advanced gastric cancer (165). Significant PFS improvement was demonstrated (primary end point met) with cisplatin added to irinotecan as second-line treatment of advanced gastric cancer in 130 patients, providing the first evidence supporting combination chemotherapy in the second-line setting (median PFS, 3.8 vs 2.8 months, P = .04; disease control rate, 75.0% vs 54.0%; P = .02).
In the second-line setting, targeted HER2 therapy with TKIs has been a failure (166,167). Lapatinib has been investigated in a large 420-patient study (TyTAN trial), which randomized HER2-positive patients to lapatinib plus paclitaxel (L+P) versus paclitaxel alone. Median OS was 11.0 months for L+P and 8.9 months for paclitaxel alone in the intent-to-treat population (HR, 0.84; P = .2088). In a preplanned subgroup analysis, median OS in the HER2 IHC 3+ subgroup was 14.0 months for the combination therapy and 7.6 months for paclitaxel alone (HR, 0.59; P = .0176) (167). Interestingly, it has recently been demonstrated that although the study mandated IHC HER2 positivity, 35% of patients in TyTAN had tumors classified as IHC 0/1 (167).
Equally disappointing, the most recent UK Gefitinib for Oesophageal Cancer Progressing After Chemotherapy (COG) trial in patients with adenocarcinoma of the esophagogastric junction types I/II (tumors extending to the esophagus 5 cm above and 2 cm below the GEJ) in the second-line setting (168) randomized 449 patients to receive gefitinib or placebo. The primary end point was OS. Secondary end points were PFS and quality-of-life outcomes. However, the median OS was 3.73 months for patients who received gefitinib and 3.63 months for those who received placebo (HR, 0.9; P = .29). There was a minor prolongation of PFS by 0.4 months for patients who received gefitinib compared to those who received placebo (HR, 0.80; P = .02).
Multiple studies highlight the importance of identification and targeting of driver mutations and their usefulness in the creation of appropriate biomarkers to direct care (169,170). MET amplification and/or overexpression of its protein product has long been implicated in the pathogenesis of gastric cancer, supporting its role as a poor prognostic factor (41). This has been studied in two phase II trials using the monoclonal antibodies rilotumumab and onartuzumab. Rilotumumab demonstrated prolonged PFS for patients whose tumors had high total c-MET expression (171), whereas onartuzumab failed to prolong PFS in patients with MET-positive tumors (172). Recently, the investigational oral MET TKI AMG 337 trial is generating excitement based on early-phase results, where 8 of 13 patients who were found to have MET-amplified gastroesophageal adenocarcinomas showed partial to near-complete responses to the small-molecule inhibitor AMG-337 (173).
The role of poly (ADP-ribose) polymerase (PARP) inhibitors in gastric cancer was investigated in a phase II study where 124 patients who progressed on fluoropyrimidines (second-line metastatic setting) were randomized to olaparib plus paclitaxel versus paclitaxel alone (174). There was no improvement in PFS, but the addition of olaparib significantly improved OS (HR, 0.56; 95% CI, 0.35-0.87; P = .010). A phase III trial is ongoing.
Apatinib is a small-molecule multitargeted TKI with activity against VEGF receptor (VEGFR). After showing improved PFS and OS in heavily pretreated metastatic gastric cancer patients in a phase II trial (175), apatinib was evaluated in a phase III trial in 271 patients with advanced gastric cancer (176). Patients had prior failure to second-line chemotherapy and were stratified according to the number of metastatic sites (≤ or >2 sites). This trial met its primary end point, showing significant improvement in OS and PFS. The median OS time was 6.5 months for apatinib and 4.7 months for placebo (HR, 0.71; 95% CI, 0.54-0.94; P = 0.015), and the median PFS was 2.6 months for apatinib and 1.8 months for placebo (HR, 0.44; 95% CI, 0.33-0.61; P < .0001). This is the first phase III evidence for efficacy of a third-line therapy in advanced gastric cancer and further supports the angiogenesis inhibition as a target in this disease.
The role of mammalian target of rapamycin (mTOR) inhibitor everolimus was investigated in heavily pretreated metastatic gastric cancer patients with disappointing results. The RAD001 (Everolimus) Monotherapy Plus Best Supportive Care in Patients With Advanced Gastric Cancer (GRANITE-1) study randomized 656 patients to everolimus plus BSC versus placebo plus BSC. Unfortunately, this study did not achieve its primary OS end point (5.4 months with everolimus and 4.3 months with placebo; HR, 0.90; 95% CI, 0.75-1.08; P = .124) (166). Notably, the estimated percentage of patients remaining progression free at 6 months was higher with everolimus (12.0% vs 4.3%), as were the disease control rate (43.3% vs 22.0%) and the tumor shrinkage rate (37.8% vs 12.3%). These results suggest everolimus has activity in this heavily pretreated population. Identification of specific biomarkers for various patient subpopulations with advanced gastric cancer may help define those patients who would receive the most benefit from everolimus treatment (166).
Table 20-8 lists major phase III trials for advanced/metastatic esophageal, GEJ, and gastric cancer involving chemotherapy agents, and Table 20-9 lists trials involving targeted agents in the first-, second-, and third-line settings.
Table 20-8Major Phase III Gastric Cancer Trials Involving Chemotherapy Agents in the Advanced/Metastatic Setting ||Download (.pdf) Table 20-8 Major Phase III Gastric Cancer Trials Involving Chemotherapy Agents in the Advanced/Metastatic Setting
|Trials ||No. of Patients ||Treatment Arms ||HR for OS (P value) ||Primary End Point Comparison in Months |
|Advanced gastric cancer: first line |
|Van Cutsem et al (149) (V325 study group) ||445 ||DCF vs CF ||TTP: 1.47 (< .001) OS: 1.29 (.02) || |
TTP: 5.6 vs 3.7
OS: 9.2 vs 8.6
|Cunningham et al (150) ||1,002 ||ECF vs ECX vs EOF vs EOX ||0.80 (.02) ||OS: 9.9 vs 9.9 vs 9.3 vs 11.2 |
|Koizumi et al (151) (SPIRITS) ||305 ||S-1 + cisplatin vs S-1 ||0.77 (.04) ||OS: 13.0 vs 11.0 |
|Ajani et al (178) (FLAGS) ||1,053 ||Cisplatin + S-1 vs cisplatin + 5-FU ||0.92 (.20) ||OS: 8.6 vs 7.9 |
|Advanced gastric cancer: second line |
|Thuss-Patience et al (161) (AIO) ||40 ||Irinotecan + BSC vs BSC ||0.48 (.012) ||OS: 4.0 vs 2.4 |
|Cook et al (162) (COUGAR-02) ||168 ||Docetaxel + ASC vs ASC ||0.67 (.01) ||OS: 5.2 vs 3.6 |
|Kang et al (164) ||202 ||Docetaxel or irinotecan vs BSC ||0.657 (.007) ||OS: 5.3 vs 3.8 |
|Higuchi et al (165) (TCOG GI–0801/BIRIP) ||130 ||Biweekly irinotecan + cisplatin vs irinotecan ||1.00 (.9823) || |
PFS: 3.8 vs 2.8
OS: 10.7 vs 10.1
Table 20-9Major Phase III Gastric Cancer Trials Involving Targeted Agents in the Advanced/Metastatic Setting ||Download (.pdf) Table 20-9 Major Phase III Gastric Cancer Trials Involving Targeted Agents in the Advanced/Metastatic Setting
|Trials ||No. of Patients ||Treatment Arms ||HR for OS (P value) ||Primary End Point Comparison in Months |
|Advanced gastric cancer: first Line |
|Bang et al (147) (ToGA)a ||584 ||CX/CF + trastuzumab vs CX/CF ||0.74 (.0046) ||OS: 13.8 vs 11.1 |
|Ohtsu et al (153) (AVAGAST) ||774 ||CF + bevacizumab vs CF ||0.87 (.1002) || |
OS: 12.1 vs 10.1
PFS: 6.7 vs 5.3
|Lordick et al (156) (EXPAND) ||904 ||CX + cetuximab vs CX ||1.004 (.9547) ||OS: 9.4 vs 10.7 |
|Waddell et al (157) (REAL -3) ||553 ||mEOC + panitumumab vs EOC ||1.37 (.013) ||OS: 8.8 vs 11.3 |
|Hecht et al (159) (TRIO – 013 / LOGiC) ||545 ||CapeOx + lapatinib vs CapeOx + placebo ||0.91 (.35) ||OS: 12.2 vs 10.5 |
|Advanced gastric cancer: second line |
|Fuchs et al (160) (REGARD) ||355 ||Ramucirumab + BSC vs BSC ||0.776 (.0473) ||OS: 5.2 vs 3.8 |
|Wilke et al (163) (RAINBOW) ||665 ||Paclitaxel + ramucirumab vs paclitaxel ||0.81 (.017) ||OS: 9.6 vs 7.4 |
|Ohtsu et al (166) (GRANITE-1) ||656 ||Everolimus + BSC vs placebo + BSC ||0.90 (.1244) ||OS: 5.4 vs 4.3 |
|Bang et al (167) (TyTAN) ||261 ||Lapatinib + paclitaxel vs paclitaxel ||0.84 (.2088) ||OS: 11.0 vs 8.9 |
|Dutton et al (168) (COG) ||449 ||Gefitinib vs placebo ||0.90 (.29) ||OS: 3.73 vs 3.63 |
|Advanced gastric cancer: third line |
|Qin et al (176) (apatinib) ||271 ||Apatinib + BSC vs BSC ||0.71 (.015) || |
OS: 6.5 vs 4.7
PFS: 2.6 vs 1.8
|Ohtsu et al (166) (GRANITE-1) ||656 ||Everolimus + BSC vs placebo + BSC ||0.90 (.1244) ||OS: 5.4 vs 4.3 |
The University of Texas MD Anderson Cancer Center Approach to Advanced Gastric, Gastroesophageal Junction and Esophageal Cancers
In terms of our approach to metastatic gastric, GEJ, or esophageal cancer, clearly in the context that this is no longer a curative situation, our approach is to provide palliation of symptoms and prolongation of life. In a select subgroup of patients who have small-volume disease and who are asymptomatic, it is reasonable to take a careful watch-and-wait strategy as long as the patient is comfortable with this approach. Otherwise, we would treat differently based on HER2 status. Clearly, in HER2-positive gastric cancer, there is an OS benefit with the addition of anti-HER2 therapy to first-line chemotherapy. It is our practice to typically use trastuzumab and not lapatinib because of the negative results of the lapatinib trial in combination with platinum-based doublet. Although no convincing data exist as to the benefit of the addition of HER2 therapy in gastric cancer, we extrapolate from the breast cancer trials and continue anti-HER2 therapy beyond progression, typically switching to an alternative agent. In the context of HER2-negative metastatic disease, our options continue to be limited. A reasonable option in the first-line setting is a platinum-based doublet with the addition of docetaxel or epirubicin depending on the performance status of the patient. In the second line, we use ramucirumab combined with a second chemotherapy agent. Figure 20-3B summarizes the MDACC approach to advanced gastric, GEJ, and esophageal cancer.
Although genetic profiling of tumors is becoming a more widely used tool in the treatment of gastric, GEJ, and esophageal cancer, patients are often found to have multiple and nontargetable mutations. Even when a potentially targetable mutation is found and the patient is treated with a given drug, we have found that responses are rare, likely because of our poor knowledge of driver mutations. Therefore, we do not consider genetic evaluation as a critical part of treatment, but rather emphasize the enrollment of patients into available clinical trials.
Supportive Measures for Advanced Gastric, Gastroesophageal Junction, and Esophageal Cancers
For patients with advanced gastric, GEJ, and esophageal cancers, the most important objective is symptom palliation rather than cure. The goal of symptom palliation is to optimize quality of life. Current or potential signs or symptoms that affect quality of life should be assessed during the initial evaluation of patients with unresectable disease. Available treatment options include external-beam radiotherapy without concurrent chemotherapy (177); chemotherapy; endoscopic palliation with luminal dilation, stents, or laser or chemical ablation; and palliative surgery. Palliative surgery is rarely performed because it is rare that the potential benefits clearly outweigh the risks of surgery. Several special issues to consider in this group of patients include (1) problems specifically associated with local disease, (2) nutrition, (3) diagnosis and treatment of tracheoesophageal fistulas, and (4) management of oral secretions.
All patients, especially those who present with more than 15% weight loss from their normal baseline, should undergo formal nutritional evaluation, and alternative nutritional support methods should be considered. Adequate nutrition and hydration are crucial to ensure that patients complete the full course of therapy. Jejunostomy feeding tubes (J-tubes), which are inserted primarily via a surgical procedure, can be considered in patients with gastric and GEJ cancer; they can be placed during the initial laparoscopic evaluation. Percutaneous gastrostomy feeding tubes, placed by endoscopic (percutaneous endoscopic gastrostomy) or radiologic (G-tube) guidance, can be considered for esophageal cancer. The continued use of jejunostomy, gastrostomy, or nasogastric feeding tubes is considered the first choice if nutrition cannot be supported orally.
All patients with advanced gastric, GEJ, and esophageal cancers are candidates for definitive chemoradiotherapy. Chemotherapy agents used in combination with radiotherapy include cisplatin, paclitaxel, carboplatin, or 5-FU. Patients with borderline performance status may not be candidates for definitive chemoradiotherapy, even with consistent nutritional support via feeding tubes. Therapy should be based on the patient’s most pressing symptoms. Malnutrition should be addressed, whenever feasible, with gastrostomy or a jejunostomy tube. Upper GI bleeding and pain can be palliated with radiotherapy, alone or with endoscopic cauterization. Finally, effective chemotherapy can directly improve symptoms such as dysphagia and pain, as well as indirectly improve nutrition and minimize bleeding risk and aspiration.