NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Upper gastrointestinal tract cancers originating in the esophagus, esophagogastric junction (EGJ), and stomach constitute a major health problem globally. Esophageal cancer is the sixth most common cause of cancer deaths worldwide, and is more common in men.1 It is endemic in many parts of the world, particularly in developing nations, where it is the fourth most common cause of cancer death.1 In 2014, an estimated 18,170 people were diagnosed with and 15,450 people died of esophageal cancer in the United States.2 The incidence of esophageal cancer represents one of the widest variations, with a 60-fold difference between high- and low-incidence regions.3 High-prevalence areas include Asia, southern and eastern Africa, and northern France.4 In Western countries, the most common site of esophageal cancer is in the lower third of the esophagus, which often involves the EGJ.
Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma,5 both of which are more common in men. SCC is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and most Western European countries. SCCs have become increasingly less common in the West, accounting for less than 30% of all esophageal cancers in the United States and Western Europe. Adenocarcinoma is diagnosed predominantly in white men, for whom the incidence has dramatically increased. However, the overall incidence of adenocarcinoma is gradually increasing in men of all ethnic backgrounds and in women.6 SCC seems to be more sensitive to chemotherapy, chemoradiation, and radiation therapy (RT) than adenocarcinoma, but the
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, Version 1.2015
Version 1.2015, 01-08-15 ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 2; 10.6004/jnccn.2015.0028
Staging
The TNM classification developed by the AJCC in 2002 was based on pathologic review of the surgical specimen in patients who underwent surgery as primary therapy. The revised 2010 AJCC staging classification is based on the risk-adjusted random forest analysis of the data generated by the World-wide Esophageal Cancer Collaboration (WECC) of 4627 patients treated with primary esophagectomy without preoperative or postoperative therapy.8 In the data reported by the WECC, survival decreased with increasing depth of tumor invasion (pT), presence of regional lymph node metastases (pN), and distant metastases (pM).9 Additionally, survival was somewhat worse for pT1b (submucosal) tumors than for pT1a (intramucosal) tumors, and for SCC than for adenocarcinomas.
The 2010 revised staging system includes separate stage groupings for SCC and adenocarcinoma, and is for esophageal and EGJ cancers, including cancer within the first 5 cm of the stomach that extends into the EGJ or distal thoracic esophagus.8 However, this new classification may not work well for baseline clinical staging or for patients who underwent preoperative therapy. The 2010 classification has several other shortcomings, including inclusion of proximal 5 cm of the stomach; lack of guidance for regional resectable and unresectable cancer; the emphasis on the number of lymph nodes rather than their anatomic locations and significance; and lymph node size is not addressed.
Patient outcomes may correlate with clinical stage of the cancer at diagnosis, but the best correlation with survival is associated with the surgical pathologic stage (whether or not patient has received preoperative therapy). Although surgical pathology produces the most accurate staging, the advent of better imaging techniques has improved preclinical staging.10 In North America and many western European countries, where screening programs for early detection of esophageal and EGJ cancers are not in use or practical because of low incidence, the diagnosis is often made late in the disease course. At diagnosis, nearly 50% of patients have cancer that extends beyond the locoregional confines of the primary, less than 60% of patients with locoregional cancer can undergo a curative resection, and approximately 70% to 80% of resected specimens harbor metastases in the regional lymph nodes. Thus, clinicians are often treating an advanced-stage, incurable cancer in newly diagnosed patients.
Esophagogastric Junction
In 1996, Siewert11 classified the EGJ adenocarcinoma into 3 types based on the anatomic location of the tumor epicenter or the location of the tumor mass.11 If the tumor epicenter or more than 66% of the tumor mass is located more than 1 cm above the anatomic EGJ, then the tumor is classified as an adenocarcinoma of the distal esophagus, type I. If the tumor epicenter or tumor mass is located within 1 cm proximal or 2 cm distal to the anatomic EGJ, the adenocarcinoma is classified as type II. If the tumor epicenter or more than 66% of the tumor mass is located more than 2 cm below the anatomic EGJ, the tumor is classified as type III.11
In 2000, the classification was slightly changed.12 Siewert type I tumors were defined as adenocarcinoma of the distal esophagus with the tumor center located within 1 to 5 cm above the anatomic EGJ. Siewert type II tumors were defined as the true carcinoma of the cardia with the tumor center within 1 cm above and 2 cm below the EGJ. Siewert type III was defined as the subcardial carcinoma with the tumor center between 2 to 5 cm below the EGJ, infiltrating the EGJ and the distal esophagus from below.
In the revised AJCC staging system, tumors with a midpoint in the lower thoracic esophagus, EGJ, or within the proximal 5 cm of the stomach that extends into the EGJ or esophagus (Siewert types I and II) are classified as adenocarcinoma of the esophagus for staging purposes.8 All other cancers with a midpoint in the stomach more than 5 cm distal to the EGJ or those within 5 cm of the EGJ but not extending into the EGJ or esophagus (Siewert type III) are staged using the gastric cancer staging system. This approach remains a subject of disagreement, some confusion, and debate. Based on thorough pretreatment staging, an individualized therapeutic approach may be preferred for specific patients and tumor locations. Therapeutic decisions may be refined according to the location of the individual tumor, nodal distribution, and specific requirements for local control.
Assessment of HER2/neu Overexpression
Human epidermal growth factor receptor 2 (HER2) gene and/or HER2 protein expression has been implicated in the development of gastric and EGJ adenocarcinomas.13 HER2/neu amplification and overexpression are more frequent in adenocarcinoma of the esophagus (15%–30%) than SCC of the esophagus (5%–13%).14–16 HER2/neu overexpression in esophagogastric cancer varies widely (2%–45%).17 HER2/neu-positivity has been reported to be higher in patients with EGJ cancer than in those with gastric cancer.18,19 In the ToGA trial, which evaluated the addition of trastuzumab to chemotherapy in patients with HER2/neu-positive advanced gastric cancer, HER2/neu-positivity rates were 33% and 21%, respectively, for patients with EGJ and gastric cancers.20
However, unlike in breast cancer, the prognostic significance of HER2/neu expression in patients with esophageal cancer is not clear. It has been shown that HER2/neu overexpression correlates with tumor invasion and lymph node metastasis, and therefore indicates a poor prognosis.17 HER2/neu overexpression seems to be associated with poorer survival, especially in patients with SCC of the esophagus.14
Immunohistochemistry (IHC) is the most widely used, primary test for HER2 overexpression assessment, and evaluates the membranous immunostaining of the tumor cells including intensity and the extent of staining and percentage of immunoreactive tumor cells, with scores ranging from 0 to 3+. Fluorescence in situ hybridization (FISH) is usually reserved for verifying results that are considered equivocal by IHC. These results are expressed as the ratio between the number of HER2 gene copies and the number of chromosome 17 centromere (CEP17) within the nucleus, counted in at least 20 cancer cells (HER2:CEP17).
According to the HER2 scoring system for breast cancer proposed by ASCO and the College of American Pathologists, uniform intense membrane staining in more than 30% of invasive tumor cells is considered positive for HER2 overexpression. However, because of 2 major differences in HER2 staining patterns between the breast and gastric cancer cells (incomplete membrane staining in a basolateral pattern and greater tumor heterogeneity, both of which are more frequent in gastric cancer), it was reported that the application of this scoring system would not identify many patient with gastric cancer who could otherwise be candidates for anti-HER2 therapy.21,22 Results from 2 separate series also showed that the HER2 scoring system for breast cancer identified a significantly lower percentage of patients with gastric cancer meeting the criteria for HER2-positivity by IHC (5.4% vs 11.0% in the ToGA trial).23,24
In 2008, Hoffmann et al21 developed a modified 4-tier HER2 scoring system specific for gastric cancer using the assessment area cut-off of at least 10% stained tumor cells for resection specimens and omitting this area cut-off for biopsy specimens. In a subsequent validation study (447 prospective diagnostic gastric cancer specimens), this scoring system was found to be reproducible between different pathologists.22 This modified HER2 scoring system was also used in the ToGA trial.23
HER2 testing is now recommended for all patients with metastatic EGJ adenocarcinoma at diagnosis. The NCCN Guidelines recommend that assessment of HER2 status should be performed first using IHC following the modified scoring system used in the ToGA trial21,23 (see ESOPH-B, page 205).
Surgery
Surgery is a major component of treatment for resectable disease. A major development in surgical therapy for esophageal cancer has been the marked reduction in surgical morbidity and mortality as a result of improvements in staging techniques, patient selection, support systems, and surgical experience. Recent randomized trials have shown that preoperative chemoradiation (CROSS study)25 and perioperative chemotherapy (MAGIC trial; predominantly a gastric cancer trial with a small group of patients with lower esophageal and EGJ cancers)26 significantly improved survival in patients with resectable esophageal and EGJ cancers.
All patients should be assessed for physiologic ability to undergo esophageal resection,27 including whether they are medically fit (ie, medically able to tolerate general anesthesia and major abdominal and/or thoracic surgery). Most patients with early-stage cancer can tolerate resection. For those with locally advanced disease, lymph node involvement has been shown to be a strong independent predictor of poor survival with surgery alone; these patients are therefore considered for preoperative therapy followed by surgery. Patients with potentially resectable esophageal cancer should undergo multidisciplinary evaluation.
Clinical staging using endoscopic ultrasound (EUS) with fine-needle aspiration (FNA), if indicated, with chest and abdomen CT scan, and PET scan (PET/CT preferred over PET alone) should be performed before surgery to assess resectability.28 Patients with locally advanced cancer (T3 or N1) should have access to medical and radiation oncology consultations. Pretreatment nutritional support should be considered for patients with significant dysphagia and weight loss to support them during induction chemoradiation. Enteral nutrition is the best option and a jejunostomy feeding tube is preferred over a gastrostomy feeding tube or percutaneous endoscopic gastrostomy tube.
Esophagectomy should be considered for all physiologically fit patients with localized, resectable, thoracic esophageal cancer (>5 cm from cricopharyngeus) and intra-abdominal esophageal or EGJ cancer. Esophagectomy should be performed in high-volume esophageal cancer centers by experienced surgeons.29 Resection type is dictated by size, stage, and location of the primary tumor, as well as the surgeon’s experience and the patient’s preference. Cervical or cervicothoracic esophageal cancers less than 5 cm from the cricopharyngeus should be treated with definitive chemoradiation. Palliative esophagectomy can be considered for patients with cervical esophageal cancer who develop localized, resectable esophageal recurrence or untreatable stricture after definitive chemoradiation if there is no distant recurrence.30
The surgical approach for Siewert type I and II EGJ tumors is similar to that described previously. Siewert type III tumors are treated as gastric cancers, and the surgical approach is similar to that described in the NCCN Guidelines for Gastric Cancer11,31,32 (to view the most recent version of these guidelines, visit NCCN.org). In some cases, additional esophageal resection may be necessary to obtain adequate surgical margins.
Laparoscopy may be useful in select patients for the detection of radiographically occult metastatic disease, especially in patients with Siewert type II or III tumors.33 Positive peritoneal cytology in the absence of overt peritoneal metastases is associated with a poor prognosis in patients with EGJ adenocarcinoma.34 Patients with advanced tumors, clinical stage T3 tumors, or node-positive tumors should be considered for laparoscopic staging with peritoneal washings.
Lymph node dissections (or lymphadenectomy) can be performed using the standard or extended (en bloc) technique. In a retrospective SEER analysis of 29,659 patients diagnosed with invasive esophageal cancer, patients who had more than 12 lymph nodes examined had a significant reduction in mortality compared with those who had no lymph node evaluation, and patients who had 30 or more lymph nodes examined had a significantly lower mortality than any other groups.35 The number of lymph nodes removed has also been shown to be an independent predictor of survival after esophagectomy.36,37 A recent report from the WECC database, which analyzed 4627 patients who had esophagectomy alone, also suggested that a greater extent of lymphadenectomy was associated with increased survival for all patients with pN0M0 moderately and poorly differentiated cancers and all node-positive (pN+) cancers.37 For patients undergoing esophagectomy without preoperative chemoradiation, these NCCN Guidelines for Esophageal and EGJ Cancers recommend that at least 15 lymph nodes should be removed for adequate nodal staging (to view the complete and most recent version, visit NCCN.org). The optimum number of nodes to be removed and examined after preoperative chemoradiation is unknown, although similar lymph node resection is recommended.
Combined Modality Therapy
Combined modality therapy has been used for the treatment of esophageal and EGJ cancers because of the poor overall survival (OS) rates in patients treated with resection alone.38
Definitive Chemoradiation Therapy
Concurrent chemoradiation therapy versus RT, each without resection, was studied in the only randomized trial (RTOG 85-01) designed to deliver adequate doses of systemic chemotherapy with concurrent RT.39,40 In this trial, patients with SCC or adenocarcinoma with clinical stage T1–3,N0–1,M0 received 4 cycles of 5-FU and cisplatin (CF),39,40 and RT (50 Gy at 2 Gy/d) was given concurrently with day 1 of chemotherapy. The control arm was RT alone (64 Gy). Patients who were randomly assigned to receive combined modality therapy showed a significant improvement in both median survival (14 vs 9 months) and 5-year OS (27% vs none), with projected 8-year and 10-year survival rates of 22% and 20%, respectively. The incidence of local failure as the first site of failure (defined as local persistence plus recurrence) was also lower in the combined modality arm (47% vs 65%).
The INT 0123 trial was the follow-up trial to RTOG 85-01, which compared 2 different RT doses used with the same chemotherapy regimen (CF).41 In this trial, 218 patients with either SCC (85%) or adenocarcinoma (15%) and clinical stage T1–4,N0–1,M0 were randomly assigned to a higher dose of RT (64.8 Gy) or the standard dose (50.4 Gy) with the same chemotherapy regimen (CF). No significant difference was observed in median survival (13 vs 18 months), 2-year survival (31% vs 40%), and locoregional failure or locoregional persistence of cancer (56% vs 52%) between the high-dose and standard-dose RT arms, respectively.
The results of RTOG 85-01 and INT 0123 established definitive chemoradiation with CF using the RT dose of 50.4 Gy as the standard of care for patients with SCC or adenocarcinoma of the esophagus.
Recent reports have also confirmed the efficacy of definitive chemoradiation in patients with locally advanced esophageal cancer.42–45 Definitive chemoradiation with docetaxel and cisplatin resulted in a high overall response rate in patients with SCC (98%; 71% complete response). At the median follow-up of 18 months, median OS time was 23 months.42 The rate of locoregional progression-free survival (PFS), PFS, and 3-year OS rates were 60%, 29%, and 37%, respectively. Definitive chemoradiation with carboplatin and paclitaxel was also well tolerated resulting in superior OS, disease-specific survival, durable locoregional control, and palliation in approximately half of the patients with unresectable esophageal cancer.43,44 In a recent randomized phase III trial, 267 patients with unresectable esophageal cancer or those medically unfit for surgery were randomized to definitive chemoradiation with either FOLFOX4 (5-FU, leucovorin, and oxaliplatin) or CF.45 Most patients had SCC, and the median follow-up was 25.3 months. Median PFS was 9.7 months in the FOLFOX4 arm and 9.4 in the 5-FU and cisplatin arm (P=.64).45 Although definitive chemoradiation with FOLFOX was not associated with a PFS benefit compared with chemoradiation with CF, the investigators suggest that FOLFOX may be a more convenient option for patients with localized esophageal cancer who may not be candidates for surgery.
Preoperative Chemoradiation Therapy
Preoperative chemoradiation followed by surgery is the most common approach for patients with resectable esophageal cancer, although this approach remains investigational.46 Results of 2 meta-analyses have shown that preoperative chemoradiation therapy plus surgery significantly reduced 3-year mortality and locoregional recurrence; preoperative chemoradiation therapy also downstaged the tumor when compared with surgery alone.47,48 Another recent meta-analysis (1854 patients;12 randomized trials comparing preoperative chemoradiation vs surgery alone) showed a significant survival benefit for preoperative chemoradiation in patients with resectable adenocarcinoma of the esophagus.49 In patients with locally advanced esophageal cancer, Swisher et al50 reported that preoperative chemoradiation was associated with increased pathologic complete response (28% vs 4%) and 3-year OS (48% vs 29%) compared with preoperative chemotherapy. In a retrospective analysis of 363 patients with adenocarcinoma of the lower esophagus, OS after preoperative chemoradiation was significantly shorter for patients with Barrett esophagus compared with those without (32 vs 51 months, respectively).51
However, randomized trials comparing surgery alone with preoperative chemoradiation followed by surgery in patients with clinically resectable cancer have shown conflicting results.25,52–58 Results from the multicenter, phase III, randomized CROSS study, the largest trial in its class, showed that preoperative chemoradiation with carboplatin and paclitaxel significantly improved OS and disease-free survival (DFS) compared with surgery alone in patients with resectable (T2–3,N0–1,M0) esophageal or EGJ cancers (368 patients;75% had adenocarcinoma and 23% had SCC).25 The R0 resection rate was higher in the chemoradiation arm compared with the surgery alone arm (92% and 69%, respectively). Median survival was 49 months in the chemoradiation arm compared with 24 months in the surgery alone arm. The 1-, 2, 3-, and 5-year survival rates were 82%, 67%, 58%, and 47%, respectively, in the chemoradiation arm compared with 70%, 50%, 44%, and 34%, respectively, in the surgery alone arm. The pathologic complete response rate was higher in patients with SCC than in those with adenocarcinoma (49% and 23%, respectively; P=.008); histologic type was not a prognostic factor for survival. After a minimum follow-up of 24 months, the overall recurrence rate was 35% in the chemoradiation arm compared with 58% in the surgery arm. Preoperative chemoradiation significantly reduced locoregional recurrence from 34% to 14% (P<.001) and peritoneal carcinomatosis from 14% to 4% (P<.001).59
In contrast, the results of another phase III, randomized, controlled study (FFCD 9901) showed that preoperative chemoradiation therapy with CF did not improve the R0 resection rate and OS, but enhanced the postoperative mortality rate for patients with localized stage I or II esophageal cancer compared with surgery alone.58 After a median follow-up of 93.6 months, the R0 resection rate was 93.8% for chemoradiation versus 92.1% for surgery alone (P=.749). The 3-year OS rates were 47.5% and 53.0%, respectively (P=.94), and the postoperative mortality rate was 11.1% for chemoradiation compared with 3.4% for surgery alone (P=.049).
The CALGB 9781 trial was a prospective randomized Intergroup trial that evaluated trimodality therapy versus surgery alone for the treatment of patients with stage I–III esophageal cancer.60 The study fell short of its accrual goals with only 56 patients enrolled. Patients were randomized to undergo either surgery alone or receive concurrent chemoradiation therapy with CF; the median follow-up was 6 years. An intent-to-treat analysis showed a median survival of 4.5 versus 1.8 years, favoring trimodality therapy. Patients receiving trimodality therapy also had a significantly better 5-year survival rate (39% vs 16%). Although the accrual rate was low, the observed difference in survival was significant, and this study showed that trimodality therapy may be an appropriate standard of care for patients with localized esophageal cancer.
In a recent phase II randomized study, preoperative chemoradiation with CF did not show any survival benefit compared with preoperative chemotherapy in patients (n=75) with resectable adenocarcinoma of the esophagus and EGJ.61 Median PFS was 26 and 14 months for chemotherapy and chemoradiation, respectively (P=.37). The corresponding median OS was 32 and 30 months, respectively (P=.83). However, the pathologic response rate (31% vs 8%; P=.01) and R1 resection rate (0% vs 11%; P=.04) favored chemoradiation therapy.
Postoperative Chemoradiation Therapy
The landmark Intergroup trial SWOG 9008/INT-0116 investigated the effect of surgery plus postoperative chemoradiation on the survival of patients with resectable adenocarcinoma of the stomach or EGJ.62 In this trial, 556 patients (20% had EGJ adenocarcinoma) with resected adenocarcinoma of the stomach or EGJ (stage IB-IV,M0 according to 1988 AJCC staging criteria) were randomly assigned to surgery plus postoperative chemoradiation (n=281; bolus 5-FU and leucovorin before and after concurrent chemoradiation with 5-FU and leucovorin) or surgery alone (n=275). The majority of patients had T3–T4 tumors (69%) and node-positive disease (85%), whereas only 31% of the patients had T1–T2 tumors and 14% had node-negative tumors. Surgery was not part of the trial protocol, but resection of all detectable disease was required for participation. Patients were eligible for the study only after recovery from surgery. Postoperative chemoradiation (offered to all patients with tumors ≥T1, with or without lymph node metastases) significantly improved OS and relapse free survival. Median OS was 27 and 36 months in the surgery-only and chemoradiation groups, respectively (P=.005). The chemoradiation group had better 3-year OS (50% vs 41%) and relapse-free survival rates (48% vs 31%) than the surgery-only group. A significant decrease was also seen in the chemoradiation group in local failure as the first site of failure (19% vs 29%). With more than 10 years of median follow-up, survival remains improved in patients with stage IB–IV,M0 gastric or EGJ adenocarcinoma treated with postoperative chemoradiation. No increases in late toxic effects were noted.63
Results of the INT-0116 trial have established postoperative chemoradiation therapy as a standard of care in patients with completely resected gastric or EGJ adenocarcinoma who have not received preoperative therapy. However, the regimen used in this trial (bolus 5-FU and leucovorin before and after chemoradiation with the same combination) was associated with high rates of grade 3 or 4 hematologic and gastrointestinal toxicities (54% and 33%, respectively). Among the 281 patients assigned to the chemoradiation group, only 64% of patients completed treatment and 17% discontinued treatment because of toxicity, and 3 patients died as a result of chemoradiation-related toxic effects, including pulmonary fibrosis, cardiac event, and myelosuppression.
Although the INT-0116 trial formed the basis for the recommendation of postoperative chemoradiation for patients with completely resected gastric or EGJ adenocarcinoma, the recommended doses or schedule of chemotherapy agents used in the trial are no longer recommended because of concerns about toxicity. In retrospective analyses, the addition of postoperative chemoradiation has been associated with survival benefit in patients with lymph node–positive locoregional esophageal cancer.64,65 Data from a more recent retrospective analysis also showed that postoperative chemoradiation according to the INT-0116 protocol resulted in improved DFS after curative resection in patients (n=211) with EGJ adenocarcinomas and positive lymph nodes who did not receive neoadjuvant chemotherapy.66 The 3-year DFS rate after postoperative chemoradiation was 37% compared with 24% after surgery alone.
Alternative postoperative chemoradiation regimens have been evaluated by other investigators.67,68 In a phase II nonrandomized trial that evaluated postoperative concurrent chemoradiation with CF in patients with poor-prognosis esophageal and EGJ adenocarcinoma, the projected rates of 4-year OS, freedom from recurrence, distant metastatic control, and locoregional control were 51%, 50%, 56%, and 86%, respectively, for patients with lymph node–positive tumors (T3 or T4), which are better than the historical outcomes with surgery alone.67 In the randomized Intergroup trial CALGB 80101, postoperative chemoradiation with epirubicin, cisplatin, and 5-FU (ECF) before and after 5-FU and RT did not improve survival compared with the INT-0116 regimen in patients who have undergone curative resection for gastric or EGJ adenocarcinoma.68 The efficacy of postoperative chemoradiation compared with surgery alone has not been demonstrated in a randomized trial of patients with esophageal cancer.
Chemotherapy
Preoperative Chemotherapy
Chemotherapy alone has been investigated in the preoperative setting. The RTOG 8911 (Intergroup 0113) trial randomized patients with potentially resectable esophageal cancer of both histologic types to either receive preoperative chemotherapy (CF) or surgery alone. Preliminary results did not show any survival benefit between the 2 groups.69 Long-term results showed that 63% of patients treated with chemotherapy followed by surgery underwent complete resection (R0) compared with 59% treated with surgery alone.70 Although preoperative chemotherapy decreased the incidence of R1 resection (4% vs 15% in the surgery-only group), there was no improvement in OS between the 2 groups.
In the MRC OEO2 trial, 802 patients with potentially resectable esophageal cancer were randomly assigned to either 2 cycles of preoperative 5-FU (1000 mg/m2/d via continuous infusion for 4 days) and cisplatin (80 mg/m2 on day 1) repeated every 21 days followed by surgery, or surgery alone.71 However, this trial had several clinical methodology problems. Nearly 10% of patients received off-protocol preoperative RT, and patients accrued in China were excluded. At a short median follow-up time of 2 years, patients treated with preoperative chemotherapy had a 3.5-month survival time advantage (16.8 vs 13.3 months). Long-term follow-up confirmed that preoperative chemotherapy improves survival in patients with resectable esophageal cancer.72 At a median follow-up of 6 years, DFS and OS were significantly longer for the preoperative chemotherapy group. The difference in survival favoring the preoperative chemotherapy group (23% vs 17% for surgery) was consistent in patients with SCC and adenocarcinoma.72
Long-term results of another randomized trial also demonstrated that preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved OS and DFS in patients (n=169) with SCC of the esophagus.73 Median OS was 16 months for patients assigned to preoperative chemotherapy followed by surgery compared with 12 months for surgery alone; 5-year survival rates were 26% and 17%, respectively.
An individual, patient, data-based meta-analysis showed a small but significant OS and DFS benefit favoring preoperative chemotherapy over surgery alone.74 The results of an updated meta-analysis, which included 1981 patients from 9 randomized trials comparing preoperative chemotherapy versus surgery alone, showed a survival benefit for preoperative chemotherapy in patients with resectable adenocarcinoma of the esophagus.49
Perioperative Chemotherapy
The Medical Research Council performed the first well-powered phase III trial (MAGIC trial) that evaluated perioperative chemotherapy for patients with resectable gastroesophageal cancer.26 In this trial, 503 patients were randomized to receive either surgery alone or perioperative chemotherapy (preoperative and postoperative chemotherapy) with ECF and surgery. Patients were randomized before surgical intervention. Most (74%) of the patients had stomach cancer, whereas a small group of patients had adenocarcinoma of the lower esophagus (14%) and EGJ (11%). Most patients had T2 or higher tumors (12% had T1 tumors, 32% had T2 tumors, and 56% had T3–T4 tumors), and 71% of patients had node-positive disease. The perioperative chemotherapy group had a greater proportion of T1 and T2 tumors (51.7%) and less advanced nodal disease (N0 or N1; 84%) than the surgery group (36.8% and 70.5%, respectively). Perioperative chemotherapy significantly improved PFS (P<.001) and OS (P=.009). The 5-year survival rates were 36% among those who received perioperative chemotherapy and 23% in the surgery group.
In a more recent FNCLCC/FFCD trial (N=224; 75% with adenocarcinoma of the lower esophagus or EGJ and 25% had gastric cancer), Ychou et al75 reported that perioperative chemotherapy with 5CF significantly increased the curative resection rate, DFS, and OS in patients with resectable cancer. At the median follow-up of 5.7 years, the 5-year OS rate was 38% for patients in the surgery plus perioperative chemotherapy group and 24% for those in the surgery-only group (P=.02); corresponding 5-year DFS rates were 34% and 19%, respectively. This trial was prematurely terminated because of low accrual.
The results of these 2 studies have established perioperative chemotherapy as another option for the standard of care for patients with resectable adenocarcinoma of the lower esophagus and EGJ.
Chemotherapy for Locally Advanced or Metastatic Cancer
Cisplatin is one of the most active chemotherapeutic agents, with a single-agent response rate consistently in the range of 20% or greater.76 Several other agents including irinotecan,77–79 docetaxel,80,81 paclitaxel,82,83 and etoposide84 have also shown single-agent activity in patients with advanced or metastatic esophageal cancer. CF is the most investigated and most commonly used regimen for patients with esophageal cancer, resulting in response rates of 20% to 50%.
Cisplatin plus paclitaxel or docetaxel, with or without 5-FU, has also demonstrated activity in patients with locally advanced EGJ or metastatic esophageal cancers.85–90 In a randomized multinational phase III study (V325), 445 untreated patients were randomized to receive either docetaxel, cisplatin, and 5-FU (DCF; every 3 weeks) or CF.89 Most patients had advanced gastric cancer and 19% to 25% had EGJ cancer. At a median follow-up of 13.6 months, time to progression was significantly longer with DCF compared with CF (5.6 vs 3.7 months; P<.001). Median OS was significantly longer for DCF compared with CF (9.2 vs 8.6 months; P=.02), at a median follow-up time of 23.4 months; the overall confirmed response rate was also significantly higher with DCF than CF (37% and 25%, respectively; P=.01).89 Various modifications of the DCF regimen with the intent to improve tolerability are being evaluated in clinical trials for patients with advanced esophagogastric cancer.91–95
The REAL-2 trial (30% of patients with esophageal cancer) was a randomized, multicenter, phase III study comparing capecitabine with 5-FU and oxaliplatin with cisplatin in 1002 patients with advanced esophagogastric cancer.96 Patients with histologically confirmed adenocarcinoma, SCC, or undifferentiated cancer of the esophagus, EGJ, or stomach were randomized to receive 1 of 4 epirubicin-based regimens: ECF; epirubicin, oxaliplatin, and 5-FU (EOF); epirubicin, cisplatin, and capecitabine (ECX); and epirubicin, oxaliplatin, and capecitabine (EOX). Median follow-up was 17.1 months. Results from this study suggest that capecitabine and oxaliplatin are both as effective as CF in patients with previously untreated advanced esophagogastric cancer. Compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. The toxic effects from 5-FU and capecitabine were not different.
Irinotecan-based combination regimens have also been evaluated in prospective studies as first-line therapy for patients with advanced or metastatic esophageal or EGJ cancers.97–103 The results of a randomized phase III study (N=337) showed that irinotecan in combination with 5-FU (IF) and folinic acid was noninferior to CF in terms of PFS (estimated probabilities of PFS at 6 and 9 months were 38% and 20% for IF, respectively, vs 31% and 12%, respectively for CF) but not for OS (9.0 vs 8.7 months for CF) and time to treatment progression (5.0 vs. 4.2 months for CF; P=.018).98 IF was associated with a more favorable toxicity profile. In a phase II study that evaluated 5-FU and folinic acid (AIO regimen) in combination with irinotecan in patients with locally advanced or metastatic esophageal cancer (adenocarcinoma or SCC), partial response was achieved in 33% of evaluable patients (n=19); 38% had stable disease and 8% had progressive disease.99 Median survival was 20 and 10 months, respectively, for patients with adenocarcinoma and SCC. A more recent randomized phase III study (French Intergroup Study) compared 5-FU, leucovorin, and irinotecan (FOLFIRI) with ECF as first-line treatment in patients with advanced or metastatic gastric or EGJ adenocarcinoma.103 In this study, 416 patients (65% had gastric adenocarcinoma and 33% had EGJ adenocarcinoma) were randomized to receive either FOLFIRI or ECF. After a median follow-up of 31 months, median time to treatment failure was significantly longer with FOLFIRI than with ECX (5.1 vs 4.2 months; P=.008).103 There were no significant differences in median PFS (5.3 vs 5.8 months; P=.96), median OS (9.5 vs 9.7 months; P=.95), or response rate (39.2% vs 37.8%). FOLFIRI was less toxic and better tolerated than ECF. The NCCN panel felt that FOLFIRI is an acceptable option for first-line therapy for patients with advanced or metastatic EGJ adenocarcinoma.
Irinotecan in combination with 5-FU or docetaxel or capecitabine has also demonstrated activity in patients with advanced or metastatic esophagogastric cancer that have progressed on platinum-based chemotherapy.100,104,105
Combination chemotherapy regimens containing oxaliplatin,106,107 carboplatin,108 mitomycin,109 and gemcitabine110,111 have also shown activity in patients with advanced or metastatic esophageal cancer. A phase III trial conducted by the German Study Group showed that the combination of 5-FU, leucovorin, and oxaliplatin (FLO) was associated with significantly less toxicity and showed a trend toward improved median PFS (5.8 vs 3.9 months) compared with 5-FU, leucovorin, and cisplatin (FLP) in patients with metastatic esophagogastric cancer.107 However, no significant differences were seen in median OS (10.7 vs 8.8 months, respectively) between the FLO and FLP regimens. In patients older than 65 years, FLO resulted in significantly superior response rates (41.3% vs 16.7%), time to treatment failure (5.4 vs 2.3 months), and PFS (6.0 vs 3.1 months), and an improved OS (13.9 vs 7.2 months) compared with FLP, respectively. Combination of carboplatin and paclitaxel was moderately active with a response rate of 43% in patients with advanced esophageal cancer.108 However, 52% of patients had neutropenia (grade 3/4). In a prospective randomized study, the combination of mitomycin, cisplatin, and fluorouracil (protracted intravenous infusion) was equally efficient to ECF (protracted intravenous infusion) for patients with advanced esophagogastric cancer, but the quality of life was superior with the ECF regimen.109
In randomized clinical trials, no consistent benefit was seen for any specific chemotherapy regimen, and chemotherapy showed no survival benefit compared with best supportive care for patients with advanced esophageal cancer.112 Palliative chemotherapy is not known to provide any survival advantage, but it may improve the quality of life in patients with metastatic or unresectable esophageal cancer.113 Adequately powered phase III studies are lacking.
Targeted Therapies
The ToGA study is the first randomized, prospective, multicenter, phase III trial to evaluate the efficacy and safety of trastuzumab in HER2/neu-positive gastric and EGJ adenocarcinoma in combination with cisplatin and a fluoropyrimidine.23 In this trial, 594 patients with HER2/neu-positive (3+ on IHC- or FISH-positive [HER2:CEP17 ≥2]), locally advanced, recurrent, or metastatic gastric and EGJ adenocarcinoma were randomized to receive trastuzumab plus chemotherapy (5-FU or capecitabine and cisplatin) or chemotherapy alone.23 The majority of patients had gastric cancer (80% in the trastuzumab group and 83% in the chemotherapy group). Median follow-up was 19 and 17 months, respectively. There was a significant improvement in median OS with the addition of trastuzumab to chemotherapy compared with chemotherapy alone in patients with HER2/neu overexpression or amplification (13.8 vs 11.0 months, respectively; P=.046). This study established trastuzumab in combination with chemotherapy as a new standard of care for patients with HER2/neu-positive advanced or metastatic gastric and EGJ adenocarcinoma.
However, the benefit of trastuzumab was limited only to patients with a tumor score of IHC 3+ or IHC 2+ and were FISH-positive. There was no significant survival benefit for patients whose tumors were IHC 0 or 1+ and were FISH-positive.23 In the posthoc subgroup analysis of the ToGA trial, the addition of trastuzumab to chemotherapy substantially improved OS in patients with tumors that were IHC 2+ and FISH-positive or IHC 3+ (n=446; 16.0 vs 11.8 months; hazard ratio [HR], .65) compared with those with tumors that were IHC 0 or 1+ and FISH-positive (n=131; 10.0 vs 8.7 months; HR, 1.07).
Ramucirumab, a VEGFR-2 antibody, has shown promising results in the treatment of patients with previously treated advanced or metastatic gastric or EGJ cancers in phase III clinical trials.114,115 An international, randomized, multicenter, placebo-controlled, phase III trial (REGARD) demonstrated a survival benefit for ramucirumab in patients with advanced gastric or EGJ adenocarcinoma progressing after first-line chemotherapy.114 In this study, 355 patients were randomized to receive either ramucirumab (n=238; 178 patients with gastric cancer; 60 with EGJ adenocarcinoma) or placebo (n=117; 87 patients with gastric cancer; 30 with EGJ adenocarcinoma). Median OS was 5.2 months for patients treated with ramucirumab compared with 3.8 months for placebo (P=.047). Ramucirumab was associated with higher rates of hypertension than the placebo group (16% vs 8%), whereas rates of other adverse events were mostly similar between the 2 groups. In a more recent international phase III randomized trial (RAINBOW) that evaluated paclitaxel with or without ramucirumab in patients with metastatic gastric or EGJ adenocarcinoma progressing on first-line chemotherapy, combination paclitaxel and ramucirumab resulted in significantly higher OS, PFS, and overall response rate compared with paclitaxel alone.115 In this study, 665 patients were randomized to ramucirumab plus paclitaxel (n=330) or paclitaxel alone (n=335). Median OS was significantly longer for ramucirumab plus paclitaxel compared with paclitaxel alone (9.63 vs 7.36 months; P<.0001). The median PFS was 4.40 and 2.86 months, respectively, for the treatment groups. The overall response rate was 28% for ramucirumab plus paclitaxel compared with 16% for paclitaxel alone (P=.0001). Neutropenia and hypertension were more common with ramucirumab plus paclitaxel.
Based on the results of these 2 studies, ramucirumab as single agent or in combination with paclitaxel was recently FDA approved for the treatment for patients with advanced EGJ adenocarcinoma refractory to or progressive following first-line therapy with platinum- or fluoropyrimidine-based chemotherapy.
Treatment Guidelines
The management of patients with esophageal and EGJ cancers requires the expertise of several disciplines, including surgical, medical, and radiation oncology, and gastroenterology, radiology, and pathology. Additionally, the presence of nutritional services, social workers, nursing, palliative care specialists, and other supporting disciplines are also desirable. Geneticists should be engaged when appropriate. Hence, the panel believes in an infrastructure that encourages multidisciplinary treatment decision-making by members of any discipline taking care of patients with esophagogastric cancer. Optimally at each meeting, the panel encourages participation of all relevant disciplines. The recommendations made by the multidisciplinary team may be considered advisory to the primary group of treating physicians of the particular patient. (See “Principles of Multidisciplinary Team Approach for Esophagogastric Cancers,” available online, in these guidelines, at NCCN.org [ESOPH-E]).
Workup
Patients who are newly diagnosed should undergo a complete history, physical examination, CBC and chemistry profile, biopsy (to confirm histologic classification and metastatic cancer), and an endoscopy with biopsy of the entire upper gastrointestinal tract (ESOPH-1, page 196). If the cancer is located at or above the carina, bronchoscopy (including biopsy of any abnormality and cytology of the washings) should be performed. For patients in whom the upper gastrointestinal tract cannot be visualized, a double-contrast barium study of the upper gastrointestinal tract is optional. CT scan (with oral and intravenous contrast) of the chest and abdomen should also be performed. Pelvic CT should be obtained when clinically indicated. EUS and PET/CT evaluation is recommended if metastatic cancer is not evident. HER2/neu testing is recommended if metastatic disease is documented or suspected (see “Assessment of HER2/neu Overexpression,” page 212). The NCCN Guidelines recommended assessment of Siewert tumor type as part of the initial workup in all patients with EGJ adenocarcinoma.11,12 The NCCN Guidelines also recommend screening for family history of esophageal or EGJ cancers. Referral to a cancer genetics professional is recommended for those with a known high-risk syndrome associated with esophageal and EGJ cancers.
PET/CT scans are useful for the initial staging and evaluation of patients after chemoradiation before surgery for the detection of distant lymphatic and hematogenous metastases.116–118 PET/CT scan has been shown to improve lymph node staging and the detection of stage IV esophageal cancer.119 It has also been shown to be an independent predictor of OS in patients with nonmetastatic esophageal cancer.120 Additionally, a recent study reported that combined PET/CT scans are more accurate than EUS-FNA and CT scan for predicting nodal status and complete response after neoadjuvant therapy in patients with esophageal cancer.121 When used alone, PET/CT and CT suggest targets for biopsy; however, false-positive results are common. Combined PET/CT scans are emerging and seem to be useful for restaging patients and monitoring response to primary therapy. A recent retrospective analysis involving patients with biopsy-proven esophageal cancer identified in a prospectively held database showed that the addition of PET/CT to standard staging led to changes in the multidisciplinary recommendations in 38.2% patients, improving the patient selection for radical treatment.122
Initial workup enables patients to be classified into 2 groups with the following characteristics: locoregional cancer (stages I–III) or metastatic cancer (stage IV).
Additional Evaluation
In patients with apparent locoregional cancer, additional evaluations may be needed to assess their medical condition and feasibility of resection, especially for patients with celiac-positive disease. These evaluations may include pulmonary function studies, cardiac testing, and nutritional assessment. Nasoduodenal or jejunostomy tube should be considered for preoperative nutritional support; percutaneous endoscopic gastrostomy is not recommended. In patients with adenocarcinoma of the esophagus or EGJ, laparoscopic staging of the peritoneal cavity should be considered (optional) if there is no evidence of metastatic disease (M1).33 Evaluation of the colon using barium radiograph or colonoscopy may be warranted if colon interposition is planned as part of the surgical procedure. A superior mesenteric artery angiogram should be considered only in selected patients when colon interposition is planned.
Patients with locoregional cancer are further classified into the following groups after additional evaluation:
-
Medically fit patients
-
Nonsurgical candidates able to tolerate chemotherapy or chemoradiation
-
Nonsurgical candidates unable to tolerate chemotherapy or chemoradiation
Management of Locoregional Cancer in Medically Fit Patients
Primary Treatment: Primary treatment options for patients with T1b, N+ and those with locally advanced resectable tumors (T2-T4a, any regional N) include preoperative chemoradiation (preferred),25 definitive chemoradiation (only for patients who decline surgery),40,41,45 perioperative chemotherapy,26 or esophagectomy (for patients with low-risk and well-differentiated lesions <2 cm; see ESOPH-13, page 198).
Definitive chemoradiation is the preferred treatment for patients with unresectable T4b tumors and occasionally can facilitate surgical resection in selected patients.44
Fluoropyrimidine- or taxane-based regimens are recommended for preoperative and definitive chemoradiation. See “Principles of Systemic Therapy” for list of specific regimens (available online, in these guidelines, at NCCN.org).
Additional Treatment: Restaging (eg, with CT scan with contrast, if PET/CT is not performed; PET/CT or PET; upper gastrointestinal endoscopy with biopsy [optional after preoperative chemoradiation]) is recommended after completion of preoperative or definitive chemoradiation for all patients with SCC or adenocarcinoma. Response assessment with PET/CT or PET scan (category 2B) should be performed 5 to 6 weeks after completion of preoperative therapy (see ESOPH-14, page 199).
Adjuvant treatment options (after preoperative and definitive chemoradiation) are based on the outcome of response assessment. Esophagectomy is recommended for patients with no evidence of disease and for those with persistent local disease after preoperative chemoradiation. Alternatively, patients with no evidence of disease may be observed (category 2B) and those with persistent local disease can be managed with palliative therapy. Following definitive chemoradiation, patients with no evidence of disease can be observed and those with persistent local disease can be treated with esophagectomy or palliative therapy.
Esophagectomy is the preferred treatment option for all patients after preoperative chemotherapy for patients with adenocarcinoma.
Patients with unresectable or metastatic disease after definitive or preoperative chemoradiation should be considered for palliative therapy, depending on their performance status.
Postoperative Treatment: Postoperative treatment is based on the surgical margins, nodal status, and histology. The efficacy of postoperative treatment has not been established in randomized trials for patients with esophageal cancer. Available evidence for the use of postoperative chemoradiation (only for patients who have not received preoperative therapy) and perioperative chemotherapy for patients with adenocarcinoma of the distal esophagus or EGJ comes from prospective randomized clinical trials involving patients with gastric cancer that have included patients with adenocarcinoma of the distal esophagus or EGJ.26,62
For Patients Who Have Not Received Preoperative Therapy: No further treatment is necessary for patients with Tis and T1, N0 tumors if no residual disease is present at the surgical margins (R0 resection). Based on the results of the INT-0116 trial, the panel included postoperative fluoropyrimidine-based chemoradiation for all patients with T3–T4a tumors and node-positive T1–T2 tumors.62,63 Given the lack of evidence from randomized clinical trials showing any survival benefit for postoperative chemoradiation for patients with T2, N0 tumors, postoperative chemoradiation is recommended (category 2B) only for selected patients with high-risk features (poorly differentiated or higher-grade cancer, lymphovascular invasion, neural invasion, or age <50 years) if no residual disease is present at the surgical margins (R0 resection).123 Alternatively, patients with node-negative T2–T4a tumors can also be observed (see ESOPH-15, page 200).
The panel acknowledges that the INT-0116 trial formed the basis for the recommendation of postoperative chemoradiation for patients with completely resected gastric cancer.62,63 However, the panel does not recommend the doses or the schedule of chemotherapy agents as used in the INT-0116 trial because of concerns regarding toxicity. Instead, the panel recommends the use of fluoropyrimidine (infusional 5-FU or capecitabine) before and after fluoropyrimidine-based chemoradiation.
Patients with microscopic (R1 resection) or macroscopic residual disease with no distant metastatic disease (R2 resection) should be treated with fluoropyrimidine-based chemoradiation. Palliative therapy is an alternative option for patients with macroscopic residual disease.
For Patients Who Have Received Preoperative Therapy: Postoperative chemotherapy (category 1), if received preoperatively, is recommended for all patients (irrespective of the nodal status) if no residual disease is present at the surgical margins (R0 resection).26 Observation is an option for patients who have not received preoperative chemotherapy. Alternatively, patients with node-positive adenocarcinoma could be treated with chemoradiation (category 2B), if not received preoperatively. However, this approach has not been evaluated in prospective studies.
Patients with microscopic (R1 resection) or macroscopic (R2 resection) residual disease should be treated with fluoropyrimidine-based chemoradiation if they have not received it preoperatively. Alternatively, patients with microscopic residual disease (R1 resection) can be observed until progression, and patients with macroscopic residual disease (R2 resection) can be treated with palliative therapy.
Management of Locoregional Cancer in Nonsurgical Candidates
Fluoropyrimidine- or taxane-based definitive chemoradiation is the preferred treatment option for technically resectable locally advanced cancer (T2–T4a, any regional N) in nonsurgical candidates who are able to tolerate chemotherapy or chemoradiation. Alternatively, these patients can also be treated with chemotherapy or RT or best supportive care.
Palliative RT or best supportive care are the appropriate options for nonsurgical candidates who are unable to tolerate chemotherapy or chemoradiation (see ESOPH-17, page 202).
Follow-up After Resection or Definitive Chemoradiation
All patients should be followed systematically. For asymptomatic patients, follow-up should include a complete history and physical examination every 3 to 6 months for 1 to 2 years, then every 6 to 12 months for 3 to 5 years, and annually thereafter. A CBC, multichannel serum chemistry evaluation, upper gastrointestinal endoscopy with biopsy, and imaging studies should be obtained as clinically indicated. In addition, some patients may require dilatation of an anastomotic or a chemoradiation-induced stricture. Nutritional assessment and counseling may be extremely valuable. HER2/neu testing should be performed if metastatic adenocarcinoma was present at diagnosis.
Management of Locally Advanced, Metastatic, or Recurrent Disease
Locoregional recurrence after esophagectomy can be treated with fluoropyrimidine- or taxane-based concurrent chemoradiation in patients who have not received prior chemoradiation (see ESOPH-18, page 203). Other options include best supportive care or surgery or chemotherapy. Selected patients with anastomotic recurrences can undergo re-resection.
When recurrence develops after chemoradiation therapy with no prior esophagectomy, the clinician should determine whether the patient is medically fit for surgery and if the recurrence is resectable (see ESOPH-18, page 203). If both criteria are met, esophagectomy remains an option. When patients experience another recurrence after surgery, the cancer is assumed to be incurable and palliative therapy should be provided as described for locally advanced or metastatic cancer. Palliative therapy is recommended for medically unfit patients and those who develop an unresectable or metastatic recurrence.
Phase III trials for locally advanced or metastatic esophageal cancer have not been performed for many years. The survival benefit of second-line chemotherapy compared with best supportive care has been demonstrated in a small cohort of patients with lower esophageal or EGJ adenocarcinoma included in gastric adenocarcinoma phase III trials.124,125 In a randomized phase III study, second-line chemotherapy with irinotecan significantly prolonged OS compared with best supportive care in patients with metastatic or locally advanced gastric or EGJ adenocarcinoma (n=40).124 The study was closed prematurely because of poor accrual. Median survival was 4.0 months in the irinotecan arm compared with 2.4 months in the best supportive care-only arm. In a recent open-label, multicenter, phase III, randomized trial, the addition of docetaxel to active symptom control was associated with a survival benefit for patients with advanced, histologically confirmed adenocarcinoma of the esophagus, EGJ junction, or stomach that had progressed on or within 6 months of treatment with combination chemotherapy with platinum and fluoropyrimidine.125 In this study, patients (n=168) with an ECOG performance status of 0–2 were randomly assigned to receive docetaxel plus active symptom control or active symptom control alone. After a median follow-up of 12 months, the median OS was 5.2 months for patients with the docetaxel group compared with 3.6 months for those in the active symptom control group (P=.01). Docetaxel was associated with higher incidence of grade 3/4 neutropenia, infection, and febrile neutropenia. However, disease-specific, health-related quality-of-life measures also showed benefits for docetaxel in reducing dysphagia and abdominal pain.
Docetaxel and irinotecan are included as options for second-line therapy for patients with locally advanced or metastatic disease. Other regimens included in the guidelines for patients with locally advanced or metastatic disease are derived from the gastric adenocarcinoma phase III trials that have included patients with lower esophageal and/or EGJ cancer.
First-line therapy with 2-drug chemotherapy regimens is preferred for patients with advanced or metastatic disease. Three-drug regimens should be reserved for medically fit patients with good performance status and access to frequent toxicity evaluation. The selection of a second-line therapy regimen depends on prior therapy and performance status. The panel consensus was that no category 1 evidence supports any specific regimens as second-line or third-line therapy for patients with advanced or metastatic disease. This remains an active area of investigation.
Based on the results of the ToGA trial, the guidelines recommend trastuzumab with chemotherapy for patients with a tumor score of IHC 3+ and IHC 2+ with evidence of HER2 amplification by FISH (HER2:CEP17 ratio ≥2).23 Trastuzumab is not recommended for patients with a tumor score of IHC 0 or 1+. The use of trastuzumab in combination with an anthracycline is not recommended. Based on recent FDA approvals, the guidelines have included ramucirumab as a single agent or in combination with paclitaxel as options for second-line therapy in patients with advanced or metastatic esophageal or EGJ adenocarcinoma (category 1 for EGJ adenocarcinoma; category 2A for esophageal adenocarcinoma).114,115
Best supportive care is always indicated for patients with locally advanced, metastatic, or recurrent disease. The decision to offer best supportive care alone or with chemotherapy is dependent on the patient’s performance status (see ESOPH-19, page 204). Karnofsky Performance Status (KPS)126,127 and ECOG Performance Status (ECOG PS)128 are the 2 commonly used scales to assess the performance status of patients with cancer. Patients with a KPS score of 60 or lower or an ECOG PS score of 3 or higher should probably be offered best supportive care only. Patients with better performance status (KPS score ≥60 or an ECOG PS score ≤2) may be offered chemotherapy along with best supportive care. Further treatment after 2 sequential regimens depends on the patient’s performance status and availability of clinical trials. See “Principles of Systemic Therapy” for a list of specific regimens (ESOPH-14, page 199).
Summary
Multidisciplinary team management is essential for patients with esophageal and EGJ cancers. Several advances have been made in staging procedures and therapeutic approaches. Targeted therapies have produced encouraging results in the treatment of patients with advanced esophageal and EGJ cancers. Trastuzumab plus chemotherapy is recommended for patients with HER2/neu-positive advanced or metastatic adenocarcinoma. Ramucirumab as a single agent or in combination with paclitaxel is included as option for second-line therapy for patients with advanced or metastatic adenocarcinoma. Best supportive care is an integral part of treatment, especially in patients with locally advanced or metastatic disease. The panel encourages patients to participate in well-designed clinical trials investigating novel therapeutic strategies to enable further advances.
Individual Disclosures of the NCCN Esophageal and Esophagogastric Junction Cancers
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