General Workup

WORKUP:
• H & P
• Upper GI endoscopy and biopsy
• Chest/abdominal CT with oral and IV contrast
• Pelvic CT with contrast as clinically indicated
• PET/CT evaluation (skull base to mid-thigh) if no evidence of M1 disease
• CBC and comprehensive chemistry profile
• Endoscopic ultrasound (EUS), if no evidence of M1 unresectable disease
• Endoscopic resection (ER) is essential for the accurate staging of early-stage cancers (T1a or T1b)
• Biopsy of metastatic disease as clinically indicated
• MSI-H/dMMR testing if metastatic disease is documented/suspected
• HER2 and PD-L1 testing if metastatic adenocarcinoma is documented/suspected
• Bronchoscopy, if tumor is at or above the carina with no evidence of M1 disease
• Assign Siewert category
• Nutritional assessment and counseling
• Smoking cessation advice, counseling, and pharmacotherapy as indicated
• Screen for family history

CLINICAL STAGE: Stage I–III (locoregional disease) VS Stage IV (metastatic disease)

HISTOLOGIC CLASSIFICATION: Squamous cell carcinoma VS Adenocarcinoma

ADDITIONAL EVALUATION

HISTOLOGY/CLINICAL STAGE: Squamous cell carcinoma, Stage I–III (locoregional disease*)

Multidisciplinary evaluation
• Consider enteric feeding tube (jejunostomy tube preferred) or PEG tube for preoperative nutritional support**
• Medically fit for surgery*** VS Non-surgical candidate****

* Celiac nodal involvement in cancers of the esophagogastric junction/distal esophagus may still be considered for combined modality therapy
** Percutaneous endoscopic gastrostomy (PEG) tube may be considered for patients with cervical esophagus receiving definitive chemoradiation or for patients with marginally resectable disease. Multidisciplinary expertise is recommended prior to placement of PEG tube.
*** Medically able to tolerate major surgery.
**** Medically unable to tolerate major surgery or medically fit patients who decline surgery.

ADDITIONAL EVALUATION

HISTOLOGY/CLINICAL STAGE: Adenocarcinoma, Stage I–III (locoregional disease*)

Multidisciplinary evaluation
• Consider enteric feeding tube (jejunostomy tube preferred) or PEG tube for preoperative nutritional support**
• Laparoscopy (optional) if no evidence of M1 disease and tumor is at esophagogastric junction (EGJ)
• Medically fit for surgery*** VS Non-surgical candidate****

* Celiac nodal involvement in cancers of the esophagogastric junction/distal esophagus may still be considered for combined modality therapy
** Multidisciplinary expertise is recommended prior to placement of PEG tube.
*** Medically able to tolerate major surgery.
**** Medically unable to tolerate major surgery or medically fit patients who decline surgery.

PRINCIPLES OF ENDOSCOPIC STAGING

Endoscopy has become an important tool in the diagnosis, staging, treatment, and surveillance of patients with esophageal and esophagogastric junction EGJ cancers. Although some endoscopy procedures can be performed without anesthesia, most are performed with the aid of conscious sedation administered by the endoscopist or assisting nurse or deeper anesthesia (monitored anesthesia care) provided by the endoscopist, nurse, a nurse anesthetist, or an anesthesiologist. Some patients who are at risk of aspiration during endoscopy may require general anesthesia.

DIAGNOSIS
• Diagnostic and surveillance endoscopies are performed with the goal of determining the presence and location of esophageal neoplasia and to biopsy any suspicious lesions. Thus, an adequate endoscopic exam addresses both of these components.
• The location of the tumor relative to the teeth and EGJ, the length of the tumor, the extent of circumferential involvement, and the degree of obstruction should be carefully recorded to assist with treatment planning. If present, the location, length, and circumferential extent of Barrett’s esophagus should be characterized in accordance with the Prague criteria, and mucosal nodules should be carefully documented.
• High-resolution endoscopic imaging and narrow-band imaging are presently available and may enhance visualization during endoscopy, with improved detection of lesions in Barrett’s and non-Barrett’s esophagus and stomach.
• Multiple biopsies, six to eight, using standard size endoscopy forceps should be performed to provide sufficient material for histologic interpretation. Larger forceps are recommended during surveillance endoscopy of Barrett’s esophagus for the detection of dysplasia.
• Endoscopic resection (ER) of focal nodules should be performed in the setting of early-stage disease to provide accurate depth of invasion, degree of differentiation, and the presence of vascular and/or lymphatic invasion. ER should be considered in the evaluation of areas of Barrett’s esophagus associated with high-grade dysplasia (HGD) and also patches of squamous cell dysplasia, specifically focusing on areas of nodularity or ulceration. Pathologists should be asked to provide an assessment of the depth of tumor infiltration into the lamina propria, muscularis mucosa, and submucosa; invasion of vascular structures and nerves; and the presence of tumor or dysplastic cells at the lateral and deep margins. ER may be fully therapeutic when a lesion less than or equal to 2 cm in diameter is fully removed and histopathologic assessment demonstrates well or moderate differentiation, invasion no deeper than the superficial submucosa, no lymphovascular invasion (LVI), and clear lateral and deep margins.
• Cytologic brushings or washings are rarely adequate in the initial diagnosis.

STAGING

• Endoscopic ultrasound (EUS) performed prior to any treatment is important in the initial clinical staging of neoplastic disease. Careful attention to ultrasound images provides evidence of depth of tumor invasion (T designation), presence of abnormal or enlarged lymph nodes likely to harbor cancer (N designation), and occasionally signs of distant spread, such as lesions in surrounding organs (M designation).
• Hypoechoic (dark) expansion of the esophageal wall layers identifies the location of tumor, with gradual loss of the layered pattern of the normal esophageal wall corresponding with greater depths of tumor penetration, correlating with higher T-categories. A dark expansion of layers 1–3 correspond with infiltration of the superficial and deep mucosa plus the submucosal, T1 disease. Isolated thickening of the mucosal layer alone may be difficult to appreciate resulting in loss of sensitivity of EUS for superficial disease. Similarly, standard EUS scopes, with 7.5–12 MHz frequency transducers, may lack the resolution to accurately distinguish the penetration of the tumor through the muscularis mucosa, or superficial from deep penetration of the submucosa. A dark expansion of layers 1–4 correlates with penetration into the muscularis propria, T2 disease, and expansion beyond the smooth outer border of the muscularis propria correlates with invasion of the adventitia, T3 disease. Loss of a bright tissue plane between the area of tumor and surrounding structures such as the pleura, diaphragm, and pericardium correlates with T4a disease, while invasion of surrounding structures such as the trachea, aorta, lungs, heart, liver, or pancreas correlates with T4b disease.
• For small, nodular lesions less than or equal to 2 cm, ER is encouraged as it provides a more accurate depth of invasion than the results of EUS. A decision to proceed to further therapy such as resection or ablation, or to consider the ER completely therapeutic would depend on the final pathologic assessment of the resection specimen.
• Mediastinal and perigastric lymph nodes are readily seen by EUS, and the identification of enlarged, hypoechoic (dark), homogeneous, well- circumscribed, rounded structures in these areas correlates with the presence of malignant or inflammatory lymph nodes. The accuracy of this diagnosis is significantly increased with the combination of features, but is also confirmed with the use of fine-needle aspiration (FNA) biopsy for cytology assessment. FNA of suspicious lymph nodes should be performed if it can be performed without traversing an area of primary tumor or major blood vessels, and if it will impact treatment decisions. The pre-procedure review of CT and PET scans is recommended, when available, prior to esophagogastroduodenoscopy (EGD)/EUS, to become fully familiar with the nodal distribution for possible FNA.
• Obstructing tumors may increase the risk of perforation while performing staging EUS exams. The use of wire-guided EUS probes, or miniprobes, may permit EUS staging with a lower risk of perforation. In certain cases, dilating the malignant stricture to allow completion of staging may be appropriate, but there is increased risk of perforation after dilation.

PRINCIPLES OF ENDOSCOPIC THERAPY

PRIMARY TREATMENT
• The goal of endoscopic therapy [by endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and/or ablation] is the complete removal or eradication of early-stage disease (pTis, pT1a, selected superficial pT1b without LVI) and pre-neoplastic tissue (Barrett’s esophagus).
• Early-stage disease, Tis, also known as HGD, needs to be fully characterized, including evaluating presence of nodularity, lateral spread, and ruling out multifocal disease, as well as ruling out lymph node metastases by EUS in select higher risk cases. This is important to permit decisions on endoscopic therapy with ablative methods such as radiofrequency ablation (RFA), cryoablation, photodynamic therapy (PDT), and/or ER. Areas of nodularity or ulceration should be resected rather than ablated. Completely flat, small lesions (≤2 cm) of squamous cell HGD/Tis (carcinoma in situ) and Barrett’s esophagus associated with flat HGD should be treated by ER as it provides more accurate histologic assessment of the lesion. Larger flat lesions (>2 cm) can be treated effectively by ER, but this is associated with greater risk of complications. Such lesions can be effectively treated by ablation alone, but there are very limited data on treating squamous cell HGD by ablation alone.
• Lesions that are found to be pathologically limited to the lamina propria or muscularis mucosae (pT1a), or the superficial submucosa (pT1b), in the absence of evidence of lymph node metastases, LVI, or poor differentiation grade can be treated with full ER. However, a thorough and detailed discussion regarding comparative risk of esophagectomy versus potential for concurrent nodal disease should be undertaken, preferably between patient and surgeon, especially in cases with larger tumors or deeper invasion. Ablative therapy of residual Barrett’s esophagus should be performed following ER. Complete eradication of Barrett’s esophagus can also be performed with more aggressive application of EMR (widefield EMR) or ESD at the initial intervention, if necessary to completely resect an area of superficial tumor or mucosal nodularity less than or equal to 2 cm in maximal dimension.
• The level of evidence for ablation of squamous cell carcinoma (SCC) after ER is low. However, additional ablation may be needed if there is multifocal HGD/carcinoma in situ elsewhere in the esophagus. Ablation may not be needed for lesions that are completely excised.
• Endoscopic therapy is considered “preferred” for patients with limited early-stage disease (Tis and T1a, less than or equal to 2 cm, and well or moderately differentiated carcinoma), because the risk of harboring lymph node metastases, local or distant recurrence, and death from esophageal cancer is low following endoscopic therapy.

TREATMENT OF SYMPTOMS
• Esophageal dilation can be performed with the use of dilating balloons or bougies to temporarily relieve obstruction from tumors, or treatment-related strictures. Caution should be exercised to avoid overdilation, to minimize the risk of perforation.
• Long-term palliation of dysphagia can be achieved with endoscopic tumor ablation by Nd:YAG Laser, PDT and cryoablation, or endoscopic and radiographic-assisted insertion of expandable metal or plastic stents.
• Long-term palliation of anorexia, dysphagia, or malnutrition may be achieved with endoscopic or radiographic-assisted placement of feeding gastrostomy or jejunostomy. The placement of a gastrostomy in the preoperative setting may compromise the gastric vasculature, thereby interfering with the creation of the gastric conduit in the reconstruction during esophagectomy and should be avoided.

POST-TREATMENT SURVEILLANCE
• Consider deferring assessment endoscopy with biopsy to 6 weeks or later after completion of preoperative therapy in patients whom avoidance of surgery is being considered.
• EUS exams performed after chemotherapy or radiation therapy have a reduced ability to accurately determine the present stage of disease. Similarly, biopsies performed after chemotherapy or radiation therapy may not accurately diagnose the presence of residual disease.
• Endoscopic surveillance following definitive treatment of esophageal cancer requires careful attention to detail for mucosal surface changes, and multiple biopsies of any visualized abnormalities. Strictures should be biopsied to rule out neoplastic cause. EUS-guided FNA should be performed if suspicious lymph nodes or areas of wall thickening are seen on cross-sectional imaging.
• Endoscopic surveillance after ablative therapy or ER of early-stage esophageal cancer should continue after completion of treatment. Biopsies should be taken of the neosquamous mucosa even in the absence of mucosal abnormalities as dysplasia may occasionally be present beneath the squamous mucosa.
• Endoscopic surveillance should also include a search for the presence of Barrett's esophagus and four-quadrant biopsies to detect residual or recurrent dysplasia. The ablation of residual or recurrent high-grade and low-grade dysplasia using RFA or cryoablation should be considered.
• Patients who have received therapeutic ER should have endoscopic surveillance.

PRINCIPLES OF PATHOLOGIC REVIEW AND BIOMARKER TESTING

Assessment of Overexpression or Amplification of HER2 in Esophageal and Esophagogastric Junction Cancers.

For patients with inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the esophagus or EGJ for whom trastuzumab therapy is being considered, assessment for tumor HER2 overexpression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) or other in situ hybridization methods is recommended.

*The NCCN Guidelines Panel recommends that HER2 immunohistochemistry be ordered/performed first, followed by in situ hybridization (ISH) methods in cases showing 2+ (equivocal) expression by IHC. Positive (3+) or negative (0 or 1+) HER2 IHC results do not require further ISH testing. Cases with HER2:CEP17 ratio ≥2 or an average HER2 copy number ≥6.0 signals/cell are considered positive by ISH/FISH.

Microsatellite Instability (MSI)* or Mismatch Repair (MMR)* Testing
• MMR or MSI testing should be considered on locally advanced, recurrent, or metastatic esophageal adenocarcinoma or EGJ, in patients who are candidates for treatment with PD-1 inhibitors. The testing is performed on formalin-fixed paraffin-embedded tissue and results are interpreted as MSI-high or mismatch protein repair-deficient in accordance with guidelines for colorectal cancer specimens.
MMR or MSI testing should be performed only in CLIA-approved laboratories.

PD-L1 Testing
• PD-L1 testing may be considered on locally advanced, recurrent, or metastatic esophageal adenocarcinoma in patients who are candidates for treatment with PD-1 inhibitors. An FDA-approved companion diagnostic test for use on formalin-fixed paraffin-embedded tissue is available as an aid in identifying gastroesophageal junction adenocarcinoma patients for treatment with PD-1 inhibitors. PD-L1 testing should be performed only in CLIA-approved laboratories.
• Assessment of PD-L1 Protein Expression in Esophageal and Esophagogastric Junction Cancers
This is a qualitative immunohistochemical assay using anti-PD-L1 antibodies for the detection of PD-L1 protein in formalin-fixed, paraffin- embedded (FFPE) tissues from esophageal or EGJ adenocarcinoma. A minimum of 100 tumor cells must be present in the PD-L1–stained slide for the specimen to be considered adequate for PD-L1 evaluation. A specimen is considered to have PD-L1 expression if the Combined Positive Score (CPS) ≥ 1. CPS is the number of PD-L1 staining cells (ie, tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.

PRINCIPLES OF SYSTEMIC THERAPY

• Systemic therapy regimens recommended for advanced esophageal and EGJ adenocarcinoma, SCC of the esophagus, and gastric adenocarcinoma may be used interchangeably (except as indicated).

• Regimens should be chosen in the context of performance status (PS), comorbidities, and toxicity profile.

• Trastuzumab should be added to chemotherapy for HER2 overexpressing metastatic adenocarcinoma.

• Two-drug cytotoxic regimens are preferred for patients with advanced disease because of lower toxicity. Three-drug cytotoxic regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation.

• Modifications of category 1 regimen or use of category 2A or 2B regimens may be preferred (as indicated), with evidence supporting more favorable toxicity profile without compromising efficacy.

• Doses and schedules for any regimen that is not derived from category 1 evidence is a suggestion, and subject to appropriate modifications depending on the circumstances.

• Alternate combinations and schedules of cytotoxics based on the availability of the agents, practice preferences, and contraindications are permitted.

• Preoperative chemoradiation is the preferred approach for localized adenocarcinoma of the thoracic esophagus or EGJ. Perioperative chemotherapy is an alternative option for distal esophagus and EGJ.

• In the adjuvant setting, upon completion of chemotherapy or chemoradiation, patients should be monitored for any long-term treatment- related complications.

The selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex.
Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, nutritional status, and comorbidity.
The optimal delivery of anticancer agents therefore requires a health care delivery team experienced in the use of anticancer agents and the management of associated toxicities in patients with cancer.

Gemcitabine and cisplatin (Southwest Oncology Group, Phase II trial)
Urba SG, et al. Invest New Drugs, 2004
Gemcitabine 1 gm/M2 on days 1,8,15 + cisplatin 100 mg/M2 on day 15. Repeat every 28 days.
Results: 64 patients from 37 institutions.
52 patients (81%) had adenocarcinoma, 10 patients (16%) had squamous cell carcinoma, 1 adenosquamous, and 1 undifferentiated.
32 patients had measurable disease. 26% of patients had prior chemotherapy, 30% had prior radiation, and 35% had prior surgery.
The treatment was generally well-tolerated. All 64 patients have died. 3 months/1 year survivals were 81%/20%. Median survival: 7.3 months.

Gemcitabine and cisplatin in patients with locally advanced/metastatic esophageal cancer. (Phase II trial)
Millar J, et al. British J of Cancer, 2005
Gemcitabine 1.25 gm → 1 gm/M2 on days 1,8 + cisplatin 75 mg/M2 on days 1. Repeat every 21 days.
Results: 32 patients with measurable disease: 3 CR and 18 PR. 9 patients had stable disease.
Overall response rate was 45%. (Squamous cell carcinoma: 71%, adenocarcinoma: 33%, p=0.036)
Median survival: 11 months.

Gemcitabine and cisplatin in patients with esophageal squamous cell carcinoma. (Phase II trial)
Huang J, et al. Chin Med J (Engl), 2011
Gemcitabine 1 gm/M2 over 30 minutes on days 1,8 + cisplatin 40 mg/M2 on days 1,2. Repeat every 21 days.
Results: 38 patients, Median follow-up 76 months.
Overall response rate was 42.1% (95%CI, 25.5%-56.5%).
Median progression-free/overall survivals: 4.1 months/10 months.
1 year/2 years/5 years survivals were 36.8%/10.5%/5.3%.

Preoperative Chemoradiation
(Infusional fluorouracil can be replaced with capecitabine)
Preferred Regimens
• Paclitaxel* and carboplatin (category 1)
• Fluorouracil and oxaliplatin (category 1)
Other Recomended Regimens
• Fluorouracil and cisplatin (category 1)
• Irinotecan and cisplatin (category 2B)
• Paclitaxel and fluoropyrimidine (5FU or capecitabine) (category 2B)

Perioperative Chemotherapy
(Only for adenocarcinoma of the thoracic esophagus or EGJ)
(3 cycles preoperative and 3 cycle postoperative)
Preferred Regimens
• Fluoropyrimidine and oxaliplatin**
• Fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) (category 1)***
Other Recomended Regimens
• Fluorouracil and cisplatin (category 1)

Preoperative Chemotherapy (2 cycles)
(Only for adenocarcinoma of the thoracic esophagus or EGJ)
• Fluorouracil and cisplatin (category 2B)

Definitive Chemoradiation
Infusional fluorouracil can be replaced with capecitabine
Preferred Regimens
• Fluorouracil and cisplatin (category 1)
• Fluorouracil* and oxaliplatin (category 1)
• Paclitaxel and carboplatin

Other Recomended Regimens
• Cisplatin with docetaxel or paclitaxel
• Irinotecan and cisplatin (category 2B)
• Paclitaxel and fluoropyrimidine
(fluorouracil or capecitabine) (category 2B)

Postoperative Chemoradiation
• Fluoropyrimidine (infusional fluorouracil* or capecitabine) before and after fluoropyrimidine-based chemoradiation

Postoperative Chemotherapy
• Capecitabine and oxaliplatin****

* Leucovorin is indicated with certain fluorouracil-based regimens.
** The use of this regimen and dosing schedules is based on extrapolations from published literature and clinical practice.
*** Due to toxicity, three-drug regimens are recommended only in select patients who are medically fit.
**** Cisplatin may not be used interchangeably with oxaliplatin in this setting.

PRINCIPLES OF SYSTEMIC THERAPY

Systemic Therapy for Unresectable Locally Advanced, Recurrent or Metastatic Disease (where local therapy is not indicated)
• Trastuzumab should be added to first-line chemotherapy for HER2 overexpressing metastatic adenocarcinoma
--- Combination with fluoropyrimidine and cisplatin (category 1)
--- Combination with other chemotherapy agents (category 2B)
--- Trastuzumab is not recommended for use with anthracyclines

First-Line Therapy
• Two-drug cytotoxic regimens are preferred because of lower toxicity.
• Three-drug cytotoxic regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation.
Preferred Regimens
• Fluoropyrimidine (fluorouracil* or capecitabine) and cisplatin (category 1) • Fluoropyrimidine (fluorouracil* or capecitabine) and oxaliplatin
Other Recommended Regimens
• Paclitaxel with cisplatin or carboplatin
• Docetaxel with cisplatin
• Fluoropyrimidine (fluorouracil* or capecitabine)
• Docetaxel
• Paclitaxel
• Fluorouracil* ** and irinotecan
• DCF modifications
--- Docetaxel, cisplatin, and fluorouracil*
--- Docetaxel, oxaliplatin, and fluorouracil
--- Docetaxel, carboplatin, and fluorouracil (category 2B)
• ECF (epirubicin, cisplatin, and fluorouracil) (category 2B)
• ECF modifications (category 2B)
--- Epirubicin, oxaliplatin, and fluorouracil
--- Epirubicin, cisplatin, and capecitabine
--- Epirubicin, oxaliplatin, and capecitabine

* Leucovorin is indicated with certain fluorouracil-based regimens.
** Capecitabine cannot be used interchangeably with fluorouracil in regimens containing irinotecan.

Second-Line or Subsequent Therapy
• Dependent on prior therapy and PS

Preferred Regimens
• Ramucirumab and paclitaxel for adenocarcinoma (category 1 for EGJ adenocarcinoma; category 2A for esophageal adenocarcinoma)
• Docetaxel (category 1)
• Paclitaxel (category 1)
• Irinotecan (category 1)
• Fluorouracil* ** and irinotecan • Pembrolizumab --- For second-line or subsequent therapy for MSI-H or dMMR tumors

Other Recommended Regimens
• Ramucirumab for adenocarcinoma (category 1 for EGJ adenocarcinoma; category 2A for esophageal adenocarcinoma)
• Irinotecan and cisplatin
• Pembrolizumab
--- For third-line or subsequent therapy for PD-L1 positive esophageal and EGJ adenocarcinoma
• Docetaxel and irinotecan (category 2B)

Treatment

Definitive Chemoradiation
For patients who are deemed either medically inoperable or have tumors that are unresectable, the efficacy of definitive chemoradiation has been established in numerous randomized controlled trials. For patients with squamous cell carcinomas of the esophagus, definitive chemoradiation may offer equivalent outcomes compared with preoperative chemoradiation followed by surgical resection.

Evidence (definitive chemoradiation):

A Radiation Therapy Oncology Group trial (RTOG-8501) randomly assigned patients to chemotherapy and radiation therapy versus radiation therapy alone. Patients were randomly assigned to receive radiation therapy alone (64 Gy in 32 fractions) or chemoradiation (50 Gy in 25 fractions) with concurrent cisplatin (75 mg/m2) and continuous-infusion 5-FU (1,000 mg/m2 on days 1 to 4 in weeks 1 and 5 followed by two additional cycles of chemotherapy administered 3 weeks apart).[Level of evidence: 1iiA]
There was an improvement in 5-year survival for the combined modality group (27% vs. 0%).
An 8-year follow-up of this trial demonstrated an OS rate of 22% for patients receiving chemoradiation therapy.

Intergroup-0123 (RTOG-9405 [NCT00002631]) was conducted in an attempt to improve upon the results of RTOG-8501. Intergroup-0123 randomly assigned 236 patients with localized esophageal tumors to undergo chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of 5-FU and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[Level of evidence: 1iiA]
Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using high-dose radiation.
At a 2-year median follow-up, no statistically significant differences in median survival were observed between the high-dose and conventional-dose radiation therapy arms (13 months vs. 18 months), 2-year survival (31% vs. 40%), or local and regional failures (56% vs. 52%).
There was a higher treatment mortality in the higher-dose arm (9% vs. 2%); however, 7 of 11 deaths in the high-dose arm occurred in patients who had received 50.4 Gy or less.

An Eastern Cooperative Oncology Group trial (EST-1282) evaluated 135 patients.[Level of evidence: 1iiA]
This trial showed that chemotherapy plus radiation therapy provided a better 2-year survival rate than did radiation therapy alone, similar to results from the intergroup trial.

The PRODIGE5/ACCORD17 (NCT00861094) trial sought to evaluate and compare the efficacy and safety of oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) versus 5-FU and cisplatin as the chemotherapy backbone among patients treated with definitive chemoradiation for localized esophageal cancer. In this multicenter, randomized, phase II and III trial, 267 patients were randomly assigned to receive either six cycles of FOLFOX (three cycles concomitant with radiation therapy), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), bolus 5-FU (400 mg/m2) and infusion 5-FU (1,600 mg/m2 over 46 hours) or four cycles of 5-FU (1,000 mg/m2 for 4 days) and cisplatin (75 mg/m2 on day 1). All patients received radiation therapy (50 Gy in 25 fractions).[Level of evidence: 1iiDiii]
With a median follow-up of 25.3 months, there was no significant difference in PFS (9.7 months with FOLFOX vs. 9.4 months with 5-FU and cisplatin; P = .64).
There was one death caused by toxicity in the FOLFOX group versus six deaths in the 5-FU and cisplatin arm (P = .066).
There were no significant differences in grade 3 or 4 adverse events between treatment groups. Among toxicities of all grades, paresthesia, sensory neuropathy, and increases in aspartate transaminase and alanine transaminase were more common in the FOLFOX group; whereas, increases in serum creatinine, mucositis, and alopecia were more common in the 5-FU and cisplatin group.
A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. OS was the primary outcome.[Level of evidence: 1iiA]
The analysis of 172 eligible, randomly assigned patients showed that OS at 2 years was not statistically significantly different between the two treatment groups (arm A, 39.9%; 95% CI, 29.4%–50.4%; arm B, 35.4%; 95% CI, 25.2%–45.6%; log-rank test for equivalence with 0.15, P < .007).
Local PFS was higher in the surgery group (2-year PFS, 64.3%; 95% CI, 52.1%–76.5%) than in the chemoradiation therapy group (2-year PFS, 40.7%; 95% CI, 28.9%–52.5%; HR for arm B vs. arm A, 2.1; 95% CI, 1.3–3.5; P < .003).
Treatment-related mortality was higher in the surgery group (12.8%) than in the chemoradiation therapy group (3.5%) (P < .03).

FFCD 9102 (NCT00416858) randomly assigned 259 patients with T3N0–1M0 thoracic esophageal cancer to receive either two cycles of 5-FU and cisplatin (days 1–5 and 22–26) and either conventional radiation therapy (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26). Patients with response were then randomly assigned to receive either surgical resection (arm A) or continuation of chemoradiation (arm B: three cycles of 5-FU plus cisplatin and either conventional 20 Gy or split-course 15 Gy radiation therapy).[Level of evidence: 1iiA]
Of the 259 randomly assigned patients, 230 (89%) had squamous cell carcinoma, and 29 patients (11%) had adenocarcinomas. The 2-year OS was 34% in patients randomly assigned to receive surgery versus 40% in patients randomly assigned to receive definitive chemoradiation (HR, 0.90; P = .44). Median survival was 17.7 months for surgery and 19.3 months for definitive chemoradiation.
The 3-month mortality rate was 9.3% in the surgery arm compared with 0.8% in the chemoradiation arm (P = .002).

Current Treatment of Esophageal Cancer and Promising Clinical Trials Underway

Siewert type I and type II tumors are to be esophageal tumors
With regard to adjuvant and neoadjuvant treatment of esophageal and gastroesophageal adenocarcinomas, we very much continue to administer preoperative chemoradiation. In general, treatment is given preoperatively. It is usually very difficult to give adjuvant treatment, but particularly so after an esophagectomy.
Esophageal adenocarcinoma: Preoperative chemoradiation + surgery. Complete response rates with chemoradiation alone are quite low, between 20% and 25%.
Esophageal squamous cell cancer: Definitive chemoradiation with observation. Pathologic response rate of almost 50%.

A potential alternative for adenocarcinoma tumors at the gastroesophageal junction is perioperative chemotherapy. Studies of perioperative chemotherapy for gastric cancer, such as the MAGIC and FLOT4 studies, have also included patients with gastroesophageal junction cancers. We still prefer to give chemoradiation to these individuals. This is mainly because, when the tumor is involving the esophagus and the gastroesophageal junction, a complete or R0 resection is achieved only about 70% of the time. The R0 resection rate is up to 90% with chemoradiation. However, in select patients, perioperative chemotherapy for gastroesophageal junction adenocarcinoma can also be considered, but such a decision should be made following a multidisciplinary review.

What therapy options are available for patients with advanced esophageal tumors?
Treatment differs for adenocarcinomas vs squamous cell carcinomas. With the exception of the KEYNOTE-181 study, treatment of squamous esophageal tumors has not really changed over the last 30 to 40 years and primarily consists of chemotherapy. The same chemotherapy drugs are active in both histologies: fluoropyrimidine, platinum agents, taxanes, and irinotecan. The normal sequence, throughout much of the world, is to consider a fluoropyrimidine/platinum doublet in the first-line setting; in the United States, the most widely used regimen is FOLFOX
In the second- or third-line setting, we would consider either a taxane or irinotecan.

Targeted therapies for adenocarcinomas
In 2010, based on the results of the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab was approved as the first targeted therapy for use in gastroesophageal and gastric cancer. Trastuzumab is used to treat tumors that are human epidermal growth factor receptor 2 (HER2)-positive (about 20% to 25% of tumors). The HER2 positivity rate is even higher in distal esophageal and gastroesophageal junction adenocarcinomas than it is in gastric cancer. So, trastuzumab in combination with FOLFOX is the standard of care for all HER2-positive esophageal or gastric adenocarcinomas.

in 2014, the anti-VEGF receptor antibody ramucirumab was approved in combination with paclitaxel in the second-line setting. Again, the approval was based on a gastric cancer study that also included patients with gastroesophageal junction adenocarcinomas. Since we now know that adenocarcinomas of the distal esophagus, gastroesophageal junction, and proximal stomach are molecularly the same based on the results of The Cancer Genome Atlas analysis,[5] we extrapolate that same data to distal esophageal adenocarcinomas as well.

In September 2017, the FDA approved pembrolizumab based on the results of the KEYNOTE-059 trial. This single-arm study evaluated almost 260 patients who received pembrolizumab as third-line or greater therapy. In patients with PD-L1–positive tumors, there did appear to be modest benefits; specifically, the response rate in this treatment-refractory patient population was about 12%. There was also durable survival: the 12-month survival rate was approximately 25% in a treatment-refractory population.
the FDA approval of pembrolizumab is contingent on the tumor cells being PD-L1–positive. This is determined using a specific assay with the 22C3 antibody. PD-L1 positivity is defined as a combined positive score of at least 1, which indicates that there is some staining in either the tumor cells or the peritumoral mononuclear cells.
(Note: On July 30, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication.)