Рак пищевода

The American Cancer Society’s Oncology in Practice: clinical management (2018)

Edited by American Cancer Society


Введение

Наблюдается значительное изменение в менеджменте рака пищевода или гастроэзофагеального соединения (GEJ) от операции только к мультимодальному подходу. Несколько клинических исследований и метаанализы продемонстрировали преимущество выживания пи неоадъювантной терапии до операции [1-3].

Заболеваемость и смертность

Ежегодно в Соединенных Штатах (США) диагностируется ~16 940 новых случаев рака пищевода (13 360 у мужчин и 3580 у женщин) (1% диагнозов рака), и наблюдается ~ 15 450 смертей от этого заболевания (2,64% смертей от рака) [4]. Уровень заболеваемости раком пищевода, основанный на случаях, диагностированных в США в период с 2009 по 2013 год, составлял ~ 4,3 на 100 000 человек в год. Около 61,79% из этих случаев рака пищевода являлись аденокарциномами (AC) и 32,8% — плоскоклеточными карциномами (SCC) [5]. Уровень смертности за тот же период составил 4,1 на 100 000 человек в год.

Во всем мире диагностируются ~455 800 случаев рака пищевода и наблюдаются 400 200 летальных случаев каждый год [6]. Показатели заболеваемости на международном уровне варьируют более чем в 21 раз, причем самые высокие показатели наблюдаются в южной и восточной части Африки и в восточной Азии, а самые низкие — в западной Америке. Заболеваемость AC пищевода увеличивается в некоторых западных странах вследствие роста ожирения, в то время как частота SCC снижается в результате сокращения курения табака и потребления алкоголя. Однако в некоторых азиатских странах, таких как Тайвань, SCC увеличивается из-за увеличения табакокурения и потребления алкоголя [4].

Этиология

Возраст, раса, этническая принадлежность и пол

The median age at diagnosis in the US is 67 years and 30.1% of patients are at least 75 years of age at the time of diagnosis. The esophageal cancer (all histologies combined) incidence rates for males and females in the US are 7.4 and 1.7 per 100,000 persons per year, respectively. The overall esophageal cancer incidence rates (per 100,000 persons per year) in the US are highest among non-Hispanic Whites (4.8) and African Americans (4.4), and are lowest for Asian Americans/Pacific Islanders (2.0) and Hispanics (2.8). Among racial and ethnic groups in the US, the proportion of adenocarcinomas among esophageal cancers is highest among Whites (69.1%), American Indians/Alaska Natives (61.3%), and Hispanics (57.4), and lowest for African Americans (16.6%) and Asian Americans/Pacific Islanders (26.7%) [5].

Плоскоклеточная карцинома

In high incidence areas, there is no gender specificity for SCC, while it is more common in men in low incidence areas. Several risk factors have been identified to predict an increased risk of SCC. The most common risk factors are smoking and alcohol consumption. Dietary factors include foods containing N-nitroso compounds found in pickled vegetables, chewing areca nuts or betel quid, high temperature beverages, red meat intake, low selenium, and zinc deficiency, while intake of fruits, vegetables, and folate are associated with a reduced risk of SCC. Increased risk is associated with pre-existing esophageal disease such as achalasia and prior caustic injury. Prior gastrectomy, atrophic gastritis, human papillomavirus, tylosis, use of bisphosphonates, previous upper aerodigestive tract cancer, and poor oral hygiene are also associated with an increased risk of SCC [7]. SCC of the esophagus is associated with several hereditary cancer predisposition syndromes, including tylosis (focal nonepidermolytic palmoplantar keratoderma, also known as Howel-Evans syndrome), Fanconi anemia, and Bloom syndrome [3].

Аденокарциномы

The most significant risk factor for the development of esophageal AC is gastroesophageal reflux disease (GERD). Chronic reflux causes the squamous epithelium to undergo columnar metaplasia to Barrett esophagus (BE) which in turn may become increasingly dysplastic and eventually evolve into AC. Although most cases of BE are sporadic, several familial clusters have been reported [3]. Other risk factors include smoking (particularly in BE patients), obesity, Helicobacter pylori infections (inverse association) [8], use of drugs that decrease lower esophageal pressure (nitroglycerine, β agonists, anticholinergics), prior cholecystectomy, and exposure to N-nitroso compounds. Alcohol is not associated with increased risk of AC, which may be lessened with wine consumption. COX2. inhibition with nonsteroidal anti-inflammatory drugs is not protective. There is also a suggestion that there might be a protective effect with cereal fiber and antioxidants [7].

Клиническая картина

Наиболее распространенный симптом — прогрессирующая дисфагия (90%-ое), ведущая к потере веса. Другие находки включают одинофагию, боль в груди, кашель и лихорадку, ассоциированную с возможными трахеоэзофагеальными фистулами, дисфонию, ассоциированную с вовлечением в опухоль рекуррентного гортанного нерва, и мелену в результате внутрипросветного кровотечения. Пациенты с кровоточащая опухолями могут испытать значительную утомляемость вследствие анемии.

Анатомия, патология и пути диссеминации

The esophagus is broken down into three regions; cervical, thoracic, and gastroesophageal junction (GEJ). The cervical esophagus starts from the inferior aspect of the cricoid cartilage at the cricopharyngeus muscle to the thoracic inlet or sternal notch. These cancers tend to behave more like head and neck cancers. The thoracic esophagus starts at the thoracic inlet and continues to the diaphragmatic hiatus. The thoracic esophagus is further subdivided into upper, middle, and distal esophageal subsites. The upper esophagus starts at the thoracic inlet at 18–20 cm (location in the esophagus is measured from the incisors) and extends to the level of the tracheal bifurcation at 23–25 cm. The mid-thoracic esophagus starts at the tracheal bifurcation and extends midway down to the GEJ at 32 cm. The distal esophagus starts at 32 cm and extends down to the GEJ, roughly 40 cm from the incisors. GEJ cancers involve the squamocolumnar transition and are further subdivided by the Siewert classification into three classes [9]. Siewert type 1 AC start in the distal esophagus and usually arise from an area with specialized intestinal metaplasia and may infiltrate the GEJ from above. Siewert type 2. tumors arise immediately adjacent to the GEJ. Siewert type 3. tumors start subcardially and extend superiorly to or past the GEJ and distal esophagus. Typically, most SCC arise in the upper and middle esophagus, while AC mostly occur in the distal esophagus and GEJ [4].

Pathways of nodal spread are dictated by tumor location, but all cancers can spread locally to invade local structures and distantly to the lungs, liver, bones, abdomen, peritoneum, and less likely, brain. Regionally, cervical esophageal cancers spread regionally to cervical, scalene, supraclavicular nodes, and mediastinal nodes. Upper and middle esophageal cancers spread to supraclavicular, mediastinal, and periesophageal lymph nodes. Tumors above the carina have a higher incidence of involved supraclavicular lymph nodes. Tumors of the distal esophagus and GEJ, involve periesophageal, celiac, perigastric, and gastrohepatic ligament lymph nodes. Siewert type 3. tumors behave more like gastric cancers and spread to periportal, peripancreatic, periduodenal, perigastric, and paraaortic nodes.

Диагностическое обследование

Diagnosis of esophageal cancer is usually through direct visualization through esophagogastroduodenoscopy with biopsy of suspicious lesions. Endoscopic ultrasound (EUS) staging is done for staging of the primary tumor, to assess invasion of local structures, for determination of resectability (invasion of pleura, pericardium or diaphragm versus aorta, trachea, bronchus, and vertebral body), and regional lymph node status, unless other examinations have already identified distant metastases. Contrast-enhanced computed tomography (CT) of the thorax and abdomen alone and in conjunction with positron emission tomography (PETCT), and EUS are used for staging [3]. PET utilizing [18. F]-fluorodeoxyglucose is more sensitive compared to CT alone or EUS for detecting the presence of metastatic disease [10–12]. PET-CT scans have been shown to affect the surgical management of up to 20% of patients [13]. While PET-CT scans are more sensitive and specific than CT, they complement each other in that a CT scan will further verify any false positives and negatives from PET-CT as most tumors have to be at least 1 cm for PET-CT detection. Finally, bronchoscopy should be performed in patients with upper or middle esophageal cancers to rule out airway invasion, tracheoesophageal fistula, and determine the need for tracheal stents. Restaging after chemoradiation with EUS, esophagogastroduodenoscopy with biopsy, and PET-CT has been examined to determine response. However, none of these techniques has a high accuracy for determining complete response pathologically. McLoughlin et al. reported that the accuracy of a negative PETCT after chemoradiation was 56% for predicting a pathologic complete response [14]. A study of postchemoradiation EUS predicted for complete response in only 17% of patients [15]. Finally, a negative endoscopic biopsy after chemoradiation had a negative predictive value of only 31% [16].

Стадийность

The American Joint Committee on Cancer and 8th Edition Cancer Staging Manual for esophageal cancer includes separate staging for SCC and AC, and incorporation of tumor grade and location to the overall staging classification (Table 3.1) [17, 18].

Таблица 3.1. Американский объединенный комитет по раку (AJCC) 8-ая ред. Стадийность рака пищевода.

Определение первичной опухоли (T)

Плоскоклеточная карцинома и аденокарцинома

T категория T критерий
TX Опухоль не может быть оценена
T0 Нет свидетельства первичной опухоли
Tis Высоко-злокачественная дисплазия, определенная как злокачественные клетки, ограниченные эпителием базальной мембраной
T1 Опухоль инвазирует собственную пластинку, мышечную пластинку слизистой или подслизистую оболочку
T1a Опухоль инвазирует собственную пластинку или мышечную пластинку слизистой
T1b Опухоль инвазирует подслизистую
T2 Опухоль инвазирует мышечную пластинку слизистой
T3 Опухоль инвазирует адвентицию
T4 Опухоль инвазирует прилегающие структуры
T4a Опухоль инвазирует плевру, перикард, непарную вену, диафрагму или брюшину
T4b Опухоль инвазирует другие прилегающие структуры, такие как аорта, тело позвонка или дыхательные пути

Определение региональных лимфатических узлов (N)

Плоскоклеточная карцинома и аденокарцинома

N категория N критерий
NX Региональные лимфатические узлы не могут быть оценены
N0 Нет метастазов в региональные лимфоузлы
N1 Метастазирование в 1-2. региональных лимфатических узла
N2 Метастазирование в 3-6. региональных лимфатических узла
N3 Метастазирование в 7. или более региональных лимфатических узла

Определение отдаленного метастазирования (M)

Плоскоклеточная карцинома и аденокарцинома

M категория M критерий
M0 Нет отдаленных метастазов
M1 Отдаленный метастаз

Определение гистологической злокачественности (G)

Плоскоклеточная карцинома и аденокарцинома

G G определение
GX Степень не может быть оценена
G1 Высокодифференцированная
G2 Умеренно дифференцированная
G3 Плохо дифференцированная, недифференцированная

Определение локализации (L)

Плоскоклеточная карцинома

Локализация играет роль в стадийной группировке эзофагеального сквамозного рака

Категория локализации Критерии локализации
X Локализация неизвестна
Верхняя Цервикальный пищевод до нижней границы непарной вены (azygos vein)
Срединная От нижней границы непарной вены до нижней границы нижней легочной вены (inferior pulmonary vein)
Нижняя От нижней границы нижней легочной вены до желудка, включая желудочно-пищеводное соединение

Примечание: локализация определяется позицией эпицентра опухоли в пищеводе

AJCC прогностические стадийные группы

Плоскоклеточная карцинома

Клиническая (cTNM)

Когда cT есть… И cN есть… И M есть… Тогда стадийная группа есть
Tis N0 M0 0
T1 N0–1 M0 I
T2 N0–1 M0 II
T3 N0 M0 II
T3 N1 M0 III
T1–3 N2 M0 III
T4 N0–2 M0 IVA
Любой T N3 M0 IVA
Любой T Любой N M1 IVB

Патологическая (pTNM)

Когда cT есть… И pN есть И M есть… И G есть И локализация есть Тогда стадийная группа есть
Tis N0 M0 N/A Любая 0
T1a N0 M0 G1 Любая IA
T1a N0 M0 G2–3 Любая IB
T1a N0 M0 GX Любая IA
T1b N0 M0 G1–3 Любая IB
T1b N0 M0 GX Любая IB
T2 N0 M0 G1 Любая IB
T2 N0 M0 G2–3 Любая IIA
T2 N0 M0 GX Любая IIA
T3 N0 M0 Любой Lower IIA
T3 N0 M0 G1 Upper/middle IIA
T3 N0 M0 G2–3 Upper/middle IIB
T3 N0 M0 GX Любая IIB
T3 N0 M0 Любой Location X IIB
T1 N1 M0 Любой Любая IIB
T1 N2 M0 Любой Любая IIIA
T2 N1 M0 Любой Любая IIIA
T2 N2 M0 Любой Любая IIIB
T3 N1–2 M0 Любой Любая IIIB
T4a N0–1 M0 Любой Любая IIIB
T4a N2 M0 Любой Любая IVA
T4b N0–2 M0 Любой Любая IVA
Любой T N3 M0 Любой Любая IVA
Любой T Любой N M1 Любой Любая IVB

Постнеоадъювантная терапия (ypTNM)

Когда yp T есть… И yp N есть… И M есть… Тогда стадийная группа есть…
T0–2 N0 M0 I
T3 N0 M0 II
T0–2 N1 M0 IIIA
T3 N1 M0 IIIB
T0–3 N2 M0 IIIB
T4a N0 M0 IIIB
T4a N1–2 M0 IVA
T4a NX M0 IVA
T4b N0–2 M0 IVA
Любой T N3 M0 IVA
Любой T Любой N M1 IVB

Аденокарцинома

Клиническая (cTNM)

Когда cT есть… И cN есть… И M есть… Тогда стадийная группа есть…
Tis N0 M0 0
T1 N0 M0 I
T1 N1 M0 IIA
T2 N0 M0 IIB
T2 N1 M0 III
T3 N0–1 M0 III
T4a N0–1 M0 III
T1‐T4a N2 M0 IVA
T4b N0–2 M0 IVA
Любой T N3 M0 IVA
Любой T Любой N M1 IVB

Патологическая (pTNM)

Когда pT есть…                                    И pN есть И M есть… И G есть… Тогда стадийная группа есть
Tis N0 M0 N/A 0
T1a N0 M0 G1 IA
T1a N0 M0 GX IA
T1a N0 M0 G2 IB
T1b N0 M0 G1–2 IB
T1b N0 M0 GX IB
T1 N0 M0 G3 IC
T2 N0 M0 G1–2 IC
T2 N0 M0 G3 IIA
T2 N0 M0 GX IIA
T1 N1 M0 Любой IIB
T3 N0 M0 Любой IIB
T1 N2 M0 Любой IIIA
T2 N1 N0 Любой IIIA
T2 N2 M0 Любой IIIB
T3 N1–2 M0 Любой IIIB
T4a N0–1 M0 Любой IIIB
T4a N2 M0 Любой IVA
T4b N0–2 M0 Любой IVA
Любой T N3 M0 Любой IVA
Любой T Любой N M1 Любой IVB

Постнеоадъювантная терапия (ypTNM)

Когда yp T есть…                                                     И yp N есть… И M есть… Тогда стадийная группа есть
T0–2 N0 M0 I
T3 N0 M0 II
T0–2 N1 M0 IIIA
T3 N1 M0 IIIB
T0–3 N2 M0 IIIB
T4a N0 M0 IIIB
T4a N1–2 M0 IVA
T4a NX M0 IVA
T4b N0–2 M0 IVA
Любой T N3 M0 IVA
Любой T Любой N M1 IVB

Предотвращение и скрининг

Пищевод Барретта

Пищевод Барретта (BE) — метапластическое замещение стратифицированного плоского эпителия пищевода столбчатым эпителием. Он, вероятно, является результатом хронической GERD [20]. BE — самый важный идентифицируемый фактор риска для эзофагеальной аденокарциномы. American College of Gastroenterology определяет BE как эндоскопически распознаваемое изменение в эпителии пищевода, который подтверждается интестинальной метаплазией на биопсии [21].

Prospective studies have documented the progression from BE to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and eventually, invasive adenocarcinoma [22]. In addition, there is a gastric-type BE that has been described. In a series of patients with gastric-type dysplasia, it was noted that neoplastic progression occurred in 64% of patients with pure gastric and 26% of patients with mixed gastric-intestinal dysplasia [23]. While esophagectomy is a standard treatment for HGD and T1 tumors, locally ablative therapies like endoscopic mucosal resection, radiofrequency ablation, photodynamic therapy, and cryotherapy have now started to play a significant role in the management of these lesions [24]. However, the accuracy of EUS staging for T1 tumors has been called into question [25]. Tumor depth was correctly staged by EUS in only 39% of pT1a tumors and 51% of pT1b tumors. Of the EUS staged cT1a (lamina propria) cN0 lesions, there were positive lymph nodes in 15% of pathologic specimens patients with pT1a (muscularis mucosa) lesions had a 9% rate of pathologic lymph node involvement, and those with pT1b tumors had a 17% rate of lymph node spread. In addition, while AC can be successfully treated with chemoradiation, this treatment will not eradicate the BE, and any remaining dysplastic epithelium is prone to forming de novo cancers. Either surgical resection with negative BE margins or ablative therapies mentioned above must be performed after chemoradiation to eliminate this high risk dysplasia [3, 26, 27].

Лечение GERD и химиопрофилактика

Американская гастроэнтерологическая ассоциация (AGA) поддерживает использование терапии GERD для облегчения симптомов рефлюкс-эзофагита у пациентов с BE [28]. Для пациентов без симптомов GERD или признаков рефлюкс-эзофагита ингибиторы протонной помпы (ИПП) могут использоваться для снижения риска неопластического прогрессирования дисплазии, независимо от отсутствия проспективных исследований. Было показано, что PPI вызывают регрессию BE, в то время как Н2-блокаторы этого не делают. В рандомизированном двойном слепом исследовании ранитидина (Н2-блокатора) по сравнению с омепразолом (ИПП) было отмечено, что омепразол обладает большей степенью кислотной супрессии и что имеет место статистически значимый регресс BE по сравнению с отсутствием изменений с ранитидином. [29]. Большое проспективное исследование продемонстрировало, что пациенты, которые использовали PPI, имели значительно низкий риск развития HGD или AC, в то время как с блокаторами H2 успешности не наблюдалось [30]. Эпидемиологические исследования показали, что профилактика BE успешна для нестероидных противовоспалительных препаратов, в частности, аспирина> 325 мг [31]. Мета-анализ также подтвердил, что использование аспирина обратно связано с частотой возникновения AC у BE пациентов [32]. Тем не менее, изучение химиопрофилактики с COX-2 ингибитором, целекоксибом, не смогло предотвратить прогрессирование BE в HGD и, в конечном итоге, AC [33]. Наконец, комбинация статинов и аспирина, по-видимому, обеспечивает синергетическую защиту от неопластического прогрессирования BE по сравнению с аспирином [34].

Скрининг и наблюдение

The 2011. AGA guidelines for the management of BE suggest screening for BE if multiple risk factors associated with esophageal AC (age 50 years or older, male sex, white race, chronic GERD, hiatal hernia, elevated body mass index, or intra-abdominal distribution of body fat) are present [28]. The AGA recommended against screening the general population with GERD for BE. For patients with BE, GERD therapy to treat symptoms and to heal reflux esophagitis is clearly indicated, as it is for patients without BE. The diagnosis of dysplasia in BE should be confirmed by at least one additional pathologist, preferably one who is an expert in esophageal histopathology. Endoscopic surveillance is suggested for patients with BE every 3–5 years if there is no dysplasia, every 6–12 months for LGD, and every 3 months for HGD. Use of biomarkers to confirm histologic diagnosis of LGD or HGD is not recommended. Endoscopic eradication therapy with radiofrequency ablation, photodynamic therapy, or endoscopic resection rather than surveillance is recommended for treatment of patients with confirmed HGD within BE. Endoscopic resection is recommended for patients who have dysplasia in BE associated with a visible mucosal irregularity.

Лечение

The three treatment modalities involved in the treatment of esophageal carcinoma include surgery, chemotherapy, and radiation therapy. While the treatment sections have been organized into each specific modality, multimodality treatment is usually required and is strongly influenced by stage. Treatment recommendations by stage are displayed in Table 3.2.

Хирургия

Single modality surgery was the mainstay of treatment for esophageal cancer prior to use of neoadjuvant multimodality techniques (see later sections). There is a direct correlation of outcome and institutional volume patients who undergo esophagectomy at high volume centers have lower treatmentrelated mortality rates, better survival, and significantly shorter hospital length of stay when compared to low volume institutions [35, 36]. This is likely related to many factors including surgeon experience [37], and the institution’s ability to deal with complications that require multidisciplinary management, dedicated intensive care teams, skilled nursing, respiratory therapy, clinical care pathways, and availability of certain therapeutic equipment.

Техника

Трансторакальная или чрезбрюшинная резекция пищевода

Transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE Ivor-Lewis esophagectomy) are the two most common techniques performed. The choice of technique depends on a number of factors including extent of lymphadenectomy, tumor location, and surgeon’s preference. THE involves a mobilization of the stomach with sparing of the gastroepipolic artery, upper abdominal lymphadenectomy, blunt dissection of the thoracic esophagus, and a left cervical esophagogastric anastomosis [38]. TTE also requires mobilization of the stomach with an upper abdominal lymphadenectomy, but differs from the transhiatal approach in that a right thoracotomy with radial dissection around the thoracic esophagus with its surrounding mediastinal lymphatic tissue is performed. The anastomosis is created within the thoracic space. The theoretical advantage with the thoracic approach is the oncological resection of the mediastinal lymph nodes and wider radial margin of the primary tumor. There are modifications of both techniques that have been described [39]. The perioperative morbidity and mortality of the two techniques was compared in a randomized trial [40]. A total of 220 patients were assigned to either a THE or TTE approach. The trial concluded that perioperative morbidity was higher with the TTE with no significant difference in in-hospital mortality or overall survival. THE was associated with a shorter operative time, lower blood loss, fewer pulmonary complications, decreased chylous leaks, shorter duration of mechanical ventilation, and shorter stay in the intensive care unit and hospital. Similar results were confirmed in a metaanalysis involving 7,527 patients from 50. studies with either TTE or THE obtaining a 5-year survival of 20% [41]; however, THE showed an increased incidence of anastomotic leaks and recurrent laryngeal nerve injury.

Таблица 3.2. Лечебные рекомендации по стадиям.

Стадия Хирургический статус Рекомендация
T1aN0M0 1)      Endoscopic mucosal resection followed by endoscopic ablation

2)      Esophagectomy* (if flat or ulcerated lesion not amenable to endoscopic removal)

T1bN0M0 Medically operable Esophagectomy*
Medically inoperable Definitive CRT**
T2N0M0 Medically operable 1)      Esophagectomy* (well differentiated and <2 cm)

2)      Preoperative CRT

T1-2N1-3M0 и T3-4aN0-3M0 Medically inoperable Definitive CRT**
Medically operable 1)      Preoperative CRT

2)      Induction chemo, preoperative CRT (if radiation field would be excessively large)

3)      Preoperative chemo (for adenocarcinoma and GEJ tumors)

Medically inoperable 1)      Definitive CRT**

2)      Induction chemo, definitive CRT**

T4bN0-3M0 Unresectable 1)      Definitive CRT**

2)      Induction chemo, definitive CRT**

TxNxM1 Inoperable by stage Systemic chemotherapy +/palliative stent, radiation, or brachytherapy

CRT, chemoradiotherapy; GEJ, gastroesophageal junction.

*Consider adjuvant chemotherapy or chemoradiation based on high risk pathologic features like positive margins or positive lymph nodes.

**Consider brachytherapy boost for local residual disease.

  1. Radiation dose: (I) definitive is 45–50.4. Gy; (II) preoperative is 41.4–50.4. Gy.
  2. Concurrent chemotherapy regimens include: (I) cisplatin (75 mg/m2. on week 1 and week 5) and weekly protracted venous infusion 5-FU (225 mg/m2; over 5. days); (II) weekly carboplatin and taxol (use lower range of radiation dose due to pneumonitis issues); (III) biweekly oxaliplatin and protracted venous infusion 5-FU (225 mg/m2; over 5. days); (IV) protracted venous infusion 5-FU (225 mg/m2; over 5. days) in the adjuvant setting.
  3. Brachytherapy boost dose is 9–15. Gy in three fractions prescribed to surface (brachytherapy should be avoided if there is involvement or close proximity to airway due to tracheoesophageal fistula).

Минимально-инвазивные методы эзофагэктомии

Multiple transhiatal and transthoracic minimally invasive esophagectomy (MIE) approaches have been described combining thoracoscopic and/or laparoscopic procedures. The first attempts at MIE involved thoracoscopic esophageal mobilization, laparotomy for gastric mobilization, and a cervical anastomosis. The morbidity of a thoracotomy was avoided while allowing for complete mediastinal dissection. This technique has been reported by several groups with excellent results [39]. Relative contraindications to laparoscopy may include prior major abdominal resections. Contraindications to thoracoscopy include extensive pleural adhesions, prior pneumonectomy, bulky tumors, and locally infiltrative tumors, especially those with airway involvement. Finally, while it has been recommended that MIE should not be performed in patients treated with neoadjuvant therapy [42], others have found MIE can safely be performed after induction therapy [33, 43]. MIE is a technically advanced surgical procedure associated with a prolonged learning curve and it has been noted that at least 17 cases are required to gain technical expertise and 35 cases have to be performed to observe differences in blood loss, postoperative pulmonary infection, and number of lymph nodes retrieved [44, 45]. Major intraoperative complications include bleeding, tracheobronchial injury, and recurrent laryngeal nerve injury have been reported with MIE [39]. A randomized controlled trial was conducted in esophageal cancer comparing MIE (59 patients) versus open esophagectomy (56 patients) [46]. Pulmonary infection in the first 2 weeks was noted in 16. (29%) patients in the open esophagectomy group versus five (9%) patients in the MIE group (relative risk (RR) 0.30, 95% CI 0.12– 0.76). In-hospital pulmonary infection was noted in 19. (34%) patients in the open esophagectomy group versus seven (12%) patients in the minimally invasive group (0.35, 0.16–0.78).

Роботизированная эзофагэктомия

While laparoscopic THE is an ideal choice of procedure, several problems arise including the instrumentation, the narrow field of the mediastinum, and the two-dimensional view. Robotic systems may overcome some of these limitations. This technique provides magnified three-dimensional visualization and greater range of instrument motion allowing for diminished intraoperative complications which have been reported by several groups [39]. de la Fuente et al. reported on a large series of robotic-assisted Ivor-Lewis (RAIL) esophagectomies with a hand-assisted laparosopic abdominal approach [47]. In the first 50 patients that underwent RAIL [47], the median number of lymph nodes resected was 18.5 and all patients achieved an R0. resection. Postoperative complications occurred in 14. (28%) patients, including atrial fibrillation in five (10%), pneumonia in five (10%), anastomotic leak in one (2%), and chyle leak in two (4%). The median intensive care unit stay and length of hospitalization were 2 and 9. days respectively. Total mean operating time calculated from time of skin incision to wound closure was 445 minutes; however, operative times decreased over time. Similarly, there was a trend toward lower complications after the first 29 cases but this did not reach statistical significance. There were no in-hospital mortalities. Hernandez et al. reported that the learning curve to become proficient in performing RAIL was 20 cases [48]. Currently, TTE, THE, MIE, and RAIL are all considered appropriate surgical options, with optimal choices among these depending on the tumor location, patient preference, and the surgeon’s preference and experience [3, 49].

PET-CT и хирургия

PET-CT may identify which patients might benefit from surgery [14, 50]. A series from Wake Forest showed that there was no benefit to surgery if patients had a negative PET-CT scan after induction therapy [50]. In contrast, a series from the Moffitt Cancer Center showed that in 81 patients, a negative and positive postchemoradiotherapy PET-CT scan had positive predictive values for predicting pathologic complete response and residual disease of 35% and 70%, respectively [14].

Роль хирургии

The role of surgery in the management of locally advanced esophageal cancer is controversial. Surgery alone is reserved for patients with HGD, or with T1N0, or T2N0 esophageal cancers. However, caution must be exercised when patients are staged as T2N0 by EUS as it has been shown that almost 50% are upstaged at the time of surgery [51]. While there are no data to address the role of surgery in AC, three randomized trials conducted by the Germans, French, and Chinese have addressed the role of esophagectomy in SCC [52–54]. All three trials showed no difference in overall survival comparing definitive versus preoperative treatment. In the German and French trials, while there was no difference in overall survival, there was a significant difference in local control and disease-free survival in favor of surgery; however, there was also higher treatment-related mortality associated with surgery. A meta-analysis of these three randomized trials of 512 patients comparing definitive chemoradiation versus preoperative chemoradiation followed by surgery or surgery alone revealed no difference in survival or morbidity but treatment-related mortality risk was lower in the definitive chemoradiation group (HR 7.6; 95% CI: 1.76–32.88) [55]. Based on these results, one may conclude that for SCC of the esophagus, patients undergoing surgery may benefit from local control and disease-free survival but are at significantly increased risk of treatment-related mortality. While prospective data and meta-analysis show no survival benefit to surgery after chemoradiation for SCC, there is a disease-free survival and local control benefit. It would seem reasonable to offer surgery for SCC patients who have biopsy-proven residual disease 6–12 weeks after treatment. For patients with AC, surgery should be part of a multimodality treatment regimen.

Лучевая терапия без химиотерапии

Radiation therapy alone is considered palliative. Local control and survival are poor despite combining with surgery either preoperatively or postoperatively [1, 2, 56]. Local recurrence rates have been reported as high as 77% with standard fractionation [56, 57]. In a retrospective review, radiation therapy alone resulted in a 5-year overall survival of 6% [58]. Several attempts were made to improve local control and survival by combining radiation and surgery. A meta-analysis of five randomized trials of 1147 patients was conducted to assess the benefit of neoadjuvant radiation versus surgery alone [59] but only showed a trend for increased survival with preoperative radiation (P = 0.06).

Химиотерапия

Предоперационная химиотерапия

There are several trials examining the benefit of preoperative chemotherapy in esophageal and GEJ cancers (Table 3.3). A survival benefit was reported in four trials [60–64]. A common finding in these trials is that response to therapy confers a survival benefit compared to nonresponse (Table 3.3). Responders are more likely to attain an R0. resection. While the MAGIC trial was conducted for gastric cancer, 25% of the patients had distal esophageal and GEJ cancer. In the MAGIC trial, 503 patients with gastric, distal esophageal, or gastroesophageal junction AC were randomized to surgery alone or three cycles of epirubicin, cisplatin, and 5-FU (ECF) given perioperatively [62]. There was a significant overall survival benefit associated with perioperative ECF (5. year overall survival 36% vs 23%, P = 0.009). In a trial similar to the MAGIC trial, Ychou et al. examined the role of perioperative cisplatin and 5-FU in gastric, distal esophageal, or gastroesophageal junction AC [64]; however, distal esophageal and GEJ adenocarcinomas comprised 75% of patients. There was a significant survival benefit associated with chemotherapy with a 5-year overall survival of 38% versus 24% (P = 0.02). In a trial by Boonstra et al., 169 patients with esophageal SCC were randomized to surgery alone versus preoperative cisplatin and 5-FU [61]. Five-year survival in the combined modality group was 27% versus 17% for surgery alone (P = 0.03). While an Radiation Therapy Oncology Group (RTOG) trial failed to show a survival benefit with preoperative cisplatin and 5-FU [65], a similar trial by the Medical Research Council in Europe showed a significant survival benefit (5-year survival 23% vs 17%, P = 0.03) with the addition of cisplatin and 5-FU preoperatively for esophageal cancer [60, 63]. There were notable differences between the two trials including twice as many patients randomized, fewer cycles of chemotherapy delivered preoperatively, more adenocarcinomas, and more patients going to surgery in the Medical Research Council trial.

Таблица 3.3. Клинические исследования неоадъювантной химиотерапии против только одной хирургии.

Study n Гистология Chemotherapy Response (%) Responders’ survival Survival P
Roth [104] 19 100% SCC Cisplatin/vind/bleomycin 47 MS MS 9 m ns
20 None 20 m vs 6 m
Nygaard [105] 50 100% SCC None 9% (3 y) 0.32
58 Cisplatin/bleomycin 3%
56 None1 21%
53 Cisplatin/bleomycin1 17%
Schlag [106] 22 100% SCC Cisplatin/5~FU 50 MS MS 10 m ns
24 None 13 m vs 5 m
Maipang [107] 24 100% SCC Cisplatin/vinb/bleomycin 53 31% (3 y) ns
22 None 36%
Law [108] 74 100% SCC Cisplatin/5~FU 58 MS MS 17 m ns
73 None 42 m vs 8 m MS 13 m
Boonstra [61] 85 100% SCC Cisplatin/etoposide 38 26% 0.03
84 None 17%
Kelsen [65] 216 52% AC Cisplatin/5~FU 19 MS 23% (3 y) ns
227 None 3.3 y vs 1.1 y 26%
Ancona [109] 48 100% SCC Cisplatin/5~FU 40 5 y 42% (4 y) ns
48 None 60% vs 12% 28%
Cunningham [62]2 250 100% AC Epirubicin/cisplatin/5~FU 36% (5 y) 0.009
253 None 23%
Allum [60, 63] 400 67% AC Cisplatin/5~FU 23% (5 y) 0.03
402 None 17%
Ychou [64]3 113 100% AC Cisplatin/5~FU 38% (5y) 0.02
111 None 24%

2 25% distal esophagus and gastroesophageal junction.

3 75% distal esophagus and gastroesophageal junction.

vind, vindesin; vinb, vinblastine; 5~FU, fluorouracil; AC, adenocarcinoma; SCC, squamous cell carcinoma; MS, median survival; ns, not significant; m, months; y, years.

Several meta-analyses examining survival after chemotherapy or chemoradiotherapy and surgery compared to surgery alone for esophageal cancer have been performed (Table 3.4). With the exception of Greer et al. [66], all analyses [55, 67–71] show a significant reduction in mortality associated with neoadjuvant chemoradiation. However, some do show a significantly higher treatment-related mortality with chemoradiation [67, 69, 70]. The most recent meta-analysis of 12 randomized trials encompassing 1,854 patients demonstrated that the hazard ratio for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78. (95% CI: 0.7–0.88; P <0.0001). In addition, the benefit was maintained for both SCC (HR 0.80; 95% CI: 0.68– 0.93; P = 0.004) and AC (HR 0.75; 95% CI: 0.59–0.95; P = 0.02)

[71]. The survival benefit of neoadjuvant chemotherapy for esophageal cancer has also been investigated [55, 68, 71] (Table 3.3). While two analyses show a significant reduction in mortality with preoperative chemotherapy [68, 71], the benefit is restricted to AC with no apparent benefit in SCC.

Адъювантная химиотерапия

There are limited data to support adjuvant chemotherapy in esophageal cancer; however, it may be recommended in patients with pathologically positive lymph nodes. Adjuvant chemotherapy after chemoradiotherapy and/or surgery is poorly tolerated and only 50% of patients are able to complete the prescribed regimens [56, 62, 64, 72]. There is little prospective data to support adjuvant chemotherapy after neoadjuvant chemoradiotherapy. There are three trials of adjuvant chemotherapy after initial surgery and all were negative for a survival benefit [73– 75]. However, a meta-analysis reported from China of seven trials encompassing 864 patients noted a 3-year survival benefit with adjuvant chemotherapy (RR 0.89; 95% CI: 0.71–0.95; P = 0.009) [76].

PET-CT и химиотерапия

One consistent finding is that the response to chemotherapy does confer a survival benefit and does increase the likelihood of an R0. resection. PET-CT has been used to monitor response to treatment as well [77–80]. A cut-off value of 35% change in PET standardized uptake value predicted for survival (P = 0.04). This result led to the MUNICON trial [78], in which patients with distal esophageal or gastroesophageal cancer had a PET after one cycle of induction chemotherapy. Responders (defined as decrease in standardized uptake value by 35%) continued chemotherapy prior to resection and nonresponders went directly to surgery. While the median survival was not reached in responders, nonresponders had a median survival of 26 months (P = 0.015). In a follow-up study, MUNICON II addressed the role of salvage chemoradiation in PET nonresponders in patients with GEJ cancer [81]. Two-year overall survival for responders and nonresponders was 71% versus 42%, respectively (P = 0.1).

Химио-лучевая терапия

Дефинитивная химиорадиотерапия

Randomized controlled data show benefit to adding mitomycin C or cisplatin-based regimens concurrent with radiation [1, 2]. Bleomycin regimens concurrent with radiation showed no benefit [82]. An Eastern Cooperative Oncology Group randomized trial that utilized concurrent mitomycin C-5FU with radiation in 119 patients with esophageal SCC showed a statistically significant difference in median overall survival of 14.8 months with chemotherapy compared to 9.3 months without chemotherapy. A significant survival benefit was shown with cisplatin5FU-radiation (50.4. Gy) compared to radiation alone to 64.8. Gy in the RTOG 85-01 trial [56]. Most of the patients had SCC. The trial was stopped after the first interim analysis showed a significant survival benefit, and additional patients were enrolled in the chemoradiation arm only. The 5-year updated survival for all patients receiving chemoradiation was 27% versus 0% for radiation alone patients [83]. Despite the survival benefit, almost 50% of patients had residual disease at 1 year. This result led to investigation of dose escalation concurrent with radiation. The intergroup 0123 trial randomized patients to chemoradiation to 50.4. Gy versus 64.8. Gy [84]. There was no benefit to dose escalation and even a suggestion of a survival detriment. A meta-analysis showed a significant survival benefit to concurrent chemoradiation while there was no benefit to sequential chemotherapy and radiation [85].

Неоадъювантная химиолучевая терапия

Several randomized trials have been conducted to determine the benefit from neoadjuvant chemoradiotherapy [1, 2] (Table 3.5). However, these trials were either underpowered, had poor performing control arms, or failed to show a significant survival benefit. Most recently, the CROSS trial showed a significant survival benefit to neoadjuvant chemoradiation [86]. In this trial, 368 patients were randomized to neoadjuvant chemoradiation with 41.4. Gy over 4.5 weeks concurrent with weekly carboplatin and paclitaxel followed by surgery versus surgery alone. An R0. resection was obtained in 92% of chemoradiation patients versus 69% in the surgery only patients (P <0.001). Pathologic complete response was documented in 29% of chemoradiation patients. With a median follow-up of 45 months, median and 5-year overall survival was 49.4 months and 47% for the chemoradiation group versus 24 months and 34% for the surgery only group (P = 0.003). The benefit of neoadjuvant chemoradiation was noted in both SCC (univariate HR 0.453, P = 0.011; multivariate HR 0.422, P = 0.007) and AC (univariate HR 0.732, P = 0.049; multivariate HR 0.741, P = 0.07).

Most importantly, the local and peritoneal recurrence rate was significantly lower with preoperative chemoradiation [87].

Several meta-analyses have been published to examine survival after chemoradiotherapy and surgery compared to surgery alone for esophageal cancer (Table 3.4). All analyses [55, 67–71] show a survival benefit to neoadjuvant chemoradiation with the exception of Greer et al. [66]. Three of the analyses do show a significantly higher treatment-related mortality with chemoradiation [67, 69, 70]. The most recent and largest meta-analysis identified 12. randomized trials of 1,854 patients comparing chemoradiation and surgery versus surgery alone. The hazard ratio for all-cause mortality for neoadjuvant chemoradiotherapy was 0.78. (P <0.0001) and the benefit was maintained for both SCC (HR 0.80; P = 0.004) and AC (HR 0.75; P = 0.02) [71].

The overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative chemoradiation reduced locoregional recurrence from 34 to 14% (P <0.001) and peritoneal carcinomatosis from 14 to 4% (P <0.001). There was a small but significant effect on hematogenous dissemination in favor of the chemoradiation group (35% vs 29%; P = 0.025) [87].

Таблица 3.4. Мета-анализы предоперационной химиотерапии или химиолучевой терапии против хирургии.

Study (year) Therapy No. of Studies n RR/OR/HR (95% CI) P-value
Urschel [70]  2003 CRT 9 1116 0.66 (0.47–0.92) (3 y survival) 0.016
1.6 (0.99–2.68) (postop mortality) 0.053
Fiorica [67] 2004 CRT 6 764 0.53 (0.31–0.93) (survival) 0.03
2.1 (1.18–3.73) (postop mortality) 0.01
Greer [66] 2005 CRT 6 738 0.86 (0.74–1.01) 0.07
Gebski [68] 2007 CRT 10 1209 0.81 (0.7–0.93) 0.002
Chemo 8 1724 0.90 (0.81–1.00) (all) 0.05 (all)
0.78 (0.64–0.95) (AC) 0.014 (AC)
0.88 (0.75–1.03) (SCC) 0.12 (SCC)
Jin [69] 2009 CRT 11 1308 1.46 (1.07–1.99) (5 y survival)1 0.02
1.7 (1.03–2.73) (postop mortality) 0.02
Kranzfelder [55] 2011 (100% SCC) CRT 9 1099 0.81 (0.7–0.95) 0.008
Chemo 8 1707 0.93 (0.81–1.08) 0.368
Sjoquist [71] 2011 CRT 12 1854 0.78 (0.7–0.88) <0.0001
Chemo 9 1981 0.87 (0.79–0.96) (all) 0.05 (all)
0.83 (0.71–0.95) (AC) 0.01 (AC)
0.92 (0.81–1.04) (SCC) 0.18 (SCC)

AC, adenocarcinoma; CI, confidence interval; CRT, chemoradiotherapy; HR, hazard ratio; OR, odds ratio; RR, relative risk; SCC, squamous cell carcinoma.

1 No benefit in SCC.

Предоперационная химиотерапия против химиорадиотерапии

The German POET study addressed whether neoadjuvant chemoradiation added to preoperative chemotherapy would benefit patients with GEJ cancers. This was a randomized trial of GEJ AC comparing preoperative chemotherapy and surgery versus preoperative chemotherapy followed by chemoradiation and surgery [88]. It was planned to enroll 354 patients; unfortunately, the trial was stopped due to poor accrual after 125 patients were enrolled. The induction chemotherapy regiment was cisplatin, leucovorin, and 5-FU. Radiation (30. Gy in 3 weeks) was delivered concurrently with cisplatin and etoposide. A trend for increased survival was observed in the chemoradiation arm where 3-year survival in the patients receiving radiation was 47% versus 27% for unirridiated patients (P = 0.07).

Adjuvant chemoradiotherapy

Results for the INT0116 trial established adjuvant chemoradiotherapy as the standard of care in patients with node-positive adenocarcinoma of the stomach and GEJ [72]. A total of 556 patients with resected GEJ or stomach adenocarcinoma were randomized to surgery alone (control arm) or surgery plus adjuvant chemoradiotherapy (experimental arm). Chemoradiation was 45. Gy over 5 weeks with infusional 5-FU. Median and 3year overall survival was increased from 27 months and 41% in the control group to 36 months and 50% in the chemoradiotherapy group (P = 0.005). In a three-arm Chinese study of stage II and III SCC of the esophagus, patients were randomized to surgery alone, preoperative chemoradiation, and postoperative chemoradiation [89]. Chemoradiation was 40. Gy in 4 weeks concurrent with cisplatin and taxol. There was a significant improvement in overall survival in patients treated with postoperative and preoperative chemoradiation.

Brachytherapy

Esophageal brachytherapy (BT) is an intraluminal treatment of radiation therapy applied directly to the tumor. It consists of the placement of a catheter down the esophagus with subsequent application of a tethered radioactive source administered down the tube to deliver a very high dose of radiation directly to the luminal component of the tumor. Treatments are short in duration and allow for better sparing of normal surrounding tissues such as the lungs, heart, and liver when compared to external beam radiation therapy. BT has been used primarily in two settings: as palliation for locally advanced obstructing or bleeding tumors and as a boost to external beam radiation therapy for definitive management of nonsurgical candidates. BT has been investigated for its use as a boost after external beam radiation therapy with or without chemotherapy. However, a trial by Calais et al and RTOG 92-07. [90, 91] concluded that survival was no different with the addition of BT. Additionally, caution must be taken given the risk for fistulas. The high fistula rate in the RTOG trial was likely due to the high BT dose delivered concurrently with chemotherapy. In regards to palliation, metal stents have shown benefit in relieving dysphagia [24]. In a multicenter Dutch study [92], patients with dysphagia due to unresectable esophageal cancer were randomized to placement of a stent (n = 108) or single dose (12. Gy) BT (n = 101). Dysphagia improved more rapidly after stent placement compared to BT, but long-term relief of dysphagia was better with BT. Higher complication rates were noted with stent placement (33% versus 21%; P = 0.02). The groups did not differ with regard to the incidence of persistent or recurrent dysphagia or median survival (P >0.20). In the long term, quality-of-life scores were higher in the brachytherapy group.

Техника

Chemoradiation for esophageal cancers has resulted in increased survival over radiation or surgery alone; however, it is fraught with high rates of acute toxicity and long-term esophagitis, strictures, pneumonitis, and pericarditis. This necessitates hospital admissions, feeding tube placement, and stent placements. Historically, radiation to the esophagus was delivered with two-dimensional techniques (as in RTOG 8501) utilizing a barium esophagram approach that treated a large volume of normal tissue. This significantly changed with the advent of CT scans and computer software that allowed patients to be scanned in the treatment position and so that the intended dose could be shaped three-dimensionally by three-dimensional conformal radiotherapy (3DCRT), utilizing customized shaped blocks to maximize the dose to the intended target and minimize the dose to the surrounding healthy tissue. More recently, intensity modulated radiation therapy (IMRT) has been utilized in the clinical setting. IMRT requires advanced treatment planning software to deliver nonuniform radiation through a series of beamlets that vary the intensity of dose across tumor–normal tissue interfaces. The beamlets can be produced through multiple prechosen beam angles or through a volumetric 360° arc delivery of a continuously modulated photon beam [1]. However, IMRT requires precise delineation of target volumes which can be achieved with either fiducial marker placement or fusion of PET scans to the treatment planning CT [93]. In addition, respiratory motion of the target volume has to be considered and addressed with either creating a larger target volume or using abdominal compression to limit respiratory excursion. Finally, daily variation of gastric distention can dramatically affect dosing of target volumes which may require planning and treatment on empty stomachs. Finally, daily image guidance with cone-beam CTs will aid in better target localization [1, 94, 95].

Comparative outcomes of IMRT versus 3DCRT have been reported. A Chinese study compared the outcomes of 60. esophageal cancer patients treated with either IMRT or 3DCRT concurrent with cisplatin and docetaxel. A total dose of 64 Gy was delivered in 30 fractions [96]. Response rates were higher in the IMRT group, but there was no difference in survival. An MD Anderson study compared outcomes of 676. esophageal cancer patients treated between 1998 and 2008. with IMRT or 3DCRT, with concurrent chemotherapy [97]. The IMRT patients were less likely to receive induction chemotherapy, had better performance status, and were less likely to die but more likely to have first failure be distant. The IMRT group was superior with respect to overall survival (P <0.001) and locoregional recurrence (P = 0.0038). There were no differences seen in cancer-related mortality or distant metastasis between the two groups. Most recently, Freilich et al. reported on a series of 232 (138 IMRT, 94 3DCRT) patients with esophageal cancer treated with 3DCRT or IMRT [94]. Median dose was 50.4 Gy (range 44–64.8) to gross disease. There was no significant difference based on radiation technique with respect to overall survival, but IMRT was associated with a significant decrease in acute grade ≥3 toxicity on univariate and multivariate analysis.

Таблица 3.5. Клинические исследования неоадъювантной химиолучевой терапии против одной только хирургии.

Study n Histology Chemoradiation regimen Pathologic complete response (%) Overall survival P-value
Walsh [110] 58 100% AC 40 Gy (3 weeks)/cisplatin/5~FU 25 MS 16 m vs 11 m 0.01
55 None 3 y 32% vs 6%
Urba [111] 50 75% AC 45 Gy (1.5 Gy BID)/cisplatin/5~FU/Vinb 28 MS 17 m vs 18 m 0.15
50 None 3 y 30% vs 16%
Lee [112] 51 100% SCC 45.6 Gy (1.2 Gy BID)/cisplatin/5~FU 43 MS 28 m vs 27 m 0.69
50 None
Burmeister [113] 128 62% AC 35 Gy (3 weeks)/cisplatin/5~FU 14 MS 29 m vs 19 m 0.57
128 None
Tepper [114] 30 75% AC 50.4 Gy (5.5 weeks)/cisplatin/5~FU 40 MS 4.5 y vs 1.8 y 0.002
26 None 5 y 39% vs 16%
Lv [89] 80 100% SCC 40 Gy (4 weeks)/cisplatin/taxol NR MS 53 m vs 36 m 0.04
80 None 5 y 44% vs 34%
Mariette [115] 97 71% SCC 45 Gy (5 weeks)/cisplatin/5~FU NR MS 32 m vs 45 m 0.68
98 None 3 y 49% vs 55%
van Hagen [116] 180 75% AC 41.4 Gy (4.5 weeks)/carboplatin/taxol 29 MS 49 m vs 24 m 0.003
188 None 5 y 47% vs 34%

AC, adenocarcinoma; BID, twice daily; 5~FU, 5~fluorouracil; MS, median survival; m, months; NR, not reported; SCC, squamous cell carcinoma; Vinb, vinblastine; y, years.

Биологическая терапия

Рецептор эпидермального фактора роста

Epidermal growth factor receptor (EGFR) expression correlates with poor prognosis and radioresistance [98]. While several phase II studies showed promise in esophageal cancer in the phase II setting with the addition of anti-EGFR antibodies [98], randomized controlled trials failed to show a survival benefit. Two randomized controlled trials looked at the role of targeted therapy with an anti-EGFR antibody, cetuximab, in combination with chemoradiotherapy for definitive treatment of esophageal cancer. The SCOPE-1 trial was a randomized phase II/III trial where patients with esophageal carcinoma (73% SCC) were treated with capecitabine-cisplatin-50 Gy with or without cetuximab [99]. They unfortunately did not meet their phase II endpoint and the trial was stopped after 258 patients were enrolled. Overall results were detrimental with the addition of cetuximab. Not only was there increased toxicity leading to increased failure to complete treatment, median survival was significantly worse in patients receiving cetuximab. After the report of this trial, accrual to the ongoing RTOG 0436 trial addressing the role of cetuximab was halted. Results were presented at the 2014. GI ASCO meeting. This was a phase III trial for patients with esophageal carcinoma treated with cisplatinpaclitaxel-50.4 Gy with or without cetuximab [100]. There was no difference in survival, toxicity, or response rate.

Рецептор эпидермального фактора роста человека-2

Amplification of the human epidermal growth factor receptor-2 (HER2) gene and overexpression of its protein product is involved in a variety of malignancies including GEJ AC and correlates with a poor prognosis [101]. A large randomized phase III trial of HER2-positive metastatic gastric or GEJ adenocarcinoma, Trastuzumab for Gastric Cancer, was conducted to assess the benefit of adding trastuzamab to cisplatin-5FU or a cisplatin-capecitabine doublet [102]. On intent-to-treat analysis, there was a significant improvement in median survival in patients receiving trastuzamab (13.8 months versus  11.1 months; P = 0.0046). Response rate, time to progression, and duration of response were significantly higher in the trastuzumab plus chemotherapy group as well. RTOG 1010 is a randomized phase III trial of HER2-positive mid to distal esophageal and GEJ adenocarcinoma being randomized to concurrent chemoradiation with carboplatin-paclitaxel-50.4. Gy versus carboplatin-paclitaxel-trastuzamab-50.4. Gy, with the primary endpoint being disease-free survival. National Comprehensive Cancer Network guidelines recommend addition of trastuzumab to chemotherapy regimens for patients with HER2overexpressing and/or HER2-amplified metastatic esophageal adenocarcinoma [3].

Другие мишени и агенты

Ramucirumab is a recombinant monoclonal antibody to VEGFR-2. that is approved for second-line treatment of gastroesophageal adenocarcinoma. Several clinical trials of immune checkpoint inhibitors are in progress [103].

Наблюдение и выживаемость

Guidelines for follow-up have been established by the National Comprehensive Cancer Network [3]. For patients with in situ or T1a disease amenable to ablative techniques, assessment with endoscopic surveillance should occur every 3 months for 1 year, then annually. For patients who undergo an R0 resection, observation is recommended. For R1 resections, adjuvant chemoradiation is recommended. If a patient received preoperative chemoradiation, then either observation or adjuvant chemotherapy is recommended. For patients with locally advanced disease treated with definitive chemoradiation, response assessment must be performed at 6–12 weeks after treatment. If there is no persistent disease, then history and physical examination, and nutritional counseling should be performed every 3–6 months for 1–2 years, then every 6–12 months for 3–5 years, then annually. Chemistry, complete blood counts, imaging, and endoscopy should be done only as clinically indicated.

Long-term side effects from chemoradiation include benign esophageal strictures requiring dilation or stent (12%), radiation pneumonitis (2%), pericardial and pleural effusions (2%), rehabilitation and hospitalization (16%), and requirement of feeding tube for nutrition (7%) [94]. Tracheoesophageal fistulas may occur after chemoradiation, but are most likely not due to treatment, but rather to progression of cancer. Aspiration and speech paralysis may occur after surgery due to recurrent laryngeal nerve injury.

Литература

  1. Shridhar R, Almhanna K, Meredith KL, et al. Radiation therapy and esophageal cancer. Cancer Control 2013;20(2):97–110.
  2. Shridhar R, Imani-Shikhabadi R, Davis B, Streeter OA, Thomas CR, Jr. Curative treatment of esophageal cancer; an evidenced based review. J Gastrointest Cancer 2013:44(4):375–84.
  3. NCCN Clinical Practice Guidelines in Oncology. Esophageal and Esaophagogastric Junction Cancers, Version 2.2016. nccn. org (accessed 18. January 2017).
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67(1):7–30.
  5. Howlader N, Noone AM, Krapcho M (eds). SEER Cancer Statistics Review, 1975–2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015. SEER data submission, posted to the SEER web site, April 2016.
  6. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87–108.
  7. Gibson M. Epidemiology, Pathobiology, and Clinical Manifestations of Esophageal Cancer, UpToDate Website. Updated February 10, 2017. Accessed October 16, 2017. https://www.uptodate.com/contents/epidemiologypathobiology-and-clinical-manifestations-of-esophagealcancer?source=contentShare&csi=6fa9591b-6e41-45ce94c9-bae062bfcd37.
  8. Lagergren J, Lagergren P. Recent developments in esophageal adenocarcinoma. CA Cancer J Clin 2013:63(4):232–48.
  9. Rьdiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002. consecutive patients. Ann Surg 2000:232(3):353–61.
  10. Flamen P, Lerut A, Van Cutsem E, et al. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18(18):3202–10.
  11. Meyers BF, Downey RJ, Decker PA, et al. The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: results of the American College of Surgeons Oncology Group Z0060 trial. J Thorac Cardiovasc Surg 2007;133(3):738–45.
  12. van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD. Staging investigations for oesophageal cancer: a meta-analysis. Br J Cancer 2008;98(3):547–57.
  13. Luketich JD, Friedman DM, Weigel TL, et al. Evaluation of distant metastases in esophageal cancer: 100. consecutive positron emission tomography scans. Ann Thorac Surg 1999;68(4):1133–6; discussion 1136–7.
  14. McLoughlin JM, Melis M, Siegel EM, et al. Are patients with esophageal cancer who become PET negative after neoadjuvant chemoradiation free of cancer? J Am Coll Surg 2008;206(5):879–86; discussion 886–7.
  15. Zuccaro G, Jr., Rice TW, Goldblum J, et al. Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J Gastroenterol 1999;94(4):906–12.
  16. Sarkaria IS, Rizk NP, Bains MS, et al. Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer. Ann Surg 2009;249(5):764–7.
  17. Rice TW, Kelsen D, Blackstone EH, et al. Esophagus and esophagogastric junction. In: Amin MB, et al. (eds) AJCC Cancer Staging Manual, 8th edn. New York: Springer, 2017.
  18. Rice TW, Ishwaran H, Kelsen DP, et al. Recommendations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus 2016;29(8):906–12.
  19. Talsma K, van Hagen P, Grotenhuis BA, et al. Comparison of the 6th and 7th Editions of the UICC-AJCC TNM Classification for Esophageal Cancer. Ann Surg Oncol 2012;19(7):2142–8.
  20. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med 1986;315(6):362–71.
  21. Sampliner RE and Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002;97(8):1888–95.
  22. Hameeteman W, Tytgat GN, Houthoff HJ, van den Tweel JG. Barrett’s esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989;96(5. Pt 1):1249–56.
  23. Mahajan D, Bennett AE, Liu X, Bena J, Bronner MP. Grading of gastric foveolar-type dysplasia in Barrett’s esophagus. Mod Pathol 2010;23(1):1–11.
  24. Vignesh S, Hoffe SE, Meredith KL, et al. Endoscopic therapy of neoplasia related to Barrett’s esophagus and endoscopic palliation of esophageal cancer. Cancer Control 2013;20(2):117–29.
  25. Bergeron EJ, Lin J, Chang AC, Orringer MB, Reddy RM. Endoscopic ultrasound is inadequate to determine which T1/ T2 esophageal tumors are candidates for endoluminal therapies. J Thorac Cardiovasc Surg 2014;147(2):765–73.
  26. Barthel JS, Kucera S, Harris C, et al. Cryoablation of persistent Barrett’s epithelium after definitive chemoradiation therapy for esophageal adenocarcinoma. Gastrointest Endosc 2011;74(1):51–7.
  27. Barthel JS, Kucera ST, Lin JL, et al. Does Barrett’s esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus? Gastrointest Endosc 2010;71(2):235–40.
  28. American Gastroenterological Association. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology 2011;140(3):1084–91.
  29. Peters FT, Ganesh S, Kuipers EJ, et al. Endoscopic regression of Barrett’s oesophagus during omeprazole treatment; a randomised double blind study. Gut 1999;45(4):489–94.
  30. Kastelein F, Spaander MC, Steyerberg EW, et al. Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2013;11(4):382–8.
  31. Omer ZB, Ananthakrishnan AN, Nattinger KJ, et al. Aspirin protects against Barrett’s esophagus in a multivariate logistic regression analysis. Clin Gastroenterol Hepatol 2012;10(7):722–7.
  32. Abnet CC, Freedman ND, Kamangar F, et al. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a metaanalysis. Br J Cancer 2009;100(3):551–7.
  33. Heath EI, Canto MI, Piantadosi S, et al. Secondary chemoprevention of Barrett’s esophagus with celecoxib: results of a randomized trial. J Natl Cancer Inst 2007;99(7):545–57.
  34. Kastelein F, Canto MI, Piantadosi S, et al. Nonsteroidal anti-inflammatory drugs and statins have chemopreventative effects in patients with Barrett’s esophagus. Gastroenterology 2011;141(6):2000–8; quiz e13–4.
  35. Markar SR, Karthikesalingam A, Thrumurthy S, Low DE. Volume-outcome relationship in surgery for esophageal malignancy: systematic review and meta-analysis 2000–2011. J Gastrointest Surg 2012;16(5):1055–63.
  36. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346(15):1128–37.
  37. Derogar M, Sadr-Azodi O, Johar A, Lagergren P, Lagergren J. Hospital and surgeon volume in relation to survival after esophageal cancer surgery in a population-based study. J Clin Oncol 2013;31(5):551–7.
  38. Barreto JC, Posner MC. Transhiatal versus transthoracic esophagectomy for esophageal cancer. World J Gastroenterol 2010;16(30):3804–10.
  39. Yamamoto M, Weber JM, Karl RC, Meredith KL. Minimally invasive surgery for esophageal cancer: review of the literature and institutional experience. Cancer Control 2013;20(2):130–7.
  40. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347(21):1662–9.
  41. Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ. Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 2001; 72(1):306–13.
  42. Nakatsuchi T, Otani M, Osugi H, Ito Y, Koike T. The necessity of chest physical therapy for thoracoscopic oesophagectomy. J Int Med Res 2005;33(4):434–41.
  43. Luketich JD, Alvelo-Rivera M, Buenaventura PO, et al. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg 2003;238(4):486–94; discussion 494–5.
  44. Osugi H, Takemura M, Higashino M, et al. Learning curve of video-assisted thoracoscopic esophagectomy and extensive lymphadenectomy for squamous cell cancer of the thoracic esophagus and results. Surg Endosc 2003;17(3):515–9.
  45. Osugi H, Takemura M, Lee S, et al. Thoracoscopic esophagectomy for intrathoracic esophageal cancer. Ann Thorac Cardiovasc Surg 2005;11(4):221–7.
  46. Biere SS, van Berge Henegouwen MI, Maas KW, et al. Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet 2012;379(9829):1887–92.
  47. de la Fuente SG, Weber J, Hoffe SE, et al. Initial experience from a large referral center with robotic-assisted Ivor Lewis esophagogastrectomy for oncologic purposes. Surg Endosc 2013;27(9):3339–47.
  48. Hernandez JM, Dimou F, Weber J, et al. Defining the learning curve for robotic-assisted esophagogastrectomy. J Gastrointest Surg 2013;17(8):1346–51.
  49. Qureshi YA, Dawas KI, Mughal M, Mohammadi B. Minimally invasive and robotic esophagectomy: evolution and evidence. J Surg Oncol 2016;114(6):731–5.
  50. Monjazeb AM, Dawas KI, Mughal M, Mohammadi B. Outcomes of patients with esophageal cancer staged with [(1) F]fluorodeoxyglucose positron emission tomography (FDG-PET): can postchemoradiotherapy FDG-PET predict the utility of resection? J Clin Oncol 2010;28(31):4714–21.
  51. Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the Society of Thoracic Surgeons database. Ann Thorac Surg 2013;96(2):382–90.
  52. Bedenne L, Michel P, Bouchй O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25(10):1160–8.
  53. Chiu PW, Chan AC, Leung SF, et al. Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the Chinese University Research Group for Esophageal Cancer (CURE). J Gastrointest Surg 2005;9(6):794–802.
  54. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005;23(10):2310–7.
  55. Kranzfelder M, Schuster T, Geinitz H, Friess H, Bьchler P. Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 2011;98(6):768–83.
  56. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326(24):1593–8.
  57. John MJ, Flam MS, Mowry PA, et al. Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation. Cancer 1989;63(12):2397–403.
  58. Earlam R, Cunha-Melo JR. Oesophogeal squamous cell carcinoms: II. A critical view of radiotherapy. Br J Surg 1980;67(7):457–61.
  59. Arnott SJ, Duncan W, Gignoux M, et al. Preoperative radiotherapy for esophageal carcinoma. Cochrane Database Syst Rev 2005(4):CD001799.
  60. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009;27(30):5062–7.
  61. Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer 2011;11:181.
  62. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355(1):11–20.
  63. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359(9319):1727–33.
  64. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29(13):1715–21.
  65. Kelsen DP, Winter KA, Gunderson LL, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 2007;25(24):3719–25.
  66. Greer SE, Goodney PP, Sutton JE, Birkmeyer JD. Neoadjuvant chemoradiotherapy for esophageal carcinoma: a metaanalysis. Surgery 2005;137(2):172–7.
  67. Fiorica F, Di Bona D, Schepis F, et al. Preoperative chemoradiotherapy for o esophageal cancer: a systematic review and meta-analysis. Gut 2004;53(7):925–30.
  68. Gebski V, Burmeister B, Smithers BM, et al. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007;8(3):226–34.
  69. Jin HL, Zhu H, Ling TS, Zhang HJ, Shi RH. Neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: a meta-analysis. World J Gastroenterol 2009; 15(47):5983–91.
  70. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003;185(6):538–43.
  71. Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011;12(7):681–92.
  72. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345(10):725–30.
  73. Ando N, Iizuka T, Kakegawa T, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg 1997;114(2):205–9.
  74. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204. J Clin Oncol 2003;21(24):4592–6.
  75. Pouliquen X, Levard H, Hay JM. 5-Fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. French Associations for Surgical Research. Ann Surg 1996;223(2):127–33.
  76. Huang WZ, Fu JH, Hu Y, Zhang X, Yang H. [Meta-analysis of postoperative adjuvant chemotherapy for localized esophageal carcinoma]. Ai Zheng 2006;25(10):1303–6.
  77. Downey RJ, Akhurst T, Ilson D, et al. Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol 2003;21(3):428–32.
  78. Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007;8(9):797–805.
  79. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19(12):3058–65.
  80. Wieder HA, Brьcher BL, Zimmermann F, et al. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 2004;22(5):900–8.
  81. zum Buschenfelde CM, Herrmann K, Schuster T, et al. (18) F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: the MUNICON II trial. J Nucl Med 2011;52(8):1189–96.
  82. Araujo CM, Souhami L, Gil RA, et al. A randomized trial comparing radiation therapy versus concomitant radiation therapy and chemotherapy in carcinoma of the thoracic esophagus. Cancer 1991;67(9):2258–61.
  83. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term

follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281(17):1623–7.

  1. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123. (Radiation Therapy Oncology Group 94-05) phase III trial of combinedmodality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20(5):1167–74.
  2. Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2006(1):CD002092.
  3. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2013;366(22):2074–84.
  4. Oppedijk V, van der Gaast A, van Lanschot JJ, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS Trials. J Clin Oncol 2014;32(5):385–91.
  5. Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009;27(6):851–6.
  6. Lv J, Cao XF, Zhu B, et al. Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma. World J Gastroenterol 2010;16(13):1649–54.
  7. Calais G, Dorval E, Louisot P, et al. Radiotherapy with high dose rate brachytherapy boost and concomitant chemotherapy for Stages IIB and III esophageal carcinoma: results of a pilot study. Int J Radiat Oncol Biol Phys 1997;38(4):769–75.
  8. Gaspar LE, Qian C, Kocha WI, et al. A phase I/II study of external beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 92-07): preliminary toxicity report. Int J Radiat Oncol Biol Phys 1997; 37(3):593–9.
  9. Homs MY, Steyerberg EW, Eijkenboom WM, et al. [Palliative treatment of esophageal cancer with dysphagia: more favourable outcome from single-dose internal brachytherapy than from the placement of a self-expanding stent; a multicenter randomised study]. Ned Tijdschr Geneeskd 2005;149(50):2800–6.
  10. Fernandez D, Hoffe SE, Barthel JS, et al. Stability of endoscopic ultrasound-guided fiducial marker placement for esophageal cancer target delineation and image-guided radiation therapy. Pract Radiat Oncol 2013;3:32–39.
  11. Freilich J, Hoffe SE, Almhanna K, et al. Comparative outcomes for 3d conformal versus intensity modulated radiation therapy for esophageal cancer. Dis Esophagus, 2015;28(4):352–7.
  12. Shridhar R, et al. Outcomes of definitive or preoperative IMRT chemoradiation for esophageal cancer. J Radiat Oncol 2012;1(4):347–54.
  13. Lin XD, Shi XY, Zhou TC, Zhang WJ. [Intensity-modulated or 3-D conformal radiotherapy combined with chemotherapy with docetaxel and cisplatin for locally advanced esophageal carcinoma]. Nan Fang Yi Ke Da Xue Xue Bao 2011;31(7):1264–7.
  14. Lin SH, Wang L, Myles B, et al. propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2012;84(5):1078–85.
  15. Ayyappan S, Prabhakar D, Sharma N. Epidermal growth factor receptor (EGFR)-targeted therapies in esophagogastric cancer. Anticancer Res 2013;33(10):4139–55.99. Crosby T, et al. SCOPE 1: A phase II/III trial of chemoradiotherapy in esophageal cancer plus or minus cetuximab. J Clin Oncol 2012. 30. (suppl 34; abstr LBA3).
  16. Suntharalingam M, et al. The initial report of RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. J Clin Oncol 2014;32(suppl 3; abstr LBA6).
  17. Yonemura Y, Ninomiya I, Yamaguchi A, et al. Evaluation of immunoreactivity for erbB-2. protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 1991;51(3):1034–8.
  18. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376(9742):687–97.
  19. Wang VE, Grandis JR, Ko AH. New strategies in esophageal carcinoma: Translational insights from signaling pathways and immune checkpoints. Clin Cancer Res 2016;22(17):4283–90.
  20. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988;96(2):242–8.
  21. Nygaard K, Hagen S, Hansen HS, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16(6):1104–9; discussion 1110.
  22. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg 1992;127(12):1446–50.
  23. Maipang T, Vasinanukorn P, Petpichetchian C, et al. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol 1994;56(3):191–7.
  24. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997;114(2):210–7.
  25. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001;91(11):2165–74.
  26. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335(7):462–7.
  27. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19(2):305–13.
  28. Lee JL, Park SI, Kim SB, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 2004;15(6):947–54.
  29. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 2005;6(9):659–68.
  30. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008;26(7):1086–92.
  31. Mariette C, et al. Surgery alone versus chemoradiotherapy followed by surgery for localized esophageal cancer: Analysis of a randomized controlled phase III trial FFCD 9901. J Clin Oncol 2010;28(15. s):4005.
  32. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012. 366(22):2074–84.