The American Cancer Society’s Oncology in Practice: clinical management (2018)
Edited by American Cancer Society
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) . 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) . 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 . 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 .
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%) .
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 . 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 .
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 . Other risk factors include smoking (particularly in BE patients), obesity, Helicobacter pylori infections (inverse association) , 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 .
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 . 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 .
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.
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 . 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 . 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 . A study of postchemoradiation EUS predicted for complete response in only 17% of patients . Finally, a negative endoscopic biopsy after chemoradiation had a negative predictive value of only 31% .
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|
Определение гистологической злокачественности (G)
Плоскоклеточная карцинома и аденокарцинома
|GX||Степень не может быть оценена|
|G3||Плохо дифференцированная, недифференцированная|
Определение локализации (L)
Локализация играет роль в стадийной группировке эзофагеального сквамозного рака
|Категория локализации||Критерии локализации|
|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
|Когда cT есть…||И cN есть…||И M есть…||Тогда стадийная группа есть…|
|Любой T||Любой N||M1||IVB|
|Когда cT есть…||И pN есть…||И M есть…||И G есть…||И локализация есть …||Тогда стадийная группа есть…|
|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…|
|Любой T||Любой N||M1||IVB|
|Когда cT есть…||И cN есть…||И M есть…||Тогда стадийная группа есть…|
|Любой T||Любой N||M1||IVB|
|Когда pT есть…||И pN есть…||И M есть…||И G есть…||Тогда стадийная группа есть…|
|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…|
|Любой T||Любой N||M1||IVB|
Предотвращение и скрининг
Пищевод Барретта (BE) — метапластическое замещение стратифицированного плоского эпителия пищевода столбчатым эпителием. Он, вероятно, является результатом хронической GERD . 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 .
Prospective studies have documented the progression from BE to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and eventually, invasive adenocarcinoma . 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 . 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 . However, the accuracy of EUS staging for T1 tumors has been called into question . 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 . 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. . 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 . Эпидемиологические исследования показали, что профилактика BE успешна для нестероидных противовоспалительных препаратов, в частности, аспирина> 325 мг . Мета-анализ также подтвердил, что использование аспирина обратно связано с частотой возникновения AC у BE пациентов . Тем не менее, изучение химиопрофилактики с COX-2 ингибитором, целекоксибом, не смогло предотвратить прогрессирование BE в HGD и, в конечном итоге, AC . Наконец, комбинация статинов и аспирина, по-видимому, обеспечивает синергетическую защиту от неопластического прогрессирования BE по сравнению с аспирином .
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 . 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.
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.
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 , 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.
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 . 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 . The perioperative morbidity and mortality of the two techniques was compared in a randomized trial . 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% ; however, THE showed an increased incidence of anastomotic leaks and recurrent laryngeal nerve injury.
Таблица 3.2. Лечебные рекомендации по стадиям.
1) Endoscopic mucosal resection followed by endoscopic ablation
2) Esophagectomy* (if flat or ulcerated lesion not amenable to endoscopic removal)
|Medically inoperable||Definitive CRT**|
1) Esophagectomy* (well differentiated and <2 cm)
2) Preoperative CRT
|T1-2N1-3M0 и T3-4aN0-3M0||Medically inoperable||Definitive CRT**|
1) Preoperative CRT
2) Induction chemo, preoperative CRT (if radiation field would be excessively large)
3) Preoperative chemo (for adenocarcinoma and GEJ tumors)
1) Definitive CRT**
2) Induction chemo, definitive CRT**
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.
- Radiation dose: (I) definitive is 45–50.4. Gy; (II) preoperative is 41.4–50.4. Gy.
- 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.
- 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 . 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 , 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 . A randomized controlled trial was conducted in esophageal cancer comparing MIE (59 patients) versus open esophagectomy (56 patients) . 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).
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 . de la Fuente et al. reported on a large series of robotic-assisted Ivor-Lewis (RAIL) esophagectomies with a hand-assisted laparosopic abdominal approach . In the first 50 patients that underwent RAIL , 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 . 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 . 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 .
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 . 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) . 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% . 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  but only showed a trend for increased survival with preoperative radiation (P = 0.06).
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 . 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 ; 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 . 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 , 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 ||19||100% SCC||Cisplatin/vind/bleomycin||47||MS||MS 9 m||ns|
|20||None||20 m vs 6 m|
|Nygaard ||50||100% SCC||None||–||–||9% (3 y)||0.32|
|Schlag ||22||100% SCC||Cisplatin/5~FU||50||MS||MS 10 m||ns|
|24||None||13 m vs 5 m|
|Maipang ||24||100% SCC||Cisplatin/vinb/bleomycin||53||–||31% (3 y)||ns|
|Law ||74||100% SCC||Cisplatin/5~FU||58||MS||MS 17 m||ns|
|73||None||42 m vs 8 m||MS 13 m|
|Boonstra ||85||100% SCC||Cisplatin/etoposide||38||–||26%||0.03|
|Kelsen ||216||52% AC||Cisplatin/5~FU||19||MS||23% (3 y)||ns|
|227||None||3.3 y vs 1.1 y||26%|
|Ancona ||48||100% SCC||Cisplatin/5~FU||40||5 y||42% (4 y)||ns|
|48||None||60% vs 12%||28%|
|Cunningham 2||250||100% AC||Epirubicin/cisplatin/5~FU||–||–||36% (5 y)||0.009|
|Allum [60, 63]||400||67% AC||Cisplatin/5~FU||–||–||23% (5 y)||0.03|
|Ychou 3||113||100% AC||Cisplatin/5~FU||–||–||38% (5y)||0.02|
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. , 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)
. 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.
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) .
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 , 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 . Two-year overall survival for responders and nonresponders was 71% versus 42%, respectively (P = 0.1).
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 . 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 . 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 . 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 . 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 .
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 . 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 .
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. . 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) .
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) .
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  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  2004||CRT||6||764||0.53 (0.31–0.93) (survival)||0.03|
|2.1 (1.18–3.73) (postop mortality)||0.01|
|Greer  2005||CRT||6||738||0.86 (0.74–1.01)||0.07|
|Gebski  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  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  2020 (100% SCC)||CRT||9||1099||0.81 (0.7–0.95)||0.008|
|Sjoquist  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 . 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).
Results for the INT0116 trial established adjuvant chemoradiotherapy as the standard of care in patients with node-positive adenocarcinoma of the stomach and GEJ . 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 . 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.
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 . In a multicenter Dutch study , 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.
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 . 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 . 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 . 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 . 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 . 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 ||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 ||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 ||51||100% SCC||45.6 Gy (1.2 Gy BID)/cisplatin/5~FU||43||MS 28 m vs 27 m||0.69|
|Burmeister ||128||62% AC||35 Gy (3 weeks)/cisplatin/5~FU||14||MS 29 m vs 19 m||0.57|
|Tepper ||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 ||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 ||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 ||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.
Рецептор эпидермального фактора роста
Epidermal growth factor receptor (EGFR) expression correlates with poor prognosis and radioresistance . While several phase II studies showed promise in esophageal cancer in the phase II setting with the addition of anti-EGFR antibodies , 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 . 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 . 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 . 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 . 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 .
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 .
Наблюдение и выживаемость
Guidelines for follow-up have been established by the National Comprehensive Cancer Network . 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%) . 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.
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